Neurophysiology of Pain Type of Receptor Sites Involved in Therapy

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Trauma and damage at the periphery results in inflammation and/or damage of cells, resulting in the release and the formation of so-called nociceptive substances, which activate peripheral nociceptor sites (Figure I-16):

1. Formation of free oxygen radicals (ROS = reactive oxygen species) like peroxides, and nitric oxide (NO),

2. release of prostanoids (prostaglandin D, E, F, I, leukotrienes), thromboxane,

3. formation of purines (adenosine, ATP),

4. release of tachykinins (substance P, neurokinin A, B),

5. increase in the level of kinine (bradykinin, kallidin, T-kinin) as well as

6. increase in local acidity by a rise in H+- and K+-protons.

All these tissue-damaging mediators are co-expressed simultaneously. They have been termed "inflammatory soup", which not only maintains the inflammatory process but also results in the initiation of nociception. Within this group prostaglandin E2 (PGE2) holds a superior position, because this substance must be present before any activation and sensitization of peripheral nociceptors by other neurotransmitters induces nociceptive sensations. In addition to these algogenic substances, other transmitters like:

• acetylcholine,

• bradykinin also directly affect peripheral afferent nociceptors resulting in the painful sensations. While histamine can only cause pain sensation in relatively high concentrations,

ATP —

TTXr-Na+ (SNS/NaN)

PGE2 —

EP

-

PKA Peripheral

NGF —

rrk;

Terminal

H+

ASIC

VKI

---

Heat

MOR

Figure I-16. Schematic representation of main peripheral nociceptors activated by various tissue-damaging stimuli resulting in a nociceptor activation (ATP = adenosinetriphosphate; P = purine/pyrimidine receptor; EP = prostanoid receptor; NGF = nerve growth factor; H+ = acidity; VRI = vanilloid receptor activated by heat, capscaicin; TrkA = tyrosine receptor kinase A; TTXr — Na+ = tetrodoxin-resistant sodium channel; ASIC = amiloride sensitive proton channel, activated by low pH; MOR = morphine; PKA = protein kinase A)

Figure I-16. Schematic representation of main peripheral nociceptors activated by various tissue-damaging stimuli resulting in a nociceptor activation (ATP = adenosinetriphosphate; P = purine/pyrimidine receptor; EP = prostanoid receptor; NGF = nerve growth factor; H+ = acidity; VRI = vanilloid receptor activated by heat, capscaicin; TrkA = tyrosine receptor kinase A; TTXr — Na+ = tetrodoxin-resistant sodium channel; ASIC = amiloride sensitive proton channel, activated by low pH; MOR = morphine; PKA = protein kinase A)

acetylcholine sensitizes the pain receptors through other mediators already being present in low concentrations.

TRANSDUCTION OF NOCICEPTIVE AFFERENCES VIA ASCENDING PATHWAYS

All peripherally-induced painful stimuli initiate action potentials, which are transmitted to the dorsal horn (lamina l and deep layers V-VI; Figure I-14). From there they ascend to higher cortical areas via two ascending pathways. The spinoreticular tracts ascend on both sides of the spinal cord via the reticular formation and terminate in the intralaminar nuclei of the right and left thalamus. The spinoreticular tracts are responsible for the general arousing effects of pain. They may also influence the perception of pain through their innervation of the anterior cingulate cortex, insular cortex, as well as other structures of the limbic system, such as the amygdala and hypothalamus. The limbic system is implicated in the emotional aspects of pain, with the central nucleus of the amygdala strongly involved in fear and autonomic responses to stress, and the cingulate cortex acting as a center for endogenous opioid activation specific to negative pain affect.

DIFFERENT THERAPEUTIC APPROACHES IN PAIN THERAPY

The most widely used medications for pain management have been opioids with morphine as its prototype (isolated in 1803), and non-steroidal anti-inflammatory drugs, where aspirin (developed in 1899) is a prototype agent (Figure I-17). In addition, a variety of non-specific agents such as anticonvulsants, and antidepres-sants are also part of the therapeutic armamentarium.

Because neuropathic pain in general is insensitive to morphine and other opioid drugs, it is best managed by antidepressants and anticonvulsants. Non-steroidal anti-inflammatory drugs (NSAIDs) are not only ineffective at ameliorating severe pain, but also produce gastrointestinal side effects and increase bleeding time. Drugs that are at least partially effective in ameliorating pain involve a wide range of compounds affecting different neurotransmitter systems. Receptors modulated by these compounds are often expressed in both the peripheral and central nervous systems. Pain research is currently targeting a complex system of receptors, ion channels and their modulators in an effort to identify newer, safer methods of alleviating pain. Some of the latest research in pain therapy involves the areas of COX inhibitors, bradykinins, opioids and a variety of neuropeptides, such as melanocortins, cholecystokinins, tachykinins, calcitonin gene-related peptide and galanin. Also, the cannabinoid system and vanilloid receptors and their modulators, recently have generated much excitement in the field of pain research. This is followed by modulators of sodium, potassium and calcium channels, P2 receptors, ionotropic glutamate receptors and finally nicotinic acetylcholine receptors, all of

Analgesics

"central analgesics" (opioids)

"peripheral analgesics" (antipyretics)

Y i

f

r ▼

Agonist/ Antagonists

Pentazocine Nalbuphine Butorphanol

Dezocine

Agonists

Methadone Sufentanil Fentanyl Remifentanil Alfentanil Morphine Pethidine Hydromorphone Levorphanol

Agonist/ Antagonists

Pentazocine Nalbuphine Butorphanol

Dezocine

Partial Agonists

Buprenorphine Meptazinol

Partial Agonists

Buprenorphine Meptazinol

Nonacetic

Acetic Acid

Acid

Derivative

Derivative

(NSAIDs)

Diclofenac

Aniline

Ibuprofen

Pyrazolone

Salicylates

derivatives

(ASA)

Figure I-17. Overview of analgesics administered in the treatment of pain which present other potential therapeutic targets while adjuvant analgesics complete the potential armamentarium in the pharmacology of pain relief.

SIGNIFICANCE OF BRADYKININS IN INFLAMMATORY PAIN

Several kinins, notably bradykinin, kallidin and T-kinin, are involved in inflammation and visceral pain. Bradykinin induces inflammation in part through the receptor-independent release of histamine and serotonin from activated mast cells. B1 and B2 receptors are localized in nociceptive parthways and contribute to inflammation and neuropathic hyperalgesia. B1 receptors are absent in healthy tissue and their expression is evoked by tissue injury or by cytokines, such as tumor necrosis factor a (TNFa), and interleukin 16 (IL-16). The B2 receptor agonist [des-Arg9]-bradykinin produces hyperalgesia that can be blocked by the B1 receptor antagonist [des-Arg'O] HOE-140. B2 receptors are expressed on nociceptors and in central and peripheral sensory ganglia. They appear to be involved in the chronic phases of the inflammation and pain response. Local increase in concentrations at the bradykinin B1- and B2-receptors have demonstrated to be involved in local inflammatory pain and in the development of a late neuropathic painful syndrome with hyperalgesia. While the B1-receptor normally is not present in normal tissue, it is only after tissue damage or an inflammation-related release of cytokines, especially of the tumor necrosis factor (TNFa) and interleukin 16 (IL-16), that this receptor is being expressed. The B2-bradykinin receptor on the other hand has been identified in peripheral as well as central ganglia. This receptor specifically is involved in the chronic inflammatory pain. Following B2 bradykinin receptor activation, the inflammatory response involves the activation of protein kinase C, which in turn increases COX-2 activity and the production and release of PGE2. Thus, the development of B1, and B2 bradykinin receptor antagonists may yield novel remedies for inflammatory pain. Following B2-receptor activation, intracellular protein kinase C (PKC) initiates an increase of the formation of cyclooxygenase-2 (COX-2) and release of prostaglandin E2 (PGE2). PGE2 especially by itself is ineffective. Only in combination with other mediators does it initiate a painful stimulus. Serotonin also is a transmitter, which holds a central role among all other nociceptive mediators.

COX INHIBITORS IN THE ALLEVIATION OF PAIN

Peripheral nociceptors, sensitive to prostaglandins and other mediators, are not specifically qualified receptors but simple nerve endings. Only by means of pressure on the sensitive nerve fiber ending over a specific threshold, is activation initiated. In chronic tissue injury, or repetitive noxious stimuli however, the nerve endings assume the property of true receptors. Via formation of intracellular cyclic aminomonophosphate (cAMP) they are involved in the area-specified sensitization and hyperalgesia in tissue damage, and during inflammation there is an increased formation of prostanoids. Prostaglandin E2-synthesis has a significant effect on the initiation of chronic persistent pain. However, prostanoids do not excite the nociceptors directly. Via sensitization, other mediators now manifest an increase in their activity. On the other hand, by means of PGE2-activation, additional sodium-channels are being generated, resulting in an increase in depolarization and transmission of nociceptive signals. While all local anesthetics such as lidocaine or procaine can block the activated sodium-channels, inhibition of prostaglandin synthesis by means of cyclooxygenase inhibition (COX-1,2-inhibition) represents an imperative analgesic principle that should earn special attention in all peripherally conditioned painful syndromes.

The enzyme cyclooxygenase (COX) is involved in the production of prostanoids, such as prostaglandin PGE2, which induces inflammation and sensitizes nociceptors, thus contributing to acute pain and hyperalgesia (Figure I-18). Two isoenzymes that have been identified, COX-1 and COX-2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the main targets of NSAIDs. COX-1 is considered to be constitutive, meaning that the activity of this enzyme is necessary for normal physiologic functions. COX-2 is considered to be inducible and has been shown to be overexpressed during inflammation and neuropathy. NSAIDs, such as aspirin, non-selectively inhibit both COX-1 and COX-2, and the relative selectivity for these isoenzymes varies across the other NSAIDs. Thus, in addition to inducing analgesic and anti-inflammatory effects mediated by inhibition of COX-2, use of drugs, such as aspirin, also leads to gastrointestinal and hematologic side effects, which are mediated predominantly by COX-1. Contrary, agents like refecoxib (Vioxx®, now withdrawn worldwide), celecoxib (Celebrex®) and the prodrug parecoxib (Dynastat®), which is changed intermediary to the active agent valdecoxib, demonstrate high COX-2 selectivity. This is of importance because those agents are largely devoid of the typical NSAID side effects, as COX-1 activity

Figure 1-18. The action of non-steroidal anti-inflammatory drugs (NSAIDs) is to inhibit the cascade after peripheral tissue damage. COX enzymes attached to the cell wall, lead to the production of prostaglandins, which result in pain and inflammation. NSAIDs enter the cell where an inhibitory portion detaches and then binds to COX enzymes, blocking the site of receptor binding. The enzyme is then unable to bind to the cell wall resulting in lesser prostaglandin synthesis followed by an inhibition of pain signals

Figure 1-18. The action of non-steroidal anti-inflammatory drugs (NSAIDs) is to inhibit the cascade after peripheral tissue damage. COX enzymes attached to the cell wall, lead to the production of prostaglandins, which result in pain and inflammation. NSAIDs enter the cell where an inhibitory portion detaches and then binds to COX enzymes, blocking the site of receptor binding. The enzyme is then unable to bind to the cell wall resulting in lesser prostaglandin synthesis followed by an inhibition of pain signals is not inhibited. On the basis of selectivity, the constitutive formation of COX-1 is still possible so that the otherwise common side effects like gastrointestinal ulcerations, hematologic side effects, and renal function impairment, especially in long-term therapy, are minimized. Recently a COX-3 isoenzyme has been identified which appears to be expressed in canine and human cortex and is selectively inhibited by analgesic antipyretic drugs, such as acetaminophen, phenacetin, antipyrine and dipyrone, as well as all other NSAIDs [31], although this notion is still controversial.

THE OPIOID RECEPTOR SYSTEM - MAIN TARGET IN PAIN THERAPY

The endogenous opioid system has a functional role in modulating pain perception and agonists, which bind at G-protein-coupled opioid receptors are potent analgesics. However, opioid receptors are also present in various other locations of the central nervous system where opioid ligands affect other functions of the body. In the hypothalamus they influence temperature regulation and control of hormonal secretion. In the brainstem they are involved in the control of respiration, blood pressure and heart rate. In the forebrain, the endogenous ligands for the opioid receptor are implicated in behavioral reinforcement and they appear to play a role in anxiety and in the expression of emotions. In addition, opioid receptors influence gastrointestinal and autonomic nervous system functions. But most of all, opioid receptors are involved in the transmission of nociception where they represent an imperative part in the strategy of survival.

Opioid peptides are the natural ligands of the opioid receptor, where enkephalin (derived from proenkephalin), dynorphin (derived from prodynorphin) and 6-endorphin (derived from pro-opiomelanocortin) - all appear to modulate pain pathway inputs. They are found in limbic structures, the hippocampus, nucleus of the stria terminalis, the hypothalamus, as well as striatum, substantia nigra, raphe nuclei, pontine-periaqueductal gray (PAG) and the spinal cord. Enkephalins bind predominantly to 8-receptors, the dynorphins have preferential affinity for K-receptors, but also bind to and 8-receptors. Another endogneous ligand, 6-endorphin activates both and 8-receptors, but has little affinity at K-binding site. Recently, the highly selective ^-(MOR) receptor agonists endomorphin-1 and endomorphin-2 have been identified in the dorsal horn of the spinal cord. These peptides display potent anti-nociceptive activity in animal models of neuropathic pain. Another endogenous peptide, nociceptin/orphanin FQ (N/OFQ) binds to an orphan opioid-like receptor ORL1. N/OFQ induces allodynia and hyperalgesia, and appears to be involved in PGE2-induced pain responses [50], while the endogenous peptide nocistatin antagonizes N/OFQ pain responses [32].

Recently, novel G protein-coupled receptors that are specific for sensory-neurons have been identified [33] and are activated by a peptide designated bovine adrenal medulla peptide 22 (BAM 22), which is produced by cleavage of proenkephalin A. These novel G protein-coupled receptors are expressed in the dorsal root ganglia and trigeminal ganglia in rats and humans and may play a role in the transmission of pain signals. However, unlike opioid receptors, these receptors are not blocked by the opioid antagonist naloxone.

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