Anatomy of Pain and Analgesia

At the site of injury, tissue damage leads to the release of several chemical factors such as adenosine 5'-triphosphate (ATP), bradykinin, substance P, chemokines, neurotrophic factors, histamine, prostaglandins, leukotrienes, serotonin, epinephrine, acetylcholine, protons and potassium ions. Any of these factors may stimulate the sensory neurons (nociceptors) that carry pain signals to the central nervous system (CNS; Figure I-3). There are two major types of nociceptors, unmyelinated and myelinated. Unmyelinated nociceptors are small-diameter, slow conducting C-fibers, which transmit burning or dull pain (Figure I-4). Myelinated nociceptors

Figure I-4. The two afferent nociceptive pathways with different conduction velocities. Small diameter cells contain non-myelinated C-, and thinly myelinated A-fibers, functionally and pharmacologically identified as mediating the long-lasting pain sensations. Contrary, the myelinated AS-fiber transmits the initial sharp-like pain sensations

Figure I-4. The two afferent nociceptive pathways with different conduction velocities. Small diameter cells contain non-myelinated C-, and thinly myelinated A-fibers, functionally and pharmacologically identified as mediating the long-lasting pain sensations. Contrary, the myelinated AS-fiber transmits the initial sharp-like pain sensations are medium to large diameter, fast-conducting AS-fibers, which sense prickling pain. Both types of nociceptor carry pain signals from the peripheral site of injury and synapse on interneurons in the dorsal horn of the spinal cord. In addition to the speed of conduction, nociceptors can differ in the neurotransmitters they contain, the receptors and ion channels they express, and their capacity for sensitization during injury or disease. Approximately 70% of all nociceptors are C-fibers, while AB-fibers comprise the remaining 30%.

SIGNIFICANCE OF C-FIBERS IN PAIN TRANSMISSION

C-fibers that express TrkA (a nerve growth factor receptor) and do not bind isolectin B4 (a lectin from a shrub, Griffonio simplicifolia) project to the outermost layers of the dorsal horn (lamina l and outer lamina II). Isolectin B4-positive C-fibers project to the inner lamina II and also express fluoride-resistant acid phosphatase and P2X3

receptors. Nociceptors expressing neurokinin (NK1) receptors constitute projection neurons and are clustered in lamina I of the dorsal horn. Small diameter nociceptors that do not express NK1 receptors seem to target interneurons in lamina II.

SIGNIFICANCE OF AB-FIBERS IN PAIN MODULATION

Medium and large neurons that innervate low threshold mechanoreceptors mediate the response to tactile and vibrational stimuli via A8- and AB-fibers that synapse in laminae III-V (Figure I-5). Neurons in the dorsal root ganglion are further classified physiologically based on the type of stimuli by which they respond. In the superficial dorsal horn, nociceptive cells are unresponsive to innocuous stimuli (i.e. gentle stimulation) because of their relatively high threshold, and thus respond only to painful stimuli. In the deep dorsal horn, a wide range of neurons responds to both innocuous and noxious stimuli. Some information is also carried in parallel by myelinated AB-fibers, which are responsible for relaying sensations of touch [10].

Transmission of Pain with Different Qualities

Already at the periphery where stimulation of nociceptors is induced by the trauma, an inhibitory activity will come into play, affecting the advanced transmission along the selective pain tract. At the peripheral site selective pain receptors are only excited once serotonin and prostaglandin are present. The excitatory substance bradykinin promotes prostaglandin synthesis, which explains why a lowered pain threshold is present in inflamed areas. Subsequent pain afference can be differentiated into distinct qualities of pain:

1. A superficial sensation of pain with a piercing-like, intense, short and well localized quality.

2. A secondary type of pain with a delayed temporal quality. It is of longer duration, has a dull quality and can hardly be localized.

3. Pain from the viscera is of dull and of colic-like nature. It is difficult to localize and is accompanied by vegetative sensations.

4. Deep-sited pain from the subcutaneous areas like muscles, joints, and bones. It is dull and radiates into the surroundings.

Such different pain qualities are mediated via two diverse nervous pathways tracks, which project to the spinal cord (Figure I-4):

• The A8-fibers with a relatively fast (15-20 m/s) conduction velocity; they mediate superficial, knife-like, and well localized pain sensations.

• The C-fibers, which result in a dull and less well localized pain quality, are characterized by a slow conduction velocity (1 m/s).

Transmission of peripheral, painful primary afferents (A8- and C-fibers) from the first order to the second order neuron (spinothalamic and spinoreticularis tract) occur in the posterior column of the spinal cord. In the substantia gelatinosa, fast A8-fibers terminate in the lamina II, III and IV (Figure I-5); the slow C-fibers end in the Lamina I and II of the spinal cord [13].

The relevant transmitter, which synapses at the spinal dendrites is a neuropeptide called substance P. Substance P is an undecapeptide consisting of 11 amino acid sequences, which can also migrate retrograde to peripheral terminals, resulting in a local irritation with swelling and reddening of the skin. Transduction from the first order to the second order neuron is an important center, where facilitation, modulation, sensitization, and decision-making of all incoming painful stimuli take place (Figure I-5). There sensory afferents are collected from different segments, being integrated and modulated. Repetitive stimuli result in lowering of action potential thresholds with a prolonged and enhanced after

Figure 1-5. Substance P, an undecapeptide and a member of the tachykinine family, with a molecular weight of 1346, is an important neurotransmitter and neuromodulator in pain processing at the periphery and the spinal cord, which binds to the NKi-receptor. Through stimulation of wide-dynamic range neurons (WDR), additional excitatory cells are recruited resulting in an increased area of pain

Figure 1-5. Substance P, an undecapeptide and a member of the tachykinine family, with a molecular weight of 1346, is an important neurotransmitter and neuromodulator in pain processing at the periphery and the spinal cord, which binds to the NKi-receptor. Through stimulation of wide-dynamic range neurons (WDR), additional excitatory cells are recruited resulting in an increased area of pain discharge (spinal sensitization with primary hyperalgesia) and an activation of prior dormant wide-dynamic range (WDR) receptors (Figure I-5). Peripherally this is characterized by a lowering in pain threshold, an increased sensitivity to threshold stimuli with evolving spontaneous pain, resulting in a larger areas of hyperalgesia and allodynia that surround the primary site of injury (secondary hyperalgesia).

Substance P, a Mediator of Pain and a Member of the Tachykinin Family

The spinal cord also is the area where the reticulospinalis tract projects (corti-cospinalis tract), which descends down from higher cortical areas, using serotonin or noradrenaline (serotinergic tract) as transmitter substances.

At the spinal relay station local endorphinergic interneurons with their transmitters endorphin, and enkephalins, inhibit ascending afferences, resulting in an increase of pain threshold (Figure I-6). It is the area where the enkephalins inhibit the release of substance P as well as other excitatory transmitters such as glutamate or the "calcitonin gene-related peptide" (CGRP), resulting in a reduction of transduction. Also, in response to an inflammatory stimulus, CGRP, an important 37 amino-acid vasodilatatory peptide is released from peripheral nerve terminals, often leading to hyperalgesia. CGRP is synthesized increasingly during inflammation and

Spinal Enkephalinergic Neurons
Figure 1-6. In addition to the release of substance P in the spinal cord, there is a retrograde axonal transport, which results in an increased permeability of local vessels, and the formation of wheal and erythema in the area surrounding injury

being co-expressed with substance P at the spinal cord level, it's release can be reduced by the administration of opioids at the spinal or epidural space. This is because such agents bind to the same receptors as enkephalines, where the target cells can be found on interspinal enkephalinergic neurons (Figure I-7). Thus, the spinal cord site can be considered as an important site of communication where among others, central analgesics exert their antinociceptive action.

During pain, the ascending spinoreticularis tract projects from both sides of the spinal cord to the reticular formation as well as to the intralaminary nuclei of the right and left thalamus, resulting in an arousal reaction. In addition, there are connections to the anterior cortex, the cinguli gyrus and structures of the limbic system (nucleus amygdalae and hypothalamus). While the latter are related to the emotional (fear) and autonomic reactions (hypertension, tachycardia), the anterior cortex is linked to individual negative sensations of pain; the cingulus is accountable for the release of endogenous opioids resulting in a reduction of pain (Figure I-8). Fibers of the spinothalamic tract also project to the brain stem (medulla and mesencephalon) where it interacts with synapses of the ventero-posterior and intrathalamic nuclei of the thalamus. Thereafter, fibers from the thalamus project to the primary somatosensory area (S1 and S2) of the cortex, where fibers connect to the rear, and the parietal section of the cortex, are ending in the nucleus amygdalae, the perirhinal cortex and the hippocampal area (Figure I-8).

It is important to point out that the primary fibers of the spinothalamic tract are composed mainly of so-called "wide dynamic range" neurons and specific

Figure I-7. Antinociceptive effect of inhibitory enkephalinergic interneurons at the spinal cord level
Figure I-8. Neuroimage of relevant subcortical areas of the brain during pain using magnetic resonance imaging (MRI): Rostral and dorsal anterior cingulate cortex (rACC/dACC), thalamus and parahip-pocampal cortex (PHCP) Adapted from [14]

neuronal pain pathways. Especially during long-term irritation, there is an additional acquisition of afferent pain-related fibers and additional nociceptive afferences.

Several researchers have questioned if the specific nociceptive afferent fibers are accountable for the sensitization of pain. According to the theory by Melzack and coworkers [15], pain is the final result of an imbalance in the neuronal network distributed over the whole body. It therefore can be regarded as the ultimate result of the body's own neuromatrix and, to a lesser degree, it is the result of an injury within the sensory nervous system. This theory was confirmed in so-called phantom pain, which appears in up to 70% of patients following amputations. There cortical reorganizations by means of a mirror image of the missing extremity resulted in a significant reduction of pain. Such data underline the proposition that clinical pain is the manifestation of a modified nervous system.

In this context it has to be pointed out that insufficient reduction in pain, especially in the post-operative period, results in an increase in postoperative morbidity and mortality [16, 17, 18], followed by chronification of pain. It is imperative in order to sufficiently block the process of chronification and the accompanying nociceptive-adaptive alterations in the nervous system, to block all nociceptive afferences before the barrage of afferent stimuli arrive at the spinal cord, the brain stem, and/or subcortical pain-related centers. Once nociceptive discharges are sufficiently reduced, temporary or permanent neuronal transformations at different areas of the CNS can be eliminated.

Supraspinal Processing of Pain

Peripheral nociceptive stimulation has been shown not only to trigger spinal neuronal signaling of the ascending nociceptive system, but also supra-spinal areas are activated. From the layers I and V of the posterior column, second order neurons originate and ascend to supraspinal pain-modulating centers (Figure I-8). Via the lateral projecting neospinothalamic tract large myelinated fibers pass cephalically to the ventro-posterior-lateral-thalamic nuclei (VPL). From there axons synapse

Respiratory Depression Cascade

with third relay of fibers projecting to the somatosensory cortex (Figure I-9). The cell-bodies of the medial part of the ascending spinothalamic tract, also called the paleospinothalamic tract, originate in the deep layer of the spinal cord. They have thin fibers, project to the reticular formation, the periaqueductal gray (PAG), the hypothalamus, and the medial as well as the intralaminar thalamic nuclei. These fibers then connect with neurons of the limbic forebrain system, which thereafter project diffusely to other parts of the brain (Figure I-9). Functionally, the phylo-genetically older medial system consists of thin fibers. They lack somatotopic organization, and are of slower transit than the lateral system. They determine the level of arousal, mediate the specific unpleasant nature of pain, affect the general behavior in fostering rest, protection, and care of the damaged area. They thereby promote healing, and recuperation. The lateral system composes relatively long and thick fibers that conduct rapidly (Figure I-10). They functionally convey discriminating information, have a discrete somatotopic organization about the onset of injury, its precise location, its intensity, and duration. It quickly can bring about a response that prevents further damage.

There is evidence that the ventrobasal thalamus and the somatosensory cortex, which receive input from the rapidly conducting lateral ascending pathway, have anatomic and physiologic characteristics that permit processing of sensory discriminative information. Moreover, the reticular formation (e.g., hypothalamus, medial thalamus, and limbic system) is involved in motivational and affective features of pain. They are strategically connected to activate and influence the hypotha-lamic and the limbic forebrain systems, which are responsible for the activation of supraspinal autonomic reflex responses such as ventilation, circulation, neuroendocrine function and the motivational drive, triggering the organism into action (fight or flight reaction) while at the same time acting as a watchdog during sleep.

The myelinated fibers of the neospinothalamic tract, end in the nuclei ventrocaudalis-parvocellularis (Figure I-11). From there fibers project directly to the rear gyrus of the cerebral cortex, the somatosensory cortex, involved in the localization of the origin of pain. The somatosensory cortex shows an exact somato-topic arrangement, a reverse "homunculus" necessary for exact localization of the injury. However, more importantly in pain therapy are the endings of the unmyeli-nated fibers of the paleospinothalamic tract, which project to intrathalamic nuclei, especially to the nucleus limitans, which lies at the border of the mesencephalon and the tegmentum (Figure I-11).

The nucleus limitans and the intrathalamic nuclei are part of the non-specific projection system of the thalamus, which, via basal ganglia, project diffusely to practically to all cortical areas. The nucleus limitans mediates the alarming, timeless, <-

Figure 1-9. The ascending nociceptive pathways originating in the dorsal horn of the spinal cord, give rise to the spinothalamic tract. The trigeminal nucleus of the brainstem carries afferents from the face and the trigeminal nerve, where fibers cross and ascend to the thalamus along the trigeminal lemniscus

Figure 1-10. Origin and course of the lateral (A) and the medial (B) ascending spinothalamic tract with its different interconnections

dull, and less localizable feeling of pain ("it hurts" = identification of pain). From the nucleus limitans and the intrathalamic nuclei, fibers project to the limbic system consisting of the nucleus amygdalae, and the hippocampal area, which give pain an aggravating, negative connotation with a dysphoric component (painful emotion). The pallidum in this respect is not only a center of motor impulses; it can be considered as a psychomotor center for conscious movements transmitting the emotional, affective component of pain [19, 20]. Between both nociceptive afferents, the fast one for localization of pain and the slower system for mediating the feeling of pain, there is an inhibiting interaction. Thus, the faster conduction system is capable to inhibit the slower system within the substantia gelatinosa of the spinal cord and the thalamus, resulting in a modulatory balance among each other [19].

Figure I-11. Topography of the nucleus limitans, an important relay station in the transmission of nociceptive afferents to higher pain modulating and discriminating centers of the CNS. This area, which mediates the unspecific feeling of pain, and contrary to the adjacent nucleus ventro-caudalis, does not show a topography (homunculus). It is closely coupled with emotions and shows a dense accumulation of opioid binding sites (Nucl. vc.pc. = nucleus ventro-caudalis parvo-cellularis). Adapted from [24]

Figure I-11. Topography of the nucleus limitans, an important relay station in the transmission of nociceptive afferents to higher pain modulating and discriminating centers of the CNS. This area, which mediates the unspecific feeling of pain, and contrary to the adjacent nucleus ventro-caudalis, does not show a topography (homunculus). It is closely coupled with emotions and shows a dense accumulation of opioid binding sites (Nucl. vc.pc. = nucleus ventro-caudalis parvo-cellularis). Adapted from [24]

TRANSDUCTION OF NOCICEPTION VIA THE SPINOTHALAMIC TRACTS

The spinothalamic tracts (Figures I-9 and I-10) send fibers through the brainstem (medulla, pons) and midbrain to synapses in the ventroposterior and intralaminar nuclei of the thalamus. Projections from the thalamus finally terminate in the primary somatosensory cortex (S1 and S2 region). From the S1 and S2 regions, the pathway proceeds to the posterior parietal cortex and insular cortex, and finally to the amygdala, the perirhinal cortex and the hippocampus. It is important to note that the types of neurons originating in the dorsal horn that give rise to the spinothalamic tract are predominantly wide dynamic range neurons together with some nociception-specific neurons. These two types of neurons are important for processing different dimensions and stages of pain. Thus, the spinothalamic tract is critical not only for sensory processing of nociceptive information, but for pain affect as well.

The sensation of pain and temperature from the head and face is carried by the trigeminal nerves that synapse in the trigeminal nucleus of the brainstem. The fibers then cross and ascend to the thalamus along the trigeminal lemniscus. Recently, a new visceral pain pathway that projects in the dorsal column of the spinal cord has been identified.

While acute pain has a meaningful purpose in the framework of tissue damage, it functions as a warning signal. At the same time it is an important diagnostic tool for the physician and the pain specialist. Contrary, chronic pain is the corollary of continuous tissue damage such as a tumor or a degenerative destruction in a joint. It does not serve as a warning signal, and often it has totally lost its connection to the origin, developing into a disease of itself.

It is apparent that the mechanisms underlying the perception of pain implicate many brain regions. In the 1960s, Melzack and Wall proposed a gate theory of pain, which postulated that certain neurons in the dorsal horn that project in the spinothalamic tract are stimulated by both large diameter sensory axons and unmyelinated axons carrying the pain signal [21]. The dorsal horn projection neuron is inhibited by an interneuron that is stimulated by the large diameter sensory axons and blocked by unmyelinated pain axons. In this fashion, activity in the axon carrying the pain signal maximally stimulates the projection neurons. However, if the mechanoreceptive sensory axons fire concurrently, they cause activation of the interneuron and suppress the nociceptive signals. Another theory proposed by Melzack suggests that pain is the result of the output of a widely distributed neural network (the body's own neuromatrix), rather than being the direct result of sensory input evoked by injury [15]. The phenomenon of phantom limb pain (pain sensed from a nonexistent limb) experienced by 70% of individuals after amputation or severe nerve damage (e.g., brachial plexus transection) supports this hypothesis [22, 23].

Opioids directly affect the pain modulating and pain discriminating centers within the CNS, especially via the nucleus limitans, an accumulation of small neurons with opioid binding sites, which lie close to the nucleus ventro-caudalis-parvo-cellularis (Nucl. v-c. p-c). The nucleus limitans is responsible for the recognizing an impulse as being painful (Figure I-11). Thus, during pain therapy with an opioid, the afferent impulse may be felt; however, it has lost its aggravating, negative character and is not recognized as being painful.

THE DESCENDING ANTINOCICEPTIVE SYSTEM

Another, clearly defined and important system, that modulates nociceptive input at the spinal cord level, is the descending tract. It originates at three different locations:

1. In the periaqueductal gray of the midbrain structure and the nucleus raphe magnus of the medullary reticular formation [25].

2. At the lateral hypothalamus, where descending fibers originate

3. In the basolateral amygdalae, where an inhibitory tract originates.

All these fibers do not project directly to the dorsal horn. Some fibers project only through connection via the rostral ventromedial medulla (RVM), and the dorsolateral pontine tegmentum (DLPT). Others project via detour to the nucleus raphe magnus and the locus ceruleus from the periaqueductal gray directly to the posterior column of the spinal cord (Figure I-12).

It also had been demonstrated that the analgesic effect of both and 8-opioid ligands work in union, resulting in an activation of this descending tract. This additive/synergistic action can be observed following systemic or local injection into the central gray or the RVM. This is also the site, where Ach-receptor sites have been identified, explaining the analgesic mode of action of cholinergic agents. The neuronal cells, which project to the posterior column of the spinal cord, are of serotonergic and noradrenergic origin, (Figure I-13). Via desensitization they selectively modulate the activity of the nociceptive posterior column neurons by means of inhibitory, enkepha-linergic interneurons and a2-adrenoreceptors relay neurons [26]. Being part of the descending inhibitory fibers, the reticulospinal tract releases different neurotrans-mitters such as glutamate, aspartate, serotonin and neurotensin, all of which had been demonstrated in the periaqueductal central gray [27,28].

Finally, the substantia gelatinosa of the posterior column in the spinal cord also is the "gate-control", as originally described by Melzack and coworkers [15]. Being activated by fast acting AB-fibers projecting from mechanoreceptors of the skin, it is the relay station where other inhibitory mechanisms propagate inhibitory interneurons in the posterior column. If nociceptive action potentials from slower A8- and C-fibers hit upon these cells, their transmission is

Figure I-12. The descending inhibitory tract being activated by opioids originating in the nucleus reticularis gigantocellularis (NRGC) of the ventromedial medulla (RVM)

Lower Brain Stom

Lower Brain Stom

Images Respiratory Depression

Inhibitory

Inhibitory

Anatomy Depression
Figure 1-13. The descending, inhibitory pathways influencing afferent nociceptive input at the spinal cord and the transmitters affecting transition (sub — P = substance P; Glu = glutamate; CGRP = calcitonin gene related peptide; 5 — HT = serotonin; NE = norepinephrine)

blocked [29]. This mechanism explains the therapeutic value when pain sensations can be relieved through simultaneous tactile or thermal activation (TENS = transcutaneous electrical nerve stimulation; Figure I-14). At the same time it is also an explanation of electrical spinal cord or dorsal cord stimulation (SCS), thalamus stimulation and of electroacupuncture, all of which inhibit nociceptive afference by means of electric stimulation, also termed counter irritation therapy. Following the "gate-control" theory, ascending nociceptive impulses from A8- and C-fibers connect with the descending inhibitory efferent input of AB-fibers at the substantia gelatinosa of the spinal cord, which collects all nociceptive input. There, pain impulses are suppressed, diminishing the actual sensation of pain, a therapeutic implication being used regularly in pain treatment by different agents [30].

In summary, within the posterior column of the spinal cord, nociceptive transmission from the first to second order neuron is characterized by three independent operating inhibitory systems:

1. Descending fibers from the locus coruleus, the reticular formation, the reticulospinal tract, the nucleus raphe magnus and the periaqueductal grey. By means of a release of serotonin and norepinephrine at nerve endings of serotonergic and noradrenergic conduction pathways in the substantia gelatinosa, the sensitivity of small relay cells to nociceptive impulses is diminished (Figure I-14).

2. Inhibitory, endorphinergic interneurons in the area of the posterior column block nociceptive transmission (Figure I-14) via the release of endogenous opioids the endorphins, in particular the enkephalins.

3. Pain fibers, which project into the posterior column of the spinal cord, not only excite the second order ascending neurons of the pain tract, they also stimulate

How Neurons Fire Wdr Deep Dorsal Horn

Figure I-14. Modulation of nociceptive transmission in the dorsal horn of the spinal cord, illustrating the interaction of small pain diameter afferents and large diameter mechanoreceptors (touch) afferents, as well as its modulation by descending neurons and enkephalinergic interneurons on afferent pain pathways (5 — STH = serotonin; NE = norepinephrine)

Figure I-14. Modulation of nociceptive transmission in the dorsal horn of the spinal cord, illustrating the interaction of small pain diameter afferents and large diameter mechanoreceptors (touch) afferents, as well as its modulation by descending neurons and enkephalinergic interneurons on afferent pain pathways (5 — STH = serotonin; NE = norepinephrine)

inhibitory cells. Thus, a self-regulatory mechanism is initiated so that afferent stimuli are either facilitated or inactivating on their conduction pathway. The substantia gelatinosa of the posterior column of the spinal cord, therefore, can be considered as a main coordinator. It is the place where incoming afferents are assembled, integrated, and modulated. At the same time it is also the location where an inhibitory pain mechanism comes into play and where it is decided, if and at which intensity nociceptive afferents are being transmitted (Figure I-14). In the context of a meaningful therapy and in order to avoid the transition of acute to chronic pain and adaptation, the substantia gelatinosa plays a significant role in any therapeutic approach. Early and sufficient pain inhibition with an opioid is one of most imperative components of useful antinociceptive strategy, where the agents not only block the transmission, but also the transfer within the spinal cord. The spinal cord is the location where an effective and twofold pain management is instigated; directly through potentiation of the endogenous mechanisms of pain control through binding at local opioid receptor sites, and indirectly by means of activation of inhibitory descending pain system.

Because nociceptive afferents regularly are modulated by descending pathways originating in a. the basolatral amygdalae, b. the lateral hypothalamus, c. the periaqueductal gray, any reduced activity and/or destruction of the descending inhibitory pathways results in an increase in nociception. Especially the midbrain structure, and the periaque-ductal gray, inhibit either directly the pain signals at the neurons of the dorsal horn or indirectly via the raphe magnus nucleus of the medullary reticular formation and via the rostral ventromedial medulla (RVM) all of which project to the spinal cord. Both the serotonergic input from raphe nuclei and the noradrenergic input from the locus ceruleus modulate the output of layer II of the spinal cord by synapsing onto the inhibitory enkephalin neurons of the dorsal horn (Figure I-15). Norepinephrine released from descending fibers act through a2-adrenoceptors, which in return decrease the sensitivity of dorsal horn relay neurons to noxious stimuli This is also the location where a2-agonists, when given epidurally, potentiate the effects of opioids such as morphine. Furthermore, agonists at the ^-opioid receptors activate neurons in the periaqueductal gray and rostral ventral medulla by reducing GABAminergic inhibition. In addition, there is a release of a brain-derived neurotrophic factor, which appears to be an endogenous modulator of painful responses in the dorsal horn, and may also contribute to sensory hypersensitivity, especially associated with inflammatory pain.

Descending

To bratn

Dorsal horn neuron

Luual

; Descending

To brain

Exaggerate pain response

IJJXI

To brain

Innocuous or ■toxious stimulus

Exaggerate pain response

\> Excitatory synapse > Inhibitory synapse

Figure I-15. Schematic representation of insufficient activity of the descending inhibitory pathway compared to control, resulting in an exaggerated response to all incoming nociceptive stimuli at the spinal cord level

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