Spine Healing Therapy

Dorn Spinal Therapy

Dorn Spinal Therapy has been in uses in the past 40 years. The credit of this method goes to Dieter Dorn, who has made a significant impact in the medical field. DORN- Method has been used on various patients where results could get witnessed instants. Due to the impact, this method has brought in the country. It has been declared the standard practice in treating Pelvical Disorders, Spinal, and Back pain. Dieter Dorn first used this method on his family, which was a sign of confidence in a method, which later gained much attention from different people in the country and also globally. Every day Dorn was able to offer treatment to 15- 20 patients in a day. His services were purely free which attracted attention both in the local and also global. The primary treatment that DORN-Method which could be treated using this method include spine healing therapy, misalignments of the spine, resolving pelvis and joints, and also solving out significant problems which could get attributed to vertebrae.

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Nociceptive spinal cord neurons with joint and muscle input

Neurons with input from joint and muscle are located in the superficial and deep dorsal horn. This distribution matches the spinal termination of joint and muscle afferents which project to the superficial dorsal horn and, in particular A - and A8-fibers, to the deep dorsal horn.7,12 Neurons with nociceptive information Neurons with input from joint and muscle project to different supraspinal sites (cerebellum, spinocervical nucleus, thalamus, reticular formation) subserving the generation of the conscious pain response and adaptations to pain (see Figure 2.1), or they project to intraspinal (segmental) interneurons and motoneurons.7,12 Spinal and supraspinal motor reflexes regulate movements and exert protective functions including flexor reflexes upon nociceptive stimulation.1 Noxious stimulation of joint afferents12, 85 and muscle afferents7, 8 can evoke nocicep- tive withdrawal reflexes. During acute chemical stimulation of the knee and electrical stimulation of muscle nerves86...

Descending Influences On Spinal Neurons With Deep Input

From brainstem nuclei, impulses descend onto the spinal cord and influence the transmission of pain signals at the dorsal horn.18,19,20 The periaqueductal gray (PAG) matter is a key region for descending inhibition. It receives inputs from the hypothalamus, cortical regions, and the limbic system and projects to the rostral ventromedial medulla (RVM), which includes several subnuclei. Neurons in RVM then project along the dor-solateral funiculus (DLF) to the dorsal horn. OFF cells of RVM exert descending inhibition of nociception, but ON cells facilitate nociceptive mechanisms at the spinal dorsal horn. Spinobulbospinal loops are significant in setting the gain of spinal processing.19 Most spinal cord neurons with joint and muscle input are tonically inhibited by descending inhibitory systems that modulate spinal cord activity.81,110 These neurons are also inhibited by DNIC.109 Tonic descending inhibition,110 as well as DNIC,109,111 are increased during acute inflammation, but may be...

Supraspinal Neurons With Input From Joint And Muscle

The thalamus and cortex contain nociceptive neurons that are activated by nociceptive deep input from muscles and joints. Most of these neurons have convergent inputs from skin and deep tissue, but small proportions of neurons respond only to noxious stimulation of muscle and tendon.113,114115 In the thalamus, such neurons are located in the ventrobasal complex, in the posterior complex114 and in the medial nucleus.116 Similarly, the somatosensory cortex contains a large proportion of neurons that respond to noxious stimulation, and a small proportion of these neurons is driven by deep input.7,117 In polyarthritic rats, a large proportion of neurons in the ventrobasal complex respond to movements and gentle pressure on to inflamed joints and often long-lasting discharges were noted, whereas only few neurons respond to these stimuli in normal rats. Some neurons also displayed paroxysmal discharges. Furthermore, neurons in the nucleus centralis lateralis acquire input from the inflamed...

Spinal dorsal horn neurons

When quantitatively examined, spinal dorsal horn neurons with visceral inputs are located in the dorsal horn of the spinal cord (lamina I, II, V), the intermediolateral cell column and sacral parasympathetic nucleus (pelvic nerve), and in lamina X. These neurons have multiple, convergent inputs from other viscera, from joints, from muscle, and from cutaneous structures. Convergent receptive fields for these neurons are therefore large with diffuse inputs. This is considered the basis of referral of visceral sensation to somatic sites (e.g. myocardial ischemia typically radiates to the left shoulder and upper arm the pain is not felt at the source - the heart). In contrast, neurons with exclusively cutaneous input are commonly identified in the spinal dorsal horn, in particular from glabrous skin. Taken together, these results suggest an imprecise organization of visceral primary inputs that would be consistent with an imprecise localization by the central nervous system....

Unique spinal pathway

The traditional pain pathway for the transmission of information from the dorsal horn of the spinal cord to the brain is via the anterolateral quadrant white matter of the spinal cord. Based on lesion and tracing studies, tracts located within these sites include the spinothalamic, spi-noreticular, spinomesencephalic, and spinohypothalamic tracts. This area is clearly important for cutaneous pain sensation because lesions of the anterolateral spinal white matter lead to pinprick analgesia in contralateral der-matomes below the level of the lesion. However, recently researchers have demonstrated that surgical lesions of the dorsal midline of the spinal cord have profound effects on visceral pain-related responses in humans, primates, and rodents. Specifically, a punctate thoracic midline mye-lotomy in humans has been demonstrated to relieve cancer-related pelvic and abdominal pain.20,2122,23,24,25 Similar lesions in nonhuman primates reduce the activity of thalamic neurons evoked by...

Supraspinal terminations of visceral input

Standard anatomical and electrophysiological tracing methods have established widespread distribution of visceral input to the brain. The axons of second-order spinal neurons that receive visceral input have been shown to ascend the spinal cord to the brain with sites of termination in the medulla, pons, mesencephalon, hypothalamus, and thalamus. Neurons excited by visceral stimuli have likewise been identified at these same sites with extensive characterizations of neurons located within the ventral posterolateral, dorsomedial, and submedius nuclei of the thalamus, the locus coeruleus, parabrachial nucleus, ventrolateral medulla, and numerous brain stem and limbic sites.36,37,3839,40,41,42 Higher-order neurons excited by visceral stimuli have also been demonstrated to be present in the somatosensory and ventrolateral orbital cerebral cortices.43,44,45 A lack of visceral sensation has been noted in neurosurgical patients who have sustained damage to their frontal lobes.46,4748

Spinal Cord Convulsions

Frequently overlooked is the fact that the spinal cord contains all the neuronal mechanisms necessary to produce tonic-clonic convulsions independent of supraspinal structures. Experiments performed early in the development of the electroshock technique demonstrated that direct electrical stimulation of the spinal cord in a decapitated rat produces the entire tonic-clonic convulsion sequence of maximal electroshock seizures.49 The spinal cord is also capable of self-sustained discharge that maintains the tonic-clonic activity after termination of the electrical stimulus.49 This indicates that the spinal cord is capable of afterdischarge, resulting in a convulsion that is virtually identical to that produced by afterdischarge in supraspinal regions. Because section of the pyramidal tracts does not affect the maximal elec-troshock response,50 it would appear that electroshock convulsions are a stereotyped response of the spinal cord to stimulation by nonspecific cerebrospinal tracts.951...

First Order Neurons Relay to the Spinal Cord

The detection of pain requires that information regarding injury, trauma, and noxious stimulation be detected by a transducer. Transducers serve the purpose of taking information (e.g., changes in temperature, chemical irritation, pressure) from some location on the body surface, muscles, or internal organs and converting it into neurochemical information that is interpretable by the brain. The transducers for pain include the free nerve endings of the first-order neurons in the pain pathway (i.e., the AS and C neurons). These neurons have long dendrites with fine terminal arborizations present in the skin, muscle, connective tissue, joints, bone, and internal organs. When these neurons are stimulated, action potentials extend from the dendrites to the cell body (in the dorsal root ganglion) and from the axon to the spinal cord. persistent, dull, aching, and burning pain that is experienced. All three types of fibers relay information to the dorsal horn of the spinal cord, where they...

Nociceptive Pathways In The Spinal Dorsal Horn

The somatosensory system is concerned with general sensation throughout the body, as opposed to specific senses, such as vision, hearing, olfaction, and taste for which specific end-organs have developed. Nociceptive pathways are activated by a subset of sensory receptors (nociceptors) that provide information about tissue damage. Under different conditions, activation of nociceptive pathways leads to the perception of pain (see Sec. III.A). We will briefly discuss here the anatomical and neurochemical organization of nociceptive pathways in the spinal dorsal horn (further details can be found, for example, in Refs. 57-60).

Pharmacology Of Spinalanesthesia

In the U.S., the drugs most commonly used in spinal anesthesia are lidocaine, tetracaine, and bupivacaine. General guidelines are to use lidocaine for short procedures, bupivacaine for intermediate to long procedures, and tetracaine for long procedures. The distribution of local anesthetics determines the height of block. Important pharmacological factors include the amount, and possibly the volume, of drug injected and its baricity. The speed of injection of the local anesthesia solution also may affect the height of the block, just as the position of the patient can influence the rate of distribution of the anesthetic agent and the height of blockade achieved (see below). For a given preparation of local anesthetic, administration of increasing amounts leads to a fairly predictable increase in the level of block attained. For example, 100 mg of lidocaine, 20 mg of bupi-vacaine, or 12 mg of tetracaine usually will result in a T4 sensory block. More complete tables of these...

Spinal Opioid Pharmacokinetics

Whilst spinal administration overcomes adverse effects secondary to distribution to the brain, there are other pharmacokinetic factors to consider delivery of a spinally administered drug to respective receptor sites within the brain and spinal cord depends on a drug's lipophicity. A lipophilic drug remains localized reasonably near the site of intrathecal delivery whereas a hydrophilic drug spreads within the cerebrospinal fluid. The practical implications of this are that a lipophilic drug should be delivered by placing the catheter near to the spinal level of the pain.9 With hydrophilic drugs, a greater proportion spreads within the cerebrospinal fluid and can diffuse cranially and have a direct effect on the respiratory center. The relatively high concentration that can reach the respiratory center can cause respiratory depression. Close monitoring is necessary until drugs have equilibrated. Notwithstanding, in the longer term, the adverse effects of spinal administration are...

Epidural Spinal Cord And Cauda Equina Compression

Hematologic malignancies that may cause disorders of the spine or an epidural compression with neurologic compromise include plasma cell dyscrasias, lymphomas and, infrequently, leukemias. In most series, lymphomas and myeloma are listed among the five most common malignancies causing epidural spinal compression.1 The epidural invasion in lymphoproliferative disorders results from diverse modes of neoplastic spread, which should be recognized for appropriate diagnostic work-up and educated selection of therapeutic modalities. Multiple myeloma is the most common primary tumor of bone. Bone lesions are the major manifestations in both solitary plasmacytomas and multiple myelomas and therefore they frequently present with vertebral destruction and spinal cord compression (SCC).1 On the other hand, vertebral lesions are detected in less than 30 of patients with SCC due to lymphoma, and are rarely present in leukemia presenting an epidural mass.1

Spinal Drug Administration

There is some evidence of benefit from spinally administered clonidine in neuropathic pain of multiple sclerosis spinal cord injury62 and cancer,63 V and a study indicating pain relief in relapsing MS from spinally administered corticosteroid (triamcinolone).64 III Spinal opioid delivery is discussed in Chapter 21, Spinal administration.

Acute Thoracic Spinal Pain continued

In the presence of trauma, xray of the thoracolumbar spine is not indicated in those who are awake, alert and have no clinical evidence of injury however those with equivocal or positive clinical findings or with an altered level of consciousness should undergo thoracolumbar spine evaluation. CT scanning is only indicated for the evaluation of the neural canal and posterior elements of the thoracic spine when fractures have been detected with plain films. There is no research to inform ancillary investigations for acute thoracic spinal pain investigations should be selected on the basis of clinical features suggesting the presence of serious conditions. The appropriate labels for non-specific 'mechanical' thoracic spinal pain are 'thoracic spinal pain of unknown origin' or 'somatic thoracic spinal pain'.

Rat Spinal Cord Injury and BMSC Transplantation

BMSC suspension (n 7) or vehicle (n 7) was transplanted into the spinal cord at the level of T9 at 7 days after the induction of SCI 2, 6 . A 7- l suspension of BMSCs (1 x 104 cells l) or phosphate-buffered saline (PBS) was injected into the spinal cord, using an automatic microinjection pump.

Anterograde Labeling of Dorsal Corticospinal Tract

To trace the dorsal corticospinal tract (dCST), the animals were anesthetized 63 days after SCI. A needle of a 10- jl Hamilton syringe was positioned 10 mm rostral to the center of the injury and was inserted into the spinal cord 1.5 mm from the surface of the dura mater. Then, a total amount of 2 jl of Fluoro-ruby (FR MW 10 000, D-1817 Molecular Probes, Eugene, OR, USA), a fluorescent axonal tracer, was injected into the spinal cord 0.5 mm lateral to the midline, on both sides, over a period of 3 min, using an automatic microinjection pump.

Impact of spine morphology on calcium signaling in dendritic spines

The morphology of the spine may impact Ca transient in the spine head in two ways. First, since the surface-to-volume ratio of a sphere is inversely proportional to the radius, changes in the size of the spine head may impact both the amplitude and kinetics of Ca transients. If Ca channels are present on the spine head at constant density or number, the amplitudes of Ca transients should be smaller in larger spines than in smaller spines. However, this simple relationship is not found experimentally and the sizes of synaptically evoked Ca transients and spine volumes are only poorly correlated.27 Similarly, at a constant density of Ca transporters and pumps, the clearance of Ca should be slower in larger spines. If Ca diffusion across the spine neck plays an important role in clearing Ca from the head, spines with longer and thinner necks or larger heads should clear Ca more slowly than spines with shorter and thicker necks or smaller heads, leading to longer lasting and larger Ca The...

Spinal cord stimulation

Some 40 years has elapsed since the first spinal cord stimulator was implanted, but it is relatively recently that its place in the management of CRPS has been validated. Grabow et al.60 I reviewed the available literature and concluded that spinal cord stimulation (SCS) is effective in the management of CRPS. However, they were unable to answer relevant questions, such as selection criteria and outcome measurement.

Supraspinal generator

A number of observations suggest that changes at more rostral levels of the central nervous system may also be important in the development of pain. Spinal local anesthetic blockade does not always result in relief of pain despite the presence of a demonstrated sensory block above the level of injury.32 In addition, peripheral, sympathetic, and spinal blockade, and even surgical cordo-tomy above the level of injury does not reliably reduce neuropathic pain following SCI.33 Changes in other supraspinal sites, beyond the thalamus, are also likely to be important in the development of persistent neuropathic pain following SCI. The extent to which these supraspinal changes are dependent on ongoing abnormal ascending inputs is unclear. However, there is increasing evidence that pathophysiological changes occur at peripheral, spinal, and supraspinal levels and may contribute in varying degrees to the development of neuropathic SCI pain.

Anesthesia at the Level of the Spinal Cord

Anesthesia at the level of the spinal cord involves application of anesthetics to influence spinal or sympathetic nerves, or both, to produce pain relief. Epidural anesthesia involves application of the anesthetic outside the dura mater the dura mater is not punctured (at least not intentionally). Epidural anesthesia has become the cornerstone of acute pain management (e.g., operative and postoperative pain). Intrathecal (subarachnoid) application of anesthetics involves inserting a needle through the dura mater and applying the anesthetic into the cerebrospinal fluid. Both epidural and intrathecal analgesia are invoked in the management of patients with chronic pain in whom pharmacologic interventions produce intolerable side effects or are insufficient to control pain. The subarachnoid administration of anesthetics allows for more direct access of anesthetics to pain-relaying and sympathetic nerves. On the other hand, the epidural space contains areolar (fat) tissue, epidural veins,...

Combined Spinal Epidural Analgesia

The combined spinal epidural analgesia (CSE) technique was first described approximately 60 years ago and came into favor approximately 20 years ago. Most commonly, the technique is performed by inserting an epidural needle into the epidural space, then inserting a long spinal needle into the subarachnoid space. Then, the spinal medication is injected and the epidural catheter is inserted through the epidural needle, once the spinal needle is removed. CSE offers the certainty and speed of onset of spinal analgesia with the flexibility and continuity of an epidural catheter. The major disadvantage is the additional potential for complications introduced by the deliberate dural puncture. The spinal component usually consists of a small dose of fentanyl (12.5-25 xg) combined with 0.5-1.0 mg of bupivacaine made up to a volume of 1 ml with saline. This combination will provide 60-90 min of analgesia with little or no motor blockade. The epidural infusion may be started immediately or when...

Central Syndromes Spinal Cord

Spinal cord injury (SCI) can be broadly defined as damage to the spinal cord that results from direct injury to the spinal cord itself or indirectly by damage to the bones and soft tissues and vessels surrounding the spinal cord. In epidemiologic reviews of SCI, the annual incidence of SCI in various countries throughout the world varies from 15 to 40 per million of the population.

Supraspinal Distribution Of The Delta Opioid Receptor

Similarly, differential distributions were found when 3H DAMGO and 3H DPDPE were employed as the radioligands, with the 5-opioid receptors having a more limited distribution than the 5-opioid receptors 61 . Similarly, autoradiography performed in rat brain sections with 3H DPDPE also showed highest densities of the 5-opioid receptor in the amygdala, caudate-putamen, nucleus accumbens, and olfactory bulb, and low binding density in the cerebellum, medulla oblongata, and the dorsal horn of the spinal cord

Spinal Distribution Of The Delta Opioid Receptor

A number of studies employing quantitative autoradiography, in situ hybridization and immunohistochemical methods have demonstrated the clear presence of the 6-opioid receptor concentrated in the superficial laminae of the dorsal horn of the spinal cord 58,64,65,72,73 . Autoradiography employing 3H DAMGO and 3H DTLET showed that the 6-opioid receptor was found in laminae I and II of the dorsal horn of the spinal cord, and accounted for only 23 of the total opioid receptor population, whereas the A-opioid receptor population accounted for 70 of the total 74,75 . However, when 3H sufentanil and 3H DPDPE were employed as the radioligands, the contribution of the A-opioid receptors to the total in lamina I-II was estimated to be 90 and that of the 6-opioid receptor was estimated at 7 76 . The relative proportions were 70 and 27 in lamina V and 65 and 33 about the central canal for the A-opioid and 6-opioid receptors, respectively 76 . In contrast, autoradiographic studies performed with...

Glutamatergic input to defined spinal neurons

The inputs to several different populations of spinal cord neurons (identified by morphological criteria, tract tracing or intracellular staining) have been examined with immunogold labeling for Glu and other compounds. Inherent to the variation of Glu immunogold labeling density within a terminal population (see Section 1), the criteria for defining a terminal as putatively glutamatergic vary somewhat between laboratories. Thus, comparisons of the percentages obtained in different studies should be made with this caution in mind. Murphy et al. (1996) examined terminals that contacted the soma or dendrites of ret-rogradely labeled motoneurons in the phrenic nucleus. Fifty-five percent of such terminals contained round vesicles and were enriched in Glu. Nerve terminals containing flattened vesicles comprised 42 , and presumably contain inhibitory amino acids. Cell bodies and dendrites displayed similar percentages of round and flattened vesicle terminals. Linda and collaborators...

Spinalsupraspinal Synergy Of 5opioid Antinociception

The fact that 5-opioid receptors act at spinal and supraspinal sites increases the possibility that, like morphine, 5-opioid agonists may exhibit a synergistic interaction between the spinal and supraspinal sites of action. It has been clearly established that the concurrent administration of ICV and ITH morphine results in a multiplicative antinociceptive interaction 130,131 . It is this supraspinal spinal multiplicative nature of morphine and its clinical analgesic utility at tolerable doses. Early studies with mice indicated only an additive interaction between ICV and ITH DPDPE against thermal endpoints in mice 131 . In contrast, however, the concomitant ICV and ITH administration of DPDPE in rats demonstrated a synergistic interaction against mechanical nociception 132,133 . However, one difficulty with these studies was that either the ITH or ICV dose was held constant while the doses given at the alternate site were altered to produce dose-effect curves 132,133 . This paradigm...

Spinal Delta Opioid Receptormediated Antinociception

There is considerable evidence that delta opioid receptor agonists act in the spinal cord to produce antinociception. This evidence includes pharmacological investigations of the antinociceptive effects of ITH- administered delta opioid receptor agonists 51,52,61,62 , electrophysiological characterization of the effects of these agonists on the response properties of dorsal horn neurons 63-66 , and neurochemical determinations of their effects on the release of neurotransmitters from the spinal cord 67-70 . Molecular cloning of the receptors and spectacular advances in recombinant DNA methods now make it possible to address the issue by a genetic approach. The activity of known genes can be modified in vivo using gene-targeting technology. An antisense oligodeoxynucleotide is a short piece of synthetic DNA with a nucleotide sequence that is the reverse of and complementary to a part of mRNA. It therefore hybridizes to mRNA and inhibits the synthesis of the encoded protein. It has been...

Involvement Of G Proteins And Ion Channels In Spinal Delta Opioid Receptormediated Antinociception

The high-affinity GTPase activity in the mouse spinal cord is increased in a concentration-dependent manner by D-Ala2 deltorphin II 82 . This increase of GTPase activity induced by D-Ala2 deltorphin II is completely blocked by coincubation with a selective delta opioid receptor antagonist NTB 82 . phate ( 35S GTPgS) 55,83-87 . 35S GTPgS addition results in accumulation of a stable Ga- 35S GTPgS complex in spinal cord membranes. Using this procedure, both DPDPE and D-Ala2 deltorphin II produce a robust stimulation of 35S GTPgS binding in membranes of the mouse spinal cord 88 . These effects are reversed by delta opioid receptor antagonists. The levels of 35S GTPgS binding stimulated by DPDPE and D-Ala2 deltorphin II in membranes of the spinal cord obtained from both heterozygous and homo-zygous MOR-1 knockout mice are similar to those found in wild-type mice 88 . Homozygous DOR-1 knockout mice display markedly reduced spinal antinociception by delta opioid receptor agonists 59 . These...

Turnover Of Delta Opioid Receptor To Produce Spinal Antinociception

Out that the inhibition of the biosynthesis of spinal delta opioid receptor protein by ITH pretreatment with antisense oligodeoxynucleotide against delta opioid receptor, but not mismatched oligodeoxynucleotide, prevents the recovery from acute tolerance to D-Ala2 deltorphin II-induced spinal anti-nociception in a dose-dependent manner 150 . However, ITH treatment with antisense oligodeoxynucleotide against delta opioid receptor cannot prevent the recovery from antinociceptive tolerance to either the mu opioid receptor agonist DAMGO or the kappa opioid receptor agonist U50,488H 150 . Under these conditions, ITH treatment with D-Ala2 deltorphin II significantly reduces the binding of 3H DSLET in membranes of the spinal cord at 3 h after treatment, but the binding returns to control levels by 24 h after treatment 150 . However, 3H DSLET binding in the spinal cord remained significantly reduces at 24 h if antisense oligodeoxynucleotide against delta opioid receptor is cotreated ITH with...

Supraspinal Antinociception Mediated By Delta Opioid Receptor Agonist And Interaction Between Mu And Delta Opioid

The ability of delta opioid receptors in the spinal cord to mediate antinoci-ception is well established but the ability of delta opioid receptors to mediate antinociception at the supraspinal level continues to be a subject of controversy. A preponderance of evidence seems to support supraspinal anti-nociception mediated by delta opioid receptors 27,42 , however, the dispute still continues. Pharmacological evidence in favor of delta opioid-mediated antinociception in the brain can be summarized as 1) the ability of highly selective delta opioid receptor agonists 35,50 to produce antinociceptive responses to chemical and thermal nociceptive stimuli in mice when give ICV 2) the ability of selective delta opioid receptor antagonists to block these agonist effects 3) the insensitivity of delta opioid receptor agonist-induced suparaspinal antinociception to mu opioid receptor antagonists and 4) a lack of cross-tolerance between selective delta and mu opioid receptor agonists to produced...

Lumbar Radiculopathy And Spinal Stenosis Patients

Patients with radiculopathy are approached with the same treatment tools in mind as the patient with only CLBP with some important additional considerations. First, the back pain and radicular leg pain component are approached as two different problems since they can act and respond to treatments in very different ways. For instance, the back pain component does not usually respond to the treatments that are helpful for the radicular component. Treatments, such as surgical disc-ectomy, epidural steroid injections, or neuropathic drugs, can eliminate radicular leg pain, but have not shown efficacy for treating axial pain.140 Most of these patients will have a discogenic or bony hypertrophic etiology for their radicular pain. Occasionally, the radicular pain comes from a synovial cyst, but serious underlying spine disease as a source of radiculopathy is extremely rare32 and only investigated if the usual low back screening red flags are positive. Patients with classical spinal stenosis...

Pathological Changes In Naag And Gcp Ii In Spinal Motoneuron Injury And Disease

In 1984 Koller et al.32 reported reductions in NAAG levels caudal to spinal cord transactions. Given this finding, along with the known association of NAAG with motoneurons21, its co-localization with cholinergic motoneurons33 and the report of marked reduction in choline acetyltransferase activity in the ventral horn of the spinal cord in postmortem studies of patients with amyotrophic lateral sclerosis ALS ,34 it was logical to study levels of NAAG in conditions known to affect motoneurons. NAAG was reported to be significantly decreased in the spinal cord (32 ) and in the cerebral cortex (43 ) of male mice with hereditary myodystrophy manifesting an associated hindlimb paralysis.23 Levels of NAA, Glu and aspartate (Asp) had previously been shown to be decreased in the brains of these mice.35 Several studies have been carried out in spinal cord tissue obtained at autopsy from patients that had died of ALS. The comparison groups were autopsy specimens taken from patients that had...

Evaluation Of Inhibitors Of Gcp Ii In Acute Spinal Cord Injury In The

Spinal intrathecal injection of the peptide Dynorphin A has been shown to reliably induce ischemia, neuronal injury and persistent flaccid hindlimb paralysis.57-63 Concentrations of the excitatory amino acid neurotransmitters Glu and Asp are significantly increased in lumbar cerebrospinal fluid in the rat, shortly after the onset of dynorphin A-induced hindlimb paralysis.62 In addition, a variety of competitive and noncompetitive inhibitors of the NMDA receptor complex have been shown to significantly improve recovery of hindlimb motor function following this insult.62-66 In light of these findings suggesting excitoxic mechanisms in this model, we chose to use it to assess GCP II inhibition as a means to ameliorate excitoxic injury in the rat spinal cord. For amino acid measurements, CSF (approximately 70 il) was collected on ice for approximately 10 min beginning 15 min after spinal subarachnoid injections of dynorphin A, acidified and frozen until assayed by method of Robinson...

Spinal Cord Primary Sensory Neurons SRIResistance

These are neurons with cell bodies located in sensory ganglia with processes terminating in the periphery (skin, viscera, other) and in the spinal cord in the CNS. They convey the first (primary) sensory information to the spinal cord. They vary in cell body size, axon diameter, conduction velocity, and their content of neurotransmit-ters and neuroactive peptides. These differences and the distribution of central and peripheral ends account for sensory modality content. Small-diameter primary sensory neurons might, in addition, liberate neuropeptides antidromically with pro-inflammatory consequences.

Spinal cord injury pain

Spinal cord injury at older age seems to be a risk factor for the development of SCI neuropathic pain 20 , while no consistent findings have emerged with respect to gender, level or extent (incomplete versus complete) of injury 18 . Sensory hypersensitivity is more common in SCI patients with neuropathic pain 5 , while there is no difference in thermal sensitivity and thus spinothalamic tract function in SCI patients with or without central pain. Box 21.2 Interventions (oral drug treatment) supported or refuted by evidence as well as commonly used interventions currently unproven in central pain following spinal cord injury but with evidence in other neuropathic pain conditions Interventions commonly used but unproven in spinal cord injury pain Antidepressants (serotonin and noradrenaline reuptake inhibitors and tricyclic antidepressants) Opioids including tramadol * Included 21 patients with central pain following spinal cord Injury and 19 with central post-stroke pain.

Duramorph Supraspinal Rostral Spread

INTRASPINAL INFUSION Administration of opioids into the epidural or intrathecal space provides more direct access to the first pain-processing synapse in the dorsal horn of the spinal cord. This permits the use of doses substantially lower than those required for oral or parenteral administration (Table 21-6), thereby decreasing systemic side effects. However, epidural opioids have their own dose-dependent side effects, such as itching, nausea, vomiting, respiratory depression, and urinary retention. Administration of hydrophilic opioids (duramorph, others) permits more rostral spread of the compound, allowing it to directly affect supraspinal sites. As a consequence, after intraspinal morphine, delayed respiratory depression can be observed for as long as 24 hours after a bolus dose. Nausea and vomiting are more prominent symptoms with intraspinal morphine. However, supraspinal analgesic centers also can be stimulated, possibly leading to syn-ergistic analgesic effects.

Inhibitory and Excitatory Effects of Nociception at the Spinal Cord Level

Excitatory Transmitter Glutamate

Within the spinal cord, either an enhancement and or an inhibition of ascending nociceptive afferences come into effect. The spinal cord is also considered as the major site where a number of analgesic agents initiate their mode of action through direct binding at selective inhibitory receptor sites (Figure I-19). Melanocortins are a group of endogenous peptides that are derived from pro-opiomelanocortin. The melanocortins include adrenocortico-tropic hormone (ACTH), and the X- and 6-melanocyte stimulating hormone (MSH). Recent studies indicate that spinal melanocortin receptors (the MC4 subtype) are upregulated in animal models of neuropathic pain. Also, both (X-MSH and 6-MSH have been identified in areas of the spinal cord associated with nociception 34 . The MC4 melanocortin receptor agonists MTII and d-Tyr-MTII increase the sensitivity of rats to painful stimuli following sciatic nerve constriction. In contrast, the pain responses are attenuated following pretreatment with the...

Spinal cord mechanisms

The sensory input from primary sensory neurons is transferred, via their central axons, to second-order neurons in the dorsal horn of the spinal cord. The synaptic contacts made between afferent central terminals and dorsal horn neurons are highly organized, both topographically and functionally to maintain accurate transfer of information regarding the peripheral noxious stimuli. Following peripheral nerve lesions, synaptic processing in the spinal cord can be subject to diverse forms of functional, chemical, and structural plasticity that are highly involved in the production of hypersen-sitivity to sensory input. Increased synaptic efficacy (the phenomenon of central sensitization), loss of inhibitory mechanisms, alterations in synaptic contacts, and the activation of nonneuronal cells all play major roles in producing increased pain sensitivity in neuropathic pain. This chapter will address each of these areas in turn. Figure 1.6 The immune system in neuropathic pain. Overview of...

Supraspinal Engrams Relevant In Transition From Acute To Chronic Pain

Nociceptive afferent signals from damaged peripheral tissue are relayed to the posterior column where they transmit to second order neurons of the spinal cord where they are being modulated. Nociceptive simuli originating in the head or the face are conveyed via the trigeminal nerve to the trigeminal nerve nucleus in the brain stem. There, all afferent signals are being modulated after which they cross to the opposite side, further ascending to the thalamus. From there, fibers ascend rostrally to lemniscal and thalamic structures, before they reach the somatosensory cortex (Figure I-44). Each long-term or even a paroxysmal increase of activity of afferents to the posterior column of the spinal cord or to the trigeminal nerve nucleus also induce an activity-dependent adaptation of the rostrally located thalamic and neocortical structures 86 . In the process of development of chronic pain, besides adaptive peripheral changes, also an alteration at the cortical level is instigated...

Modulation of Chronic Pain Spinal a2 and a3 GABAa Receptors

The canonical circuits of GABAergic control of principal cells also applies to circuits in the spinal cord with particular reference to sensory pain processing. Using the point-mutated mice described earlier, spinal a2 (and a3) GABAA receptors were identified as powerful gatekeepers of pain (Knabl et al. 2008). The experimental a2 a3 receptor ligand L-838 417 (Table 2) was highly effective in suppressing inflammatory and neuropathic pain, yet devoid of unwanted sedation and motor impairment. Most importantly, in contrast to morphine, L-838417 failed to show any tolerance in analgesic efficacy, as tested over nine days. The a2 a3 receptor ligand reduced not only the nociceptive input, but also reduced the activity in brain areas associated with the associative-emotional component of pain (fMRI) (Knabl et al. 2008). Similarly, NS11394, acting as partial agonist at a2 and a3 receptors and as almost full agonist at a5 receptors, was effective in rat models of inflammatory and neuropathic...

Opioidmediated Antinociception 71 Spinal Antinociception

That the 5-opoid receptors exist on the terminals of primary afferents in the spinal cord strongly suggests that agonists acting at these sites would be effective antinociceptive agents 83,84 . Shock titration tests performed in rats and monkeys demonstrated that 5-opioid agonists produce antinociception when given intrathecally (ITH), even in morphine-tolerant animals 85 . Both DPDPE and DPLPE given ITH produced dose-dependent antinociception after ITH injection in the mouse 86 . Furthermore, 5-mediated antinociception induced by DPDPE or DPLPE were blocked by the selective A-opioid antagonist ICI 174864 87 . In other studies, ICI 174,864 produced a right-ward shift in the antinociceptive dose-response curve for spinal DPDPE but not morphine, whereas the A-opioid antagonist h FNA blocked morphine but not DPDPE 88 . Inhibition of the tail flick reflex by applying a noxious conditioning stimulus to the hindpaw of the rat was blocked by the spinal injection of h FNA or the 5-opioid...

Who May Benefit From Spinal Surgery

Patients with CLBP and their treating physicians need to approach the issue of spinal surgery with caution. It is important to understand that the spine surgical community is indeed split as to whether they believe spinal surgery is an option for the patient with CLBP. This is a controversial area of medicine highlighted by recent published expert opinion statements critical of spinal fusion surgery146 V and in response, supportive of surgery.147 V On the other hand, recent clinical trials using a bio-psychosocial model of CLBP have shown evidence supporting conservative care for these patients. The first randomized trials comparing spinal fusion to an aggressive exercise therapy treatment approach within a CBT program have shown virtually identical results. Both groups showed improvement in pain and disability, but the surgical group had more morbidity in the interoperative and postoperative periods.133,148 II Another similarly designed comparison published earlier showed an...

Spinal Inhibitory Systems yAminobutyric acid and glycine

The g-aminobutyric acid (GABA) pathway forms a major inhibitory neurotransmitter system in the CNS. Depression of such spinal inhibitory mechanisms are thought to be important for sustained enhancement of excitatory transmission and central sensitization.129 In support of this, administration of GABA-mimetics reduces neuropathic hypersensitivity and antagonism of the GABA receptors is associated with hypersensitivity.130 Moreover, peripheral nerve injury results in a substantial loss of GABA-mediated inhibitory currents,131 decreased extracellular levels of GABA,132 a decrease in dorsal horn levels of the GABA synthesizing enzyme glutamic acid dec-arboxylase (GAD) 65kDa,131 and decreased GABA receptor levels in the spinal cord, probably due to degeneration of the primary afferent neuron terminals on which the receptor is localized.133 Apoptosis in the dorsal horn following nerve injuries may correlate to selective death of GABAergic inhibitory interneurons131 due to excessive...

Cerebrospinal fluid

Embedded within the brain are four ventricles or chambers that form a continuous fluid-filled system. In the roof of each of these ventricles is a network of capillaries referred to as the choroid plexus. It is from the choroid plexuses of the two lateral ventricles (one in each cerebral hemisphere) that cerebrospinal fluid (CSF) is primarily derived. Due to the presence of the blood-brain barrier, the selective transport processes of the choroid plexus determine the composition of the CSF. Therefore, the composition of the CSF is markedly different from the composition of the plasma. However, the CSF is in equilibrium with the interstitial fluid of the brain and contributes to the maintenance of a consistent chemical environment for neurons, which serves to optimize their function. The CSF flows through the ventricles, downward through the central canal of the spinal cord, and then upward toward the brain through the subarachnoid space that completely surrounds the brain and spinal...

Spinal generator

As mentioned above, at-level neuropathic pain may also be dependent on the presence of a spinal generator or amplifier. Several case reports of spinal local anesthetic blockade in people with SCI pain describe complete (although temporary) abolition of pain with sensory block up to and above the level of injury.24 This ability of spinal local anesthetic blockade to relieve neuropathic pain following SCI led to the proposition that there was an irritated focus'' located at or above the rostral end of the spinal cord injury. These clinical observations have, to some extent, been supported by subsequent investigations using animal models of SCI pain.23 In spinal dorsal horn neurons above the site of injury, these models demonstrate an increased neuronal responsiveness to peripheral stimuli, an increase in the level of background neuronal activity and the presence of neuronal after-discharges following a stimu-lus.25,2627 This increase in neuronal excitability may be a result of either...

Spinal factors

The increased barrage from neuromas and from DRG cells is thought to induce long-term changes in central projecting neurons in the dorsal horn, including spontaneous neuronal activity, induction of immediate-early genes, increases in spinal metabolic activity,68 and expansion of receptive fields.69 The pharmacology of spinal sensitization involves an increased activity in NMDA receptor-operated systems, and many aspects of the central sensitization can be reduced by NMDA receptor antagonists.70 In human amputees, the evoked residual limb or phantom pain caused by repetitively stimulating the residual limb can be reduced by the NMDA antagonist ketamine.71 Clinical observations confirm that spinal factors are involved in the generation of phantom pain. For example, phantom pain may appear or disappear following spinal cord neoplasia33 and spinal analgesia may modulate phantom pain.50'51

Spinal Analgesia

The use of single shot spinal analgesia alone and not as part of a CSE technique is most useful in the late stages of labor when delivery is imminent or to provide rapid analgesia for a mother who has lost control, thus allowing her to regroup and cooperate for epidu-ral catheter placement. The main consideration for single shot spinal analgesia is the limited duration of analgesia (60-90 min Table 22.4) and the risk of post-dural puncture headache. The headache risk can be reduced by using a small gauge (24-25 g) pencil point needle (Sprotte B. Braun Medical Inc., Bethlehem, PA) rather than those with cutting tips. The incidence of headache should be

The Spine Care Team

The spine clinician, as gatekeeper, has a team of spine care providers to assist in patient management. Over recent decades, the spine care team has grown. For example, specialists who act as intermediaries between primary care providers and spine surgeons include physiatrists or physicians trained in the specialty of physical medicine and rehabilitation (www.aapmr.org). Many physiatrists have a special interest in medical management of mus-culoskeletal problems like CLBP. In addition, physicians of various specialties have additional board certification in pain medicine and deal with a large proportion of CLBP patients. Some, including anesthesiologists, phy-siatrists, and radiologists among others, may have taken fellowship training in interventional spine techniques (www.spinalinjection.com). work or home ergonomic issues for CLBP patients as well. Complementary and alternative medicine practitioners, such as those who provide massage therapy, acupuncture, manipulation, or other...

Spinal Stenosis

If vascular claudication is ruled out, pain in the lower back and lower extremities exacerbated by walking may be diagnosed as neurogenic claudication. This is caused by lumbar spinal stenosis, which results in a narrowing of the central spinal canal and or the neural foramina (Fig. 26.2) (Deyo and Weinstein 2001). Spinal stenosis is commonly seen in elderly patients in whom degenerative changes in the disks, facet joints as well as including osteophyte formation and thickening of the ligamentum flavum contribute to the narrowing. Spondylolisthesis also can cause these symptoms. Classically, the patient's symptoms are relieved by forward flexion (such as leaning on the grocery cart) and rest. Symptoms may occur in younger patients from congenital stenosis, although this is less common. Spinal stenosis Spinal stenosis Figure 26.2 Herniated disk and spinal stenosis. Modified from Deyo 2001 with permission. Figure 26.2 Herniated disk and spinal stenosis. Modified from Deyo 2001 with...

Spine Injections

Cervical Facet Joint Referred Pain

Epidural steroid injections (ESIs) are the most commonly performed injection for back pain. They may be performed in all segments of the spine, but are most commonly done in the lumbar and cervical regions. The usual approach is through the interlaminar window, but this is not always possible. Removal of bone and ligament, hardware implantation, and postsurgical scarring can make the interlaminar approach both difficult and risky. Transforaminal, caudal, and sacral approaches to steroid injections may be necessary due to the anatomic alterations or pathologic changes in the spine. Clinical practice data have shown that cervical interlaminar ESI is safer than cervical transforaminal injection. Lumbar interlaminar ESIs compared with lumbar transforaminal injection are equally safe and efficacious. The interlaminar ESI is usually performed in the prone position under fluoroscopic guidance. The targeted level is identified by counting the lumbar or cervical vertebrae from a known level...

The Spine

The structure of the spine is really not suited to upright posture and carrying heavy body weight. Because of the way the spine is structured, it is very easy to strain or injure the back. The spine is a series of interconnected vertebrae and gelatinous discs. It is the major support structure for muscles, ligaments, and tendons of the body and serves as a protective structure for the spinal cord, which passes through the individual vertebrae in a hollowed out central ring. The spine consists of three separate sections of vertebrae. From the top to bottom these sections are Below the lumbar vertebrae is the sacrum consisting of five fused vertebrae and the coccyx with four fused vertebrae (Eathorne, 2007). LBP can occur at any level, including the sacrum. From each vertebra, a set of nerves starts at the spinal cord and exits the spine through the vertebral foramen. Depending on the level, the nerves control the various muscle groups. The area of the body that the nerves serve is...

Contemporary Neuroscience

Stem Cells and CNS Development, edited by Mahendra S. Rao, 2001 Neurobiology of Spinal Cord Injury, edited by Robert G. Kalb and Stephen M. Strittmatter, 2000 Cerebral Signal Transduction From First to Fourth Messengers, edited by Maarten E. A. Reith, 2000 Central Nervous System Diseases Innovative Animal Models from Lab to Clinic, edited by Dwaine F. Emerich, Reginald L. Dean, III, and Paul R. Sanberg, 2000 Mitochondrial Inhibitors and Neurode-generative Disorders, edited by Paul R. Sanberg, Hitoo Nishino, and Cesario V. Borlongan, 2000 Cerebral Ischemia Molecular and Cellular Pathophysiology, edited by Wolfgang Walz, 1999 Cell Transplantation for Neurological Disorders, edited by Thomas B. Freeman and Hakan Widner,1998 Gene Therapy for Neurological Disorders and Brain Tumors, edited by E. Antonio Chiocca and Xandra O. Breakefield, 1998

Animal Models Of Neuropathic Pain

Before exploring what is known about the pathophy-siology of neuropathic pain, three major caveats as to the nature of the existing literature need to be stated. First, the overwhelming bulk of the literature related to neuropathic pain mechanisms has emerged from rodent studies in which the major outcome measure is hypersensitivity of spinal withdrawal reflexes evoked by sensory stimuli. Thus, in this chapter, it will actually only be possible to discuss the putative mechanisms of evoked hypersensitivity, a relatively minor component of the spectrum of clinical neuropathic pain. Second, since it is also not currently possible to directly measure pain in experimental animals, the putative pain mechanisms which are to be discussed can only be interpreted in the

Overview and Introduction to Clinical Proteomics

Abbreviations CSF Cerebrospinal Fluid, SILAC Stable Isotope Labeling with Amino acids in Cell culture, FFE Free Flow Electrophoresis, IMAC Immobilized Metal Affinity Chromatography, 2DE 2-dimensional Gel electrophoresis, CBB Coomassie Brilliant Blue, SELDI Surface-Enhanced Laser Desorption Ionization, MALDI MatrixAssisted laser desorption ionization, MDLC Multi-dimensional Liquid Chromatography, LC Liquid Chromatography, TOF Time-of-Flight, CID Collision-induced dissociation, ETD Electron Transfer Dissociation, LIT Linear Ion-Trap, FT Fourier-Transform, Q Quadrupole, ELISA Enzyme-Linked Immunosorbent Assay, SISCAPA Stable Isotope Standards with Capture by Anti-Peptide Antibody, AQUA Absolute Quantitative

Matrix components and Endogenous Materials in Biological Matrices

Biological matrices include plasma, serum, cerebrospinal fluid, bile, urine, tissue homogenates, saliva, seminal fluid, and frequently whole blood. Quantitative analysis of drugs and metabolites containing abundant amounts of proteins and large numbers of endogenous compounds within these matrices is very complicated. Direct injection of a drug sample in a biological matrix into a chro-matographic column would result in the precipitation or absorption of proteins on the column packing material, resulting in an immediate loss of column performance (changes in retention times, losses of efficiency and capacity). Similar damage can occur to different components of the ESI MS MS system commonly utilized for analyzing drugs. Matrix components identified by different analytical techniques are shown in Table 1.1. Major classes encountered in plasma consist of inorganic ions, proteins and or macromolecules, small organic molecules, and endogenous materials.51-56

Excitatory Mechanisms

Dubbed central sensitization.106'107 In addition to events such as lowering of activation thresholds of spinal neurons, central sensitization is characterized by the appearance of wind-up. 108'109'110 Wind-up is characterized by an increasing response to repeated C-fiber NMDA receptors are also involved in the maintenance of central sensitization. Nerve injury induces increased release of excitatory amino acids into the spinal dorsal horn which is associated, in an NMDA receptor-dependent manner, with increased intracellular calcium concentration ( Ca21 i) in dorsal horn neurons.114 Initial NMDA receptor activation contributes to further increased concentrations of glutamate and aspartate, representing a continual positive feedback loop which maintains sensitization. The increased Ca21 could also form a positive feedback loop, potentially through indirect activation of protein kinase C (PKC), a hypothesis supported by the antihypersensitivity effect of a PKC inhibitor in the SNL model...

Descending Modulation

In addition to the peripheral and spinal mechanisms discussed, supraspinal mechanisms are thought to play an important role in neuropathic pain.173,174 The periaqueductal gray (PAG) is the most characterized part of a CNS circuit that controls nociceptive transmission at the level of the spinal cord.175 The PAG integrates inputs from areas such as the limbic forebrain, diencephalon, amygdala, and hippocampus with ascending nociceptive input from the dorsal horn176 and is therefore associated with the affective and autonomic responses to pain. The PAG is closely associated with the brainstem including the rostral ventromedial medulla (RVM), and is critical in the descending modulation of spinal activity through monoaminergic and other pathways.177 Likely via anatomically distinct pathways, the PAG and RVM can exert both facilitatory and inhibitory influences on the spinal cord.178 The balance of these two supraspinal pathways and primary afferent input, ultimately determines the...

Key Learning Points

In the central nervous system, nociceptive stimulation of deep tissue is encoded in neurons exclusively driven by deep input, and by neurons that show convergent inputs from deep tissue and skin. Peripheral sensitization induces a state of hyperexcitability in the central nociceptive system (central sensitization) that increases the gain of central nociceptive processing at spinal, thalamic, and cortical levels. Spinal hyperexcitability contributes to primary and accounts for secondary hyperalgesia. Descending systems control the nociceptive processing at the spinal level. During peripheral inflammation descending inhibition increases and reduces central sensitization. Descending facilitation may support secondary hyperalgesia.

Tissue Distribution Of Drugrelated Abc Transporters

MDR1 (ABCB1), MRP2 (ABCC2), and BCRP (ABCG2) are all expressed in the apical side of the intestinal epithelia, where they extrude xenobiotics, including many clinically relevant drugs. Key to the vectorial excretion of drugs into urine or bile, ABC transporters are expressed in polarized tissues, such as kidney and liver MDR1, MRP2, and MRP4 (ABCC4) on the brush-border membrane of renal epithelia, and MDR1, MRP2, and BCRP on the bile canalicular membrane of hepa-tocytes. Some ABC transporters are expressed specifically on the blood side of the endothelial or epithelial cells that form barriers to the free entrance of toxic compounds into tissues the BBB (MDR1 and MRP4 on the luminal side of brain capillary endothelial cells), the blood-cerebrospinal fluid (CSF) barrier (MRP1 and MRP4 on the basolateral blood side of choroid plexus epithelia), the blood-testis barrier (MRP1 on the basolateral membrane of mouse Sertoli

Innervation Of Joint Muscle And Bone

A, galanin, enkephalins, and neuropeptide Y have also been localized in joint afferents. Neuropeptides influence the inflammatory process in the periphery and modify spinal processing of joint and muscle input. They may also act on the primary afferent neurons themselves (see below under Molecular mechanisms of peripheral sensi-tization). However, these neuropeptides are not specific for deep afferents.7,12

Complexity And Heterogeneity In Multiple Sclerosis

Self-evidently, the clinical phenotype of multiple sclerosis is variable with respect both to clinical features present in any one affected individual and disease patterns among groups. Clearly, the suggestion that a patient with brainstem involvement has a different disease from the individual with spinal cord involvement is not necessarily logical these differences more probably reflect the random involvement of different sites by the same pathological process. Furthermore, there is no evidence that the patient with infrequent episodes and full recovery enjoying prolonged periods of disease inactivity necessarily has a different disease from one in whom events move quickly through the relapsing, persistent and progressive phases of the disease. That is not to say that these two extremes of clinical course are definitely expressions of the same pathological sequence more that such variations are only evidence for complexity which may or may not indicate heterogeneity. One good...

Activation Of The Nociceptive System By Noxious Deep Tissue Stimulation Under Normal And Inflammatory Conditons

Importantly, significant changes of the nociceptive processing are induced by inflammation and tissue injury which are called peripheral sensitization (sensitization of primary afferents) and central sensitization (development of hyperexcitability of nociceptive neurons in the central nervous system). Figure 2.1 summarizes the structures of the nociceptive system and the sequence of inflammation-evoked events in the nociceptive system. Inflammation leads to peripheral sensitization which in turn causes the development of hyperexcitability in the spinal cord.7,12 Ascending axons in the spinothalamic tract activate the lateral and medial thalamocortical system which evoke the conscious pain sensation with its sensory discriminative and the affective components.17 In parallel, ascending projections to the brainstem are activated. The activation of the brainstem contributes to the activation of the brain by noxious stimuli, but it also acts back on the spinal cord through descending...

Mechanosensitivity of peripheral nociceptors in the normal joint and muscle

In the muscle nerve, numerous sensory Ad- and C-fibers are only activated by noxious mechanical stimuli. These muscle nociceptors do not respond to everyday stimuli, such as weak local pressure, contractions, and muscle stretch within the physiological range. They require potentially noxious stimuli to be readily activated, and the best stimulus is noxious squeezing of the muscle belly or tendon at intensities that elicit pain in humans. Nociceptors may also respond to unphysiological stretch and maximal contraction. The threshold of a nociceptor may lay below frankly tissue-damaging intensities (small response to moderate pressure). Similar units have been found in the cat, dog, rat, and humans.28,2930,31,32,33 Electrical stimulation of such nerve fibers in human muscle nerves evokes cramp-like sensations. Electrical stimulation frequencies of 5-6 Hz are required to elicit pain sensations.34 Why such high frequencies are needed is unknown. It may be speculated that a small number of...

Assessing Anesthetic Hypotheses And Criteria

An implicit assumption of Model I is that MAC faithfully reports the status of consciousness Model I does not distinguish between loss of consciousness and lack of purposeful movement due to painful stimuli. Several studies indicate that the spinal cord processes painful sensory input and initiates a motor response independent from the brain. For example, the MAC of isoflurane in rats is unchanged after either acute decerebration13 or spinal cord transection.14 In addition, the MAC of isoflurane is increased when the anesthetic (GA) is preferentially applied to the brain of goats.15 To incorporate this into our conceptual model of anesthesia, we consider Model II (Figure 1.4). Model II consists of two neurons. The first neuron represents the consciousness center and the second neuron, which may be in the spinal cord, represents the movement center. If the two neurons are connected in series (Figure 1.4a), anesthetics acting on the consciousness center might transmit this information...

The Glutamate Synapse

Activation of the NMDA receptor opens a calcium channel. The entry of calcium into the dendritic spine activates phospholipase A2. This in turn acts on membrane phospholipids to release arachidonic acid, which leads to the activation of prostaglandin H synthase, the rate-limiting step in prostaglandin synthesis. This reaction leads to the release of large amounts of reactive oxygen species including hydrogen peroxide (H2O2), which is a freely diffusible molecule and so can enter the synaptic cleft. Here, in the presence of minute amounts of ''free'' iron, it could form the highly cytotoxic hydroxyl radical. The status of free iron in the brain is controversial. Recently, Mumby et al. (55) distinguished between free iron (iron free of high-affinity binding to transferrin), loosely bound iron (associated with proteins such as albumin), and labile iron (can be mobilized from biological ligands by oxi-dative stress). During periods of oxidative stress low molecular weight labile ferrous...

Role Of Brain Macrophages In Innate Immunity

TNF-a is a proinflammatory cytokine produced in large quantities by activated macrophages and microglia in response to various stimuli such as bacterial lipopolysaccharide products. However, members of the adaptive immune response, specifically activated human T-cells, have also been shown to induce microglia production of TNF-a.17,18 TNF-a has been identified in MS plaques,19 and elevated levels of TNF have been found in serum and cerebrospinal fluid (CSF) of MS patients. In addition to its immunoregulatory properties, such as enhancing cytokine secretion (IL-12) and activation of other cell types (natural killer (NK) cells), TNF-a can influence lymphocyte trafficking across endothelium by TNF-a itself may act as a neurotoxin. Intravitreal injection of TNF-a has been shown to induce demyelination of mouse optic nerve axons.21 Similarly, injection into mouse spinal cord causes an EAE-like response.22 In passive transfer EAE, TNF antagonists inhibit the development or severity of...

Developmental expression patterns of nmda receptors

Unique roles in brain development.3 In situ hybridization studies of rat brain slices14 have shown that only NR2B and NR2D are expressed during prenatal development. Expression starts at low levels as early as E14 and becomes gradually more enriched as embryonic development continues. NR2B expression predominates in prenatal cortex, is high in the thalamus and spinal cord, and is expressed at lower levels in the colliculi, hippocampus, and hypothalamus. Expression in these areas becomes stronger around birth and persists through P0, when it can also be detected in the cerebellum, where it is the predominant subunit during early postnatal development. NR2D, in contrast, is absent from the telencephalon but abundant in the diencephalon, mesencephalon, and spinal cord. At P0, these areas continue to show strong signals for NR2D mRNA, when the transcript can also be detected at very low levels in the cortex, hippocampus, and septum. Also at P0, NR2A and NR2C start to show expression at...

Experimentally Induced Antibodymediated Demyelination

The demyelinating effect of antibodies to specific myelin components demonstrated in vitro has been extrapolated in vivo. The presence of anti-GalC antibody or anti-MOG antibody, but not anti-MBP antibody, within CNS tissue of laboratory animals results in extensive demyelination in vivo. Such experimentally induced in vivo antibody-mediated demyelination has been demonstrated using various routes for introducing the relevant antibody within CNS tissue. Intravenous administration of demyeli-nating sera from EAE animals into naive recipients does not cause CNS demyelination 25,26 however, if the sera are injected intrathecally, demyelination does ensue.27 The specificities of the in vivo demyeli-nating antibodies in EAE sera have not been defined as such however, the specificities of in vitro demyelinating antibodies appear to be as relevant to in vivo demyelination. Thus, direct injection into the CNS of anti-GalC antibody,28-30 or of monoclonal anti-MOG antibody,31 resulted in CNS...

Nonhuman animal models

Visceral pain is not a unitary entity and so there is a need for more than one visceral pain model. It is difficult to equate pain due to infection of the normally sterile urinary bladder with painless colons containing a sewer of the same infective organisms. Some differences between organ systems are clearly developmental in that organs which derive from midline structures (i.e. the gut) are associated with bilateral sensations, highly generalized responses and processing bilaterally within the spinal dorsal horn. In contrast, those organs which derive from unilateral structures (i.e. kidneys, ureters) generally have lateralized sensations, more regionalized responses, and lateralized spinal processing. The use of multiple models and multiple types of noxious stimuli applied to different organ systems allow us to distinguish the generalities of visceral pain from its mechanistic specifics.

Reflectory Segmental Mediation of Pain Afferents

Once nociceptive activity in the spinal cord is above threshold levels, action potentials from the first order neuron are transmitted to the second order neuron of the spinothalamic tract. From there they are transmitted to higher pain-regulating centers In the substantia gelatinosa of the posterior column of the spinal cord, pain afferent stimuli directly, via interneuronal connections, interact with the lateral column of the spinal cord and transfer to the motor tract of the anterior column. It is here, where in the same segment or via collateral fibers to several neighboring segments, nociceptive impulses are switched to vegetative as well as motor neurons ( conversion afferents Figure I-37b). This explains the development of muscle spasms of the abdominal wall during pain, the expansion of visceral-sensitive pain (Figure I-37c), accompanying vegetative circulatory effects, activation of sweat glands, and the projection of pain from deep visceral structures to specific areas of the...

Assay 2 The Agmatine Assay

We use a rack designed (in house) for 100 53 4-inch Pasteur pipettes that fits over a 10 x 10 tray of 20-ml scintillation vials such that eluate from each column is collected in a vial. Each pipette (containing a glass wool plug) is filled with AG 1-X2 slurry up to the constriction in the glass using a syringe fitted with a blunted wide-bore spinal needle or a piece of stiff tubing. The needle is used to compact the glass wool at the bottom of the pipette and the column is filled as the needle is withdrawn. Before use, each column is washed with 1 ml of distilled deionized water using a repeating pipet. Each column contains 1-1.5 ml of packed resin that quantitatively retains NAD while allowing greater than 99 recovery of ADP-ribosylagmatine.

Nmda receptors and structural development of neurons

Blockade of NMDAR activity with APV reduces dendritic growth rate92 and the dynamics of tectal cell dendrites in vivo.86 Further in vivo evidence from the visual system shows that synaptic activity induced by visual stimulation promotes dendritic arbor growth and is mediated by NMDARs.93 However, other studies reported increases in dendritic spine number and dendritic branch length and number after chronic APV-treatment in vivo and in vitro.94,95 These observations support the synaptotropic hypothesis that synaptic activity guides dendritic growth.108 109 Studies of dendritic spine morphology have shown that synaptic activity mediated through glutamate receptors stabilizes spines and synapses. NMDAR activity stabilizes the actin cytoskeleton110 and increases the F-actin contents of spines.111 In addition, the NMDAR-mediated synaptic recruitment of AMPA receptors stabilizes and maintains spines.112113 Finally, NMDAR activity can activate local protein synthesis114 and the presence of...

Looking for a Physiological Role for 5HT Receptors in the Choroid Plexus

The enormous concentration of 5-HT1C receptors in the choroid plexus of all the species investigated was calling for an examination of the role of these receptors in controlling one of the functions of this tissue, namely, the volume and composition of cerebrospinal fluid. Monique Rigo cannulated rat cerebral ventricles, examined using perfusion with artificial CSF, and radiolabeled inulin alterations in the volume of CSF. We found effects of 5-HT and other drugs, but the system was too complex to carry out detailed pharmacological studies, and we did not progress enough as to get publishable data. Along the same lines in 1988, Lindvall-Axelsson and colleagues (Lindvall-Axelsson et al. 1988) from the University of Lund in Sweden published a detailed study in the rabbit, a better suited model, described the inhibition of CSF production by 5-HT and its blockade by ketanserin.

The Role Of Antibodies In Multiple Sclerosis

Oligoclonal immunoglobulin bands in the cerebro-spinal fluid (CSF) serve as an additional pathologic hallmark of MS.9 The appearance of these immunoglobulin bands in the majority of patients with MS was initially interpreted as evidence for involvement of the humoral immune response in the pathogenesis of the disease. This notion has been supported by observations in rodents with experimental autoimmune encephalitis (EAE), using antibodies directed against the myelin oligodendro-cyte glycoprotein (MOG). In these animals, intravenous injection of monoclonal antibodies (mAbs) against MOG has been shown to increase the severity of the disease, inducing relapses and enhancing demyelination.10,11 In further support of the idea that antibodies might play a pathogenic role in demyeli-nating disease is the potential involvement of pathogenic autoantibodies in peripheral neurologic disorders, especially Guillain-Barre syndrome, an inflammatory demyelinating disease of peripheral nerves which...

Distribution and Cellular Localization of NOS in the Central Nervous System

In the nervous system NOS is mainly localized in neurons. NOS is present in several regions of the mammalian brain including the telencephalon, dienceph-alon, midbrain, pons, medulla, cerebellum, and spinal cord (for review, see Ref. 34). Different neuronal types were found to contain NOS, sometimes associated with other signaling molecules in these locations. Being relevant to our work, we will briefly review the data on spinal cord localization (Figs. 2 and 3). Several investigators have described the distribution of NOS-containing neurons in the rat, mouse, cat, and primate. Positive neurons are concentrated in the dorsal horn (laminae I-IV) and the central gray matter (lamina X) at all segmental levels (35,36). Moreover, in all species studied so far, the cholinergic preganglionic autonomic neurons in the intermediolateral cell columns of the thoracic spinal cord are highly positive after either NOS immunocytochemistry or NADPH-d staining, as well as most sacral parasympathetic...

Autoantibodies Promote Remyelination In Animal Models Of Demyelinating Disease

One of the first indications that autoreactive antibodies might actually enhance endogenous myelin repair came from studies in which EAE was induced in guinea pigs by immunization with homogenized spinal cord. After the disease was fully established, the animals were injected with myelin basic protein and galactocerebroside in incomplete Freund's adjuvant. Treatment with these myelin components was able to ameliorate the disease, resulting in significant clinical improvement and significantly fewer disease relapses.14 Upon histologic examination, extensive remyelination of CNS lesions was observed. Based on these observations, this laboratory conducted similar experiments in a mouse model of demyelinating disease, the Theiler's murine encephalomyelitis virus (TMEV) model. To explore the possibility of a beneficial humoral immune response, chronic TMEV-infected mice were treated over a 5-week period with spinal cord homogenate (SCH) in incomplete Freund's adjuvant. Upon histologic...

Transition from Acute to Persistent Pain

Once C-nociceptive fibers are activated and continue to overwhelm the nerve cells in the dorsal horn, A touch sensitive fibers begin to fire and this affects nerve cell bodies in the DRG and the dorsal horn. Glutamate, an extremely fast neurotransmitter, is released at the DRG presynaptic membrane and attaches to non-NMDA nerve cell receptors in the dorsal horn. After continued bombardment by C fibers and A fibers the magnesium ion, which normally prevents NMDA post-synaptic receptors from receiving glutamate, is displaced and a process known as windup begins. Due to ongoing pain signals reaching and being amplified at the dorsal horn, the nerve cells begin to increase the number of NMDA receptors at the post-synaptic membrane. This further increases windup and exhibits increased tolerance to opioids. Windup is a term used to describe the process of increased central sensitization of the body's pain pathways in response to sustained input from...

Copyright 2008 by The McGraw Hill Companies Inc Click here for terms of use

Communicating nociceptive stimuli from the periphery to the CNS. Somatostatin, vasoactive intestinal polypeptide (VIP), and cholecystokinin may play a role in the transmission of afferent impulses from autonomic structures. ATP appears to be a neurotransmitter in certain sensory neurons, including those that innervate the urinary bladder. Enkephalins, present in interneurons in the dorsal spinal cord (within an area termed the substantia gelatinosa), have antinociceptive effects that appear to arise from presynaptic and postsynaptic actions to inhibit the release of substance P and diminish the activity of cells that project from the spinal cord to higher centers in the CNS. The excitatory amino acids glutamate and aspartate also play major roles in transmission of sensory responses to the spinal cord.

Detection Of Apoptotic Cell Death In Eae And Ms

Evidence of involvement of the apoptotic process in immune cell death was first shown in EAE. During relapse, myelin-specific T-lymphocytes attack the myelinated tissue of the CNS. The severity of the disease is well correlated with the incidence of those T-cells in the infiltrate. Ultrastructural studies indicate that as much as 49 of the T-cells in EAE lesions at the time of recovery from a relapse show signs of apoptosis.1 Apoptosis was confirmed in EAE brain macrophages and T-cells by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method, which demonstrated the typical DNA fragmentation in situ.2 Using combined TUNEL and double immunofluorescent labeling, Ray et al3 found apoptotic mononuclear phagocytes in spinal cord sections of rats with EAE. White et al4 demonstrated that, in EAE, B-cells are eliminated from the CNS via the apoptotic pathway during spontaneous recovery. These apoptotic B-cells were identified by flow cytometry and electron...

Centralautonomic Connections

There probably are no purely autonomic or somatic centers of integration extensive overlap occurs somatic responses always are accompanied by visceral responses, and vice versa. Auto-nomic reflexes can be elicited at the level of the spinal cord and are manifested by sweating, blood pressure alterations, vasomotor responses to temperature changes, and reflex emptying of the urinary bladder, rectum, and seminal vesicles. The hypothalamus and the STN are principal loci of integration of ANS functions, including regulation of body temperature, water balance, carbohydrate and fat metabolism, blood pressure, emotions, sleep, respiration, and reproduction. Signals are received through ascending spinobulbar pathways, the limbic system, neostriatum, cortex, and to a lesser extent other higher brain centers. The CNS can produce a wide range of patterned autonomic and somatic responses. Highly integrated patterns of response generally are organized at the hypothalamic level and involve...

Second Order Neurons The Spinothalamic Tract

The axons arising from neurons making up the spinothalamic tract emanate from the entire gray matter of the spinal cord. Most of these fibers cross to the other side of the spinal cord through the ventral commissure in the midline and ascend in the anterolateral aspect of the white matter (myelinated) portion of the spinal column. These fibers ascend without interruption through the spinal column and brain stem and terminate in the contralateral thalamus (Besson and Chaouch 1987 Dennis and Melzack 1977). However, a small number of fibers project to the ipsilateral thalamus. These pain relay pathways diverge into the two pathways within the spinothalamic system the neo-spinothalamic (sensory-discriminative) and the paleospinothalamic (affective-motivational) pathways (Figure 2-2). The latter is considered to be a phylo-genetically older pathway.

Parasympathetic Branch Of The

The parasympathetic branch of the ANS consists of preganglionic fibers that originate in the CNS and their postganglionic connections. The regions of central origin are the midbrain, the medulla oblongata, and the sacral part of the spinal cord. The midbrain, or tectal, outflow consists of fibers arising from the Edinger Westphal nucleus of the third cranial nerve and going to the ciliary ganglion in the orbit. The medullary outflow consists of the parasympathetic components of the seventh, ninth, and tenth cranial nerves. The fibers in the seventh (facial) cranial nerve form the chorda tympani, which innervates the ganglia lying on the submaxillary and sublingual glands. They also form the greater superficial petrosal nerve, which innervates the sphenopala-tine ganglion. The autonomic components of the ninth (glossopharyngeal) cranial nerve innervate the otic ganglia. Postganglionic parasympathetic fibers from these ganglia supply the sphincter of the iris (pupillary constrictor...

The Role Of Apoptotic Genes In Ms And

Apoptosis is associated with activation or deacti-vation of proteolytic enzymes, such as caspases, that execute the death process by cutting the DNA into distinct fragments and deaggregating the DNA and proteins.15 Studying the oligodendro-cytes in the lesioned brain and spinal cord, Kuhlmann et al16 demonstrated a strong association between the presence of bcl-2 -positive oligodendrocytes and the presence of remyelina-tion. Moreover, they found that the highest proportion of bcl-2-positive oligodendrocytes was observed in a subgroup of patients with a relaps-ing-remitting disease course, indicating that Bcl-2 increases the viability of the oligodendrocytes in MS. In EAE, it was also shown that expression of another anti-apoptotic protein, oligodendrocyte baculovirus p35 caspase inhibitor, protected mice from EAE.17 Double staining of the EAE brains by the TUNEL method and immunocytochemistry revealed that astrocytes were more likely to be eliminated by apoptotic cell death than...

Distribution and Connectivity of Nociceptive Fibers in the Dorsal Horn

According to their morphology and physiology, primary afferent nociceptive fibers in the dorsal horn are of two categories the AS and the C fibers. Both originate from small type B neurons in the dorsal root ganglia (DRG) (61). These cells give raise to centrally directed small sized unmyelinated (C) and or scarcely myelinated (AS) processes that normally reach the cord via the dorsal roots, although unmyelinated fibers originating from the DRGs are present in the ventral roots as well (see Ref. 59). AS fibers, mediating input from high-threshold mecha-noceptors, some thermal receptors and down hairs, and C fibers from cutaneous nociceptors enter ther cord via a lateral division (62). Unmyelinated primary afferent may also reach the spinal gray matter by crossing the Lissauer's tract and the dorsal part of the lateral funiculus (63). The pattern of termination is mainly ipsilateral, although the presence of contralateral projections has been reported by several investigators. AS and C...

Third Order Neurons The Thalamus and Beyond

The thalamus is the primary relay station for sensory information from the spinal cord to the cortex (Chudler and Bonica 2001 Rome and Rome 2000). The second-order neurons from the neospinothalamic tract terminate in the lateral aspect of the ventral posterior nucleus (VPN). Third-order neurons from the VPN relay information to the somatosensory cortex (parietal lobe). Through this pathway, discriminative aspects of pain, localization of the pain, and coordinated motor responses to the pain are possible (Rome and Rome 2000).

Effect of topical nitrates on analgesic effect of opioids

So far the use of a topical nitrate has been limited to its application for localized, often inflammatory pain. But it may also be that nitrates can have an effect on opioid analgesic tolerance. It has been suggested that endogenous NO may have some role in the analgesic tolerance seen with sustained opi-oid use and that therefore a synthetic NO donor such as GTN may have an effect on opioid-derived analgesia. In one study of patients taking morphine on a long-term basis for cancer-related pain, those patients co-treated with a GTN patch needed significantly less morphine to achieve adequate pain relief than those using a placebo patch. Similarly, when a GTN patch was used in patients who had received a spinal anesthetic containing the opioid sufentanil, the time to first request for additional analgesia was significantly longer than in those patients who used a placebo patch.

Preventing Transition from Acute to Chronic Pain Use of Analgesics with Different Pharmacology

An intense nociceptive impulse transmitted to the dorsal horn of the spinal cord, always results in the release of excitatory neurotransmitters and peptides. Aside from activating interneuronal cells, they also stimulate the cells of the spinotha-lamic tract resulting in a prolonged sensitization and augmentation of all incoming further nociceptive impulses. Such an effect can outlast the original impulse 7 , a phenomenon called central hypersensitization or wind-up 91, 92 . Clinically this is related to hyperalgesia in the damaged area accompanied by dysesthesia in the surrounded skin with prolonged pain 6, 69 .

Neurotransmitters and Modulators of Nociceptive Pathways in the Dorsal Horn

Glutamate was one of the first neurotransmitters proposed for primary afferent fibers (77,78). Nowadays the role of this amino acid as a major excitatory neuro-transmitter in the spinal cord and throughout the central nervous system is fully established. The evidence that primary afferent fibers use glutamate as a neurotransmitter was initially obtained after uptake studies following ligation or section of the dorsal roots (79,80). Further evidence came from physiological and pharmacological studies based on iontophoretic administration of the amino acid and or its antagonists (81-84). Later, the availability of antisera against amino acid fixed in tissue sections has made possible the visualization of glutamate and other amino acids in specific neurons and pathways that use them as neurotransmitters (85,86). Immunocytochemical studies at the light level revealed that glutamate is mainly detected in large type A neurons but also, to a lesser extent, in small type B cells within the...

Role of the Autonomic Nervous System in Pain

The autonomic nervous system plays a significant role in pain. Signals of threat and danger are relayed to the hypothalamus. From there, specifically the posterior portion, information is relayed to the spinal cord (i.e., the thoracic and lumbar regions) by sympathetic neural pathways (McMahon 1991). Ultimately, fibers from the thoracolumbar regions innervate a number of endorgans producing activation (i.e., a state of heightened arousal). Those endorgan activities that are necessary for fight-or-flight responses are promoted, whereas those that are not necessary are suppressed. Thus, the information signaling threat or danger results in elevated heart rate and blood pressure, increased oxygen use, sweating, dilation of pupils, and increased glycogen utilization within muscles. Other organ functions (e.g., peristalsis) are inhibited.

Of NOProducing Neurons Involved in Pain Modulation

An understanding of the central mechanisms by which NO acts on nociception and the functional links between NO and peptidergic neurotransmission in the dorsal horn clearly requires a multidisciplinary approach in which the synaptic circuitry of relevant pathways in the substantia gelatinosa is dissected out at the electron microscope level in parallel with a thorough analysis of the functional properties of the gelatinosa neurons, which are activated by primary afferent input. To this end, we recently carried out a series of experiments based on correlative light and electron microscopic analysis of the gelatinosa neurons that produce NO and real-time confocal microscopy of intracellular Ca2+ changes in neurons from acute spinal cord slices after loading of cells with fluorescent calcium indicators (176). The great advantage of using such an approach is that it permits one to investigate the multiple aspects of the processing of nociceptive information in a quasi-physiological...

NAAG and GAD67 Expression in Rhesus Monkey Motor Cortex

ASPA (A), NAA (B) and NAAG (C) in rat corpus callosum. Aspartoacylase (ASPA) is the only enzyme known in the brain that acts to deacetylate NAA. ASPA expression was predominantly observed in oligodendrocytes in white matter such as corpus callosum (A), as well as throughout the brain and spinal cord. NAA expression in oligodendrocytes was very low, possibly because it is broken down rapidly by ASPA (B). NAAG expression was relatively low in the corpus callosum of the rat, being present in a relatively small number of axons (C). In the cortical white matter from monkey, far more NAAG containing axons were observed, reflecting the greater expression of NAAG in pyramidal cells. Bar 100 m.

Urinary Bladder Disorders

Bethanechol may be useful in treating urinary retention and inadequate emptying of the bladder when organic obstruction is absent, as in postoperative and postpartum urinary retention and in certain cases of chronic hypotonic, myogenic, or neurogenic bladder. a Adrenergic antagonists are useful adjuncts in reducing outlet resistance of the internal sphincter (see Chapter 10). Bethanechol may enhance contractions of the detrusor muscle after spinal injury if the vesical reflex is intact, and some benefit has been noted in partial sensory or motor paralysis of the bladder. Catheterization thus can be avoided. For acute retention, multiple subcutaneous doses of 2.5 mg of bethanechol may be administered. The stomach should be empty when the drug is injected. In chronic cases, 10 50 mg of the drug may be given orally two to four times daily with meals to avoid nausea and vomiting. When voluntary or spontaneous voiding begins, bethanechol is then slowly withdrawn.

Natural Occurrence of Oleamide

The discoveries of oleamide in human serum in 1989 (Arafat et al., 1989) and rat cerebral spinal fluid in 1995 (Cravatt et al., 1995) were followed by the studies of Basile and coworkers in 1999 who were the first to quantitatively report on oleamide levels in rat plasma (10 ng mL) and cerebral spinal fluid (44 ng mL) (Hanus et al., 1999). Oleamide has also been reported to be present in three human breast cancer lines (Bisogno et al., 1998) and in human tear film, although there is disagreement over the relative contribution of oleamide to the total content of nonpolar lipids in this secretion (Butovich et al., 2007 Nichols et al., 2007). Reports on the natural occurrence of oleamide must be considered with caution, due to its widespread use as a slip agent in the production of polyethylene products commonly used in laboratory research. This complication is avoided with a biosynthetic labeling approach using either radioactive or stable mass isotopes. Biosynthetic labeling has been...

Pain Reducing Pathways

Several structures serve to diminish the pain sensory information coming into the CNS. Intuitively, pain-modulating mechanisms prevent the organism from being overcome by unbridled pain, thereby allowing the organism an opportunity to escape and tend to the injury. The four regions in the CNS that can function to reduce pain sensation and control pain awareness are 1) the cortex and limbic structures, 2) the midbrain (the periaqueductal gray PAG ), 3) the rostral ventromedial medulla (RVM), and 4) the spinal dorsal horn (Besson and Chaouch 1987 Terman and Bonica 2001). The gating mechanism of the substantia gelatinosa within the dorsal horn was described earlier in this chapter. The cortex and reticular formation can influence attention, arousal, expectations of pain, and psychological factors that can in turn influence pain experiences. The specific mechanisms by which these structures influence pain have yet to be clarified. Additionally, axons of supraspinal nuclei extend down the...

BBB Biology and Pharmacology

Two major barrier systems separate the central nervous system from the circulation the BBB and the blood-cerebrospinal fluid barrier (B-CSF-B). These barriers have distinct morphological and physiological characteristics, according to their different tasks. Figure 2.1 highlights the salient features of both barrier systems. Figure 2.1. The two main barrier systems in the mammalian brain are the blood-brain barrier (BBB) (a-c) and the blood-cerebrospinal fluid barrier (d-f). (a) Autoradiograph of a sagittal section through a rat, which received an intravenous injection of 14C -histamine 15 min earlier. The tracer distributes to all organs except for the central nervous system, where passage is prevented by the tight BBB. (b) The site of the permeability barrier at the level of the tight junctions between microvascular endothelial cells (arrow), shown schematically. (c) Silver enhanced immunogold staining of the dense brain capillary tree. Endothelial cells were labelled by perfusion in...

Concluding Remarks And Future Perspectives

Ongoing research on NO has opened a series of new frontiers in neurobiology, particularly about our common thinking of neuron-to-neuron communication. Experimental evidence has also clearly indicated that the cross-talk between neurons and glial cells is of paramount importance for modulating the final response of nerve cells to stimulation. NO is an attractive candidate for a retrograde signaling molecule that could easily transfer information from neuron to neuron and from neuron to glia. Considering its unique nature, an in-depth characterization of its biological actions and signaling pathway could possibly help to explain some puzzling or even paradoxical results so far obtained while trying to dissect out nociceptive pathways in the spinal cord. Characterization of the connectivity, physiology, and pharmacology of these pathways is of paramount importance, also considering that management of chronic pain represents a major social and economical problem. At present, even the...

Opiate Receptors and Descending Inhibition of Pain Pathways

Adapted from Terman GW, Bonica JJ Spinal Mechanisms and Their Modulation, in Bonica's Management of Pain, 3rd Edition. Edited by Loeser JD, Butler SH, Chapman CR, et al. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp. 73-152. Source. Adapted from Terman GW, Bonica JJ Spinal Mechanisms and Their Modulation, in Bonica's Management of Pain, 3rd Edition. Edited by Loeser JD, Butler SH, Chapman CR, et al. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp. 73-152. Analgesia on a spinal level is a result of the opiate activation of the K-recep-tor. Activation results in pupil constriction and sedation. The S-receptors also produce analgesia and are activated by endogenous opiates. The role of the o-receptor is more controversial. It produces no analgesia but is responsible for the dysphoria, and possibly hallucinations, associated with opiate use. Because of these disparate effects, compared with other opiate receptors, there is controversy about whether the...

Pain Augmenting Mechanisms and the Emergence of Chronic Pain

Ongoing NMDA activation can result in cell death. Death of neurons leaves areas of deafferentation in the spinal cord pathways. As a result, nearby sensory neurons often sprout collaterals into the deafferentated area to replace the synaptic connections lost after cell death. This replacement results in an innervation of pain pathways that correspond to the injured areas stimulated or activated by nearby undamaged areas.

Measurement of Lipophilicity

In 1959, Gaudette and Brodie 7 realized both the possibility for using a partition coefficient to model lipophilic character, and the relevance of lipophilicity to pharmacokinetic processes. They found a parallel between the heptane buffer partition coefficients of certain drugs, and their rate of entry into cerebrospinal fluid. However, generalised use of logP as a lipophilicity parameter did not come about until after 1964, with the Hansch octanol water system remaining to this day the standard for both experimental and theoretical investigations. In 1971, Leo, Hansch and Elkins 8 published the first comprehensive review of partition coefficients, with a tabulation of nearly 6000 values, including their own measurements on some 800 in the octanol water system. The review incorporated an account of the shake-flask method of measurement, which was discussed more exhaustively in a 1973 monograph by Purcell, Bass and Clayton 9 .

MMPs In Multiple Sclerosis

MS, the most common disabling neurological disorder among young adults, is pathologically characterized by T-cell and macrophage infiltration into the CNS, demyelination and secondary axonal injury.9-10 Pro-inflammatory cytokines, such as interferon gamma (IFN-7) and tumor necrosis factor alpha (TNF-a) are also increased and contribute to MS pathology. Several lines of evidence suggest that MMPs are involved in the pathogenesis of MS. Elevated levels of both MMP-2 and MMP-9 were demonstrated in the cerebrospinal fluid (CSF) of MS patients and experimental autoimmune encephalomyelitis (EAE) mice, an MS animal model.1112 Increased levels of MMP-9 and MMP-7 mRNA were detected in brain tissue from EAE animals.13,14 MMP-2, MMP-7 and MMP-9 expression was also found to be upregulated in MS lesions.15-17 The MMP-9 level in serum of relapsing-remitting (RR) MS patients was found to be elevated, and an additional elevation was observed during relapse.18,19 We have recently demonstrated elevated...