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Basic pharmacoological aspects of pain acting drugs

Humans have always tried to overcome pain and it is believed that opioids and salicylates present in natural products have been used since prehistoric times, however, there are still numerous unsolved questions in the pain psysiology and pharmacology. At the peripheral level, C or A delta fibres are excited by noxious stimuli. Involved molecules are released from cellular lysis, inflamed surrounding tissues and C or A delta fibres themselves. Recently, molecular biology and genomics have led to the development of new target-selective entities for use in pain relief. A number of receptors and ion channels present in sensory neurons such as tetrodotoxin insensitive Na+ channel, capsaicin-gated i.e. vanilloid receptor 1(VR1), proton-gated or acid-sensing ion channel (ASIC) channels etc. are now under investigation as potential new analgesic drug targets. During pain transmission the first synapses are modulated by glutamate and many peptides, at the end of the peripheral nerves in the dorsal horn of the spinal cord. A lot of supraspinal sites are activated: the brain stem, the pontomesencephalic regions, the thalamic sites and the cortex. Along the way, multiple mechanisms modulate the pain transmission: Descending inhibitory controls triggered by noxious stimuli wprobably play a important role, too. Currently it is also believed that neuroplasticity plays a crucial role in the onset and maintenance of pain symptoms - including upregulation of sensory neuron-specific sodium channels and vanilloid receptors, phenotypic switching of large myelinated axons, sprouting within the dorsal horn, and loss of inhibitory neurons due to apoptotic cell death (Lai at al 2003, Brune 2002, Bolay and Moskowitz 2002). 1. Classical analgesics Classical analgesics, descibed in all pharmacology textbooks, include: (1) Opiods, the most potent analgesics acting at specific opioid receptors (mu, delta and kappa, and sigma receptors, too). (2) Antipyretic analgesics, which may be further divided into the aspirin-derived (acidic) nonsteroidal anti-inflammatory drugs (NSAIDs) (eg, ibuprofen) and the phenazone and acetaminophen-like (nonacidic) antipyretic analgesics (which have little anti-inflammatory activity). NSAIDs are known to act by inhibiting COX-1 and COX-2 isoenzymes to various degrees. Pharmacological actions as well as toxicity arises primarily from undesired inhibition at these enzyme sites. 2. Anticonvulsants Neuropathic pain caused by disease of the peripheral or central nervous system does not respond well to traditional pain therapies. There might be some similarities between the pathophysiological phenomena observed in some epilepsy models and in neuropathic pain. Carbamazepine, the first anticonvulsant studied in clinical trials, probably alleviates pain by decreasing conductance in Na+ channels and inhibiting ectopic discharges. Results from clinical trials have been positive in the treatment of trigeminal neuralgia, painful diabetic neuropathy and postherpetic neuralgia. Other anticonvulsant studied include: phenytoin and lamotrigine, while based mostly on preclinical experiments antihyperalgesic and antinociceptive activities are associated with phenobarbital, clonazepam, valproic acid, topiramate, pregabalin and tiagabine. In clinical trials gabapentin, as a relatively new drug ; has the most clearly demonstrated analgesic effect for the treatment of neuropathic pain, specifically for treatment of painful diabetic neuropathy and postherpetic neuralgia. According to some authors gabapentin should be considered the first choice of therapy for neuropathic pain (Tremont-Lukats at al 2000). 2. Vanilloid receptors antagonist and canabinoid receptor agonists A subset of primary sensory neurons is distinguished by their sensitivity to capsaicin the pungent principle in hot pepper. These neurons are unique in that their initial excitation by capsaicin is followed by a lasting refractory state, traditionally referred to as desensitisation. This characteristic provides capsaicin with a clear therapeutic potential in disease states, such as neuropathic pain, pruritus, and other disorders, particularly disorders of the urinary bladder in which abnormal afferent sensory information conveyed by capsaicin-sensitive nerves is a major factor in the aetiology. Capsaicin binds to capsaicin-gated ion channell, termed vanilloid receptor 1 (VR1) activated by heat or inflammation. Resiniferatoxin, is an ultrapotent capsaicin analog present in the latex of cactus like plant Euphorbia resinifera is now intensively investigated (Szallasi and Blumberg 1999.): Anandamide (and related lipid mediators) as an endocannabinoid preferentially acts on cannabinoid CB1 receptors. However, in the peripheral nervous system, CB1 is coexpressed with VR1 on a subset of unmyelinated fibres. Arguments for and against anandamide being not only endocanabinoid but an "endovanilloid", too, have been presented, but unequivocal evidence is still lacking. Tetrahydrocannibinol is CB1 receptor agonist with no activity at the VR1 receptor. Conversely, cannabidiol is an agonist of VR1 but is inactive at CB1 receptors (DiMarzo at la 2002). 3. NMDA receptor antagonists Glutamate is dominant excitatory neurotransmitter in the brain. It binds to two major classes of glutamate receptors: ionotropic and metabotropic receptors. Ionotropic receptors contain three subtype receptors, including N-methyl-d-aspartate (NMDA) receptors. N-methyl-D-aspartate (NMDA) receptors contribute to many brain functions Activation of NMDA receptors is important for initiating long-lasting changes in synapses. However, NMDA receptor antagonists which completely block NMDA receptors, widely distributed in the central nervous system, cause numerous side effects (memory impairment, halucination, ataxia, motor incoordination). The challenge has therefore been to develop NMDA receptor antagonists that prevent the pathological activation of NMDA receptors but allow their physiological activation. There is now considerable evidence that moderate affinity channel blockers, glycineB and NR2B selective antagonists show a much better profile in animal models of chronic pain than high affinity channel blockers and competitive NMDA receptor antagonists (Parsons 2001) NMDA glutamate receptors are composed of NR1, NR2 (A, B, C, and D), and NR3 (A and B) subunits, which determine the functional properties of native NMDA receptors. Among NMDA receptor subtypes, the NR2B subunit-containing receptors appear particularly important for nociception. Transgenic mice exhibited prominent NR2B expression and enhanced NMDA receptor-mediated synaptic responses in two pain-related forebrain areas, the anterior cingulate cortex and insular cortex, but not in the spinal cord (Wei at al 2001). Although transgenic and wild type mice were indistinguishable in tests of acute pain, transgenic mice exhibited enhanced responsiveness to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant. Thus drugs targeting NMDA NR2B subunits in the forebrain could serve as a new class of medicine for controlling persistent pain in humans. Ifenprodil and a group of related compounds (eliprodil, e.g. CP101606, Ro256981 and CI1041) are selective antagonists of NR2B-containing NMDA receptors. These compounds are antinociceptive in a variety of preclinical pain models and have a much lower side-effect profile compared with other NMDA receptor antagonists. (Chizh at al. 2001). Finally, low-dose ketamine infusions as addition to opioid therapy is also targeting NMDA receptors. Analgesic concentrations of ketamine are 1/5th to 1/10th the anaesthetic concentration (Camu and Vanlersberghe 2002). 4. Botulinum toxin type A (BTX-A) The mechanism BTX-A molecular action is internalization and translocation of the toxin into the presynaptic nerve terminal and proteolytic cleavage of one of the proteins essential for vesicle post-docking and fusion prior to acetylcholine release termed SNAP-25. As a consequence, the pathological musculature contraction is abolished. Due to reasons which are less well understood, nerve terminals degenerate. The neuromuscular end plate reacts with collateral sprouting of axons that restores the initial situation within a period of several months. Thus neurotoxin causes long-lasting blockade of the release of acetylcholine at the motor end plates, since cholinergic nerves are more sensitive to the toxin than other exocytic cells. In clinical use, BTX-A is injected into precisely specific muscles to cause temporary chemodenervation and therefore relief from clinical symptoms. During recent years, there has been increasing clinical evidence that BTX-A might also have analgesic properties. Aparently the toxin treatment is efficient in treating pain due to spasticity and dystonias. Moreover, BTX-A also seems to have analgesic properties in primary pain syndromes such as chronic tension type headache, migraine, neuropathic pain, low back pain and certain types of myofascial pain without obvious correlation to muscular hypercontractility. Therefore, clinical observations suggests an antinociceptive action independent of its neuromuscular junction-blocking effect. Suprisingly there is very litlle preclinical data on the analgesic effect on BTX. There is calcium dependent inhibition of substance P release from embryonic rat dorsal root ganglia neurons in vitro and the inhibition of stimulated release of calcitonin gene-related peptide (CGRP) from rat trigeminal ganglia cultures. Therefore, the exocytosis (SNAP-25) blocking activity of BTX-A might be assumed for inhibition of neuropeptide release, as it is already known for acetylcholine release at neuromuscular junction (Aoki 2001). However, to the best of our knowledge endocytosis of BTX-A in sensory neurons was never directly demonstrated. So far, there have been only few preclinical in vivo experiments related to the analgesic phenomenology of BTX-A analgesic activity. Accordingly the mechanism of this antinociceptive BTX-A action is far from clear. Therefore, there is nowadays an obvious need not only for additional clinical experiments but also for more preclinical studies on animal models of various pain conditions not only in order to define and confirm the range of indications, but also to clarify the toxin's mechanism of analgesic action to better define its role as analgesic and to provide new perspectives in management of pain.(Bach.Royetzky 2004, Relja and Telarević 1994) References: Aoki KR, Pharmacology and immunology of botulinum toxin serotypes. J Neurol 245: I/3-I/10, 2001 Relja M, Telarovic S Botulinum toxin in tension-type headache. J Neurol 25: I/12-I/14, 2004 L. Bach-Rojecky, M. Relja, Z. Lacković: Botulinum Toxin Type A in Pain Management Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci. 2001 Dec ; 22(12):636-42 Camu F, Vanlersberghe C. Pharmacology of systemic analgesics. Best Pract Res Clin Anaesthesiol. 2002 Dec ; 16(4):475-88 Parsons CG.NMDA receptors as targets for drug action in neuropathic pain. Eur J Pharmacol. 2001 Oct 19 ; 429(1-3):71-8. Wei F, Wang GD, Kerchner GA, Kim SJ, Xu HM, Chen ZF, Zhuo M.Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci. 2001 Feb ; 4(2):164-9. A. Szallasi and P.M. Blumberg , Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 51 (1999), pp. 159– 211. Di Marzo V, Blumberg PM, Szallasi A. Endovanilloid signaling in pain. Curr Opin Neurobiol. 2002 Aug ; 12(4):372-9. Tremont-Lukats IW, Megeff C, Backonja MM.Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs. 2000 Nov ; 60(5):1029-52 Lai J, Hunter JC, Porreca F.The role of voltage-gated sodium channels in neuropathic pain. Curr Opin Neurobiol. 2003 Jun ; 13(3):291-7. Brune K. Next generation of everyday analgesics. Am J Ther. 2002 ; 9(3):215-23. Bolay H, Moskowitz MA.Mechanisms of pain modulation in chronic syndromes. Neurology. ; 59(5 Suppl 2):S2-7.

pain; neuropathic pain; NMDA receptors; vanilloid receptors; cannabinoid receptor; botulinum toxin

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