Inhibition of Substance P Release Is the Key

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1 Inhibition of Substance P Release Is the Key to Successful Management of Oral Pain David B. Goodalet Numerous analgesic agents, anesthetic gases and trigeminal nucleus."2 When a ful mechanical, therapeutic methods are available to dentist for preventing or relieving oral and myofacial. In order cavity these trigeminal neurons are activated and the chemical or bacterial insult occurs within the oral to explain how relief occurs, complicated neuronal networks, metabolic pathways and multiple nerve terminal within the spinal trigeminal nucleus.' neurotransmitter "substance P" is released from drug receptor interactions have been previously proposed. At the risk of oversimplification, a single un- different groups of neurons within the central ner- This released substance P functions by activating two ified hypothesis is presented below which attempts vous system. First a series of neurons are activated to anneal these various actions and hypotheses into which convey the messages of to higher brain an understandable concept of how dentists and oral centers for conscious proprioception. Secondly, surgeons successfully manage oral. peripheral neuronal reflexes are activated which initiate the appropriate physical and autonomic reac- Sensations of are carried from the oral region by trigeminal neurons which travel to the medullary tions to the. (See Figure 1) region of the brain stem terminating within the spinal With this understanding of the basic mechanisms Control of Substance P Neurons within the Spinal Trigeminal Nucleus er Brain Centers T. Medulla Raphe Nucleus Locus Coeruleus Trigeminal Medulla I (perception) Spinal Cord I Figure 1 tuniversity of Iowa, College of Dentistry, Iowa City, Iowa JULY-AUGUST

2 TABLE 1 involved in oral, analgesic agents must neurochemically interfere with the transmission of ful messages by substance P to the spinal neurons conveying the messages to higher brain centers. This role of substance P in transmission has been substantiated by experiments in rats when capsaicin, a compound that releases substance P from neurons, was administered chronically by means of an intrathecal catheter.3the chronic administration of capsaicin produced a selective depletion of substance P from neurons within the brain. Because substance P was no longer present in nerves to be released by a noxious stimulus, a profound state of analgesia was produced. Thus interference with substance P neurotransmission appears to be a major mechanism of providing analgesia. Clinically, intrathecal catherization is not a viable method for managing oral. Analgesic compounds presently available interfere with sensations primarily by activating specific neuronal receptors which in turn block substance P release within the spinal trigeminal nucleus.4"5 Furthermore, each class of analgesic agent such as narcotic, aspirinlike agents, monoamines, etc. has a specific group of neurons, as does enkephalin, prostaglandin, norepinephrine, etc., through which the particular drug exerts its chemotherapeutic action. (See Table 1)6 Narcotic analgesic drugs exert their pharmacologic action through the neurons which release the opioid neuropeptides; referred to collectively as the enkephalins.7 The presence of enkephalins within the spinal trigeminal nucleus has been demonstrated by neurochemical5 and fluorescent microscopic8 methods. The trigeminal system consists not only of a descending set of neurons from the medulla,9 but in addition some enkephalin neurons are located within the spinal trigeminal nucleus itself.'0 Evidence that enkephalins have a presynaptic action on substance P neurons is essentially two fold. First, dorsal rhizotomy, which lesions primary af- Classification of Analgesic Agents Class of Analgesic Narcotic Hydromorphone Diloudid Codeine Empirin Pentozocine Taiwin Meperidine Demerol Aspirin - like Acetylsalicylic Acid Aspirin Acetaminophen Tylenol Naproxen Naprosyn Zomepirac Zomax Monoamine Clonidine Catapres Neurochemical Si#t of AcfIon (mul receptors) Prostaglandins (peripheral &* CH S receptors) Norepinsphrine (alpha receptor) lndications Chronic Moderate severe Experimental acute Addlction Liability Low i moderate Low Zimelidine Zelmid Ant iconvulsant Carbamazepine Tog retol Baclofen Lioresol Serotonin (reuplbke ihibltor) GABA ( bicuculie iaseesibive receptor) Chronic Tr igeminal neuralgia Gaseous Nitrous Oxide N20 Anxiety Low Nondrug Peptide Hypnosis Acupuncture Substance P antagonist Substance P (receptor blocker) Anxiety and 104 ANESTHESIA PROGRESS

ferent neurons entering the spinal cord, dramatically decreases the number of opiate receptors without changing the spinal concentration of enkephalin.

3 ferent neurons entering the spinal cord, dramatically decreases the number of opiate receptors without changing the spinal concentration of enkephalin." The interpretation of these experiments is that as the substance P neurons degenerate after section of the dorsal root, the enkephalin receptors on these neurons also degenerate. Since the neurons from which enkephalins are released are not damaged by this procedure, no decrease in enkephalin concentration is observed. Secondly, Jessell and Iversen5 demonstrated that various narcotic agonists would inhibit the release of substance P from slices of rat spinal trigeminal nucleus. The effect was mediated through enkephalin receptors since the inhibition was reversed by the narcotic antagonist naloxone. Furthermore, if narcotic analgesics are limited to the spinal cord by intratheal administration, a potent analgesia was produced.4 The above experiments further substantiate the spinal cord and brain stem as primary sites of action for eliciting narcotic analgesia. The narcotic receptors can be subdivided into mu, kappa, delta and sigma classes depending upon their biological activities and radioreceptor binding characteristics.7"2 Thus mu and kappa receptors mediate analgesia whereas delta and sigma receptors mediate behavioral responses. Electrical stimulation of the tooth pulp has confirmed the role of mu and kappa receptors in mediating the antinociceptive properties of narcotics.'3 A further subdivision of receptors into mu 1 receptors mediating analgesia and mu 2 and delta receptors mediating respiratory depression have suggested that future narcotic drugs may be developed which are potent analgesic agents but lack the undesirable side effect of respiratory depression. 1 Aspirin-like agents inhibit the enzyme fatty acid cyclooxyzenase and thereby block the synthesis of prostaglandins, prostacyclins and thromboxanes. 15 Initially the analgesic properties of aspirin-like drugs were attributed solely to a peripheral site of action. 16 More recent studies have indicated an important analgesic action of the salicylates within the central nervous systems.'7 Several prostaglandins are formed within the central nervous system and this formation is not influenced by enkephalins. '8Although the presence of prostaglandins within the brain has been established the prostaglandin neuronal system will have to remain hypothetical due to the lack of sophisticated localization and neurochemical distribution studies. Nevertheless, inhibition of prostaglandin synthesis within the tooth pulp'9 as well as within the spinal trigeminal nucleus probably represent important mechanisms in the action of aspirinlike analgesic agents. Monoamine drugs have only recently been utilized for their analgesic properties. Two major monoamine neurons have been identified which descend to the brain stem and allow higher brain centers to control the responses to."' Thus serotonin neurons from the raphe nucleus22 and norepinephrine neurons from locus coeruleus23 have been demonstrated to inhibit incoming nociceptive signals by a presynaptic activity in the spinal trigeminal nucleus. Furthermore, serotonin has been found to specifically block the responses to substance P on spinal neurons.24 Monoamine and enkephalin neurons are closely related within the brain. Opioid drugs can stimulate both the descending serotoninergic and noradrenergic to elicit additional spinal analgesic activity.2' In addition, lesions of the raphe25 and locus coeruleus26 partially block the analgesic activity of morphine. Thus, narcotic agents elicit analgesia by interacting with enkephalin receptors at both spinal and supraspinal levels to induce a more profound level of relief than is possible with alternative analgesics.27 Clonidine, a sympathomimetic antihypertensive agent has recently been shown in rats and primates to elicit analgesia.28'29 Furthermore, alpha noradrenergic receptors appear to mediate the spinal antinociceptive actions.30 The neurochemical mechanism for clonidine producing the analgesia has been shown in Figure 1 to be a presynaptic inhibition of substance P release. However, clonidine could also be eliciting analgesia by presynaptically inhibiting a noradrenergic system which facilitates nociception. Further clinical trials will be needed to determine the utility of noradrenergic agonists for providing oral analgesia. Many studies have demonstrated the importance of the descending serotonergic system for providing analgesia Zimelidine is an inhibitor of serotonin neuronal uptake and thereby increases serotonin concentration within the synaptic cleft. Clinical studies have shown zimelidine to be an effective inhibitor of chronic when compared to placebo. 'These initial clinical studies are encouraging for the future use of serotonergic analgesic agents in the chronic syndromes. Carbamazepine is an antiepileptic drug which along with phenytoin (Dilantin) has been found to provide analgesia in 70% of patients with trigeminal neuralgia.32 Although the mechanism of action of antiepileptic compounds is still poorly understood, recent research has suggested their action may be mediated through the gamma-aminobutyric acid (GABA) neuronal system.3 Baclofen is an analogue of GABA which is more properly referred to as an antispasmotic, indicating its usefulness for the treatment of spasticity in patients with multiple sclerosis.'5 Similar to other GABA-mimetic agents,' baclofen has experimentally been shown to be an analgesic.28 In addition, pilot studies have indicated baclofen to be effective in relieving the associated with trigeminal neuralgia. Like carbamazepine, baclofen blocks excitatory synaptic potentials within the spinal trigeminal nucleus35'36 which would occur after GABA inhibition JULY-AUGUST

4 of substance P release.37 The inhibitory presynaptic GABA receptor on nerve terminals has been described as a bicuculline insensitive receptor38 which is in agreement with studies indicating that the baclofen analgesia is not reversed by this GABA receptor antagonist.28 Nitrous oxide has been found to induce a low level of analgesia which is reversible by the narcotic antagonist naloxone.3940 Similarly, the analgesia induced by acupuncture4' or hypnosis,42 has also been found to be a naloxone-reversible analgesia.43 Thus the analgesia induced by these procedures apparently results from the activation of the endogenous enkephalin neuronal system which in turn inhibits substance P release. In summary, inhibition of substance P has been demonstrated or proposed to be the important neurochemical event through which presently available analgesic agents successfully relieve oral. Pharmaceutical companies realizing these basic pharmacological mechanisms of action are feverishly attempting to develop substance P receptor antagonists which will selectively and completely block oral. Very recent reports of substance P antagonists45'46 have already appeared and may well prove to be the dawning of a new era in the successful management of oral. REFERENCES 1. Nicoll R A Schenker C and Leeman S E Substance P as transmitter candidate. Ann Rev Neurosci 3: , a 2. Goodale D B The role of substance P in simultaneously mediating oral and inflammation. Anesth Prog 28:41-43, 3. Yaksh T L Farb D H Leeman S E and Jessell T M Intrathecal capsaicin depletes substance P in the rat spinal cord and produces prolonged thermal analgesia. Science 206: , Yaksh T L and Rudy T A Analgesia mediated by a direct spinal action of narcotics. Science 192: , Jessell T M and Iversen L L Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature 268: , Melmon K L and Morrelli H F Clinical Pharmacology. York, MacMillan Co, New 7. Snyder S H and Childers S R Opiate receptors and opioid peptides. In Cowan W M Hall Z W and Kandel E R (eds) Annual Review of Neuroscience Vol 2 Palo Alto CA Annual Reviews Inc, 1979, pp Cuello A C Fiacco M D and Paxinos G The central and peripheral ends of the substance P-containing sensory neurones in the rat trigeminal system. Brain Res 152: , Hokfelt T Terenius L Kuypers H G J M and Dann 0 Evidence for enkephalin immunoreactive neurons in the medulla oblongata projecting to the spinal cord. Neurosci 14:55-60, Del Fiacco M and Cuello A C Substance P and enkephalin - containing neurones in the rate trigeminal system. Neurosci 5: , LaMotte C Pert C B and Snyder S H Opiate receptor binding in primate spinal cord: distribution and changes after dorsal root section. Brain Res 112: , Chang K J Hazum E and Cuatrecasas P Possible role of distinct morphine and enkephalin receptors in mediating actions of benzomorphan drugs (putative K and o agonists). Proc Natl Acad Sci 77: , Shingle M and Tyers M B Further studies on opiate receptors that mediate antinociception: tooth pulp stimulation in the dog. Brit J Pharmacol 70: , Pasternak G W Opiate, enkephalin, and endorphin analgesia: relations to a single subpopulation of opiate receptors. Neurology 31: , 15. Gilman A G Goodman L S and Gilman A (eds) The Pharmacological Basis of Therapeutics, 6th Ed New York, MacMillan Publishing Co Inc, Lim R K S Guzman F Rodgers D W Gotto K Braun C Dickerson G D and Engle R J Site of action of narcotic and nonnarcotic analgesics determined by blocking bradykinin-evoked visceral. Arch int Pharmacodyn 152:25-58, Ferreira S H Lorenzetti B B and Correa F M A Central and peripheral antialgesic action of aspirin-like drugs. Europ J Pharmacol 53:39-48, Vincent J E Zijlstra F J and Dzoljic M R Formation of prostaglandins in rat brain. Lack of effect of enkephalin. In Samuelsson B Ramwell P W and Paoletti R (eds) Advances in Prostaglandin and Thromboxane Research, Vol 8 New York Raven Press, Hirafuji M Satoh S and Ogura Y Prostaglandins in rat pulp tissue. J Dent Res 59: , Hodge, C J Woods C I and Delatizky J Noradrenalin, serotonin and the dorsal horn. J Neurosurg 52: , Yaksh T L Direct evidence that serotonin and noradrenaline terminals mediate the spinal antinociceptive effects of morphine in the periaqueductal gray. Brain Res 160: , Sessle B J Hu J W Dubner R and Lucier G E Functional properties of neurons in cat trigeminal subnucleus candalis (Medullary dorsal horn). II. Modulation of responses to noxious and nonnoxious stimuli by periaqueductal gray, nucleus raphe magnus, cerebral cortex, and afferent influences, and effect of naloxone. J Neurophysiol 45:193, 23. Sasa M Fujimoto S Igarashi S Munekiyo K and Takaori S Microiontophoretic studies on noradrenergic inhibition from lucus coeruleus of spinal trigeminal nucleus neurons. J Pharmacol Exp Ther 210: , Davies J E and Roberts M H T 5-Hydroxytryptamine reduces substance P responses on dorsal horn interneurones: a possible interaction of neurotransmitters. Brain Res 217: , 25. Proudfit H K Effects of raphe magnus and raphe pallidus lesions on morphine-induced analgesia and spinal cord monoamines. Pharmacol Biochem & Behav 13: , Sasa M Munekiyo K Osumi Y and Takaori S Attenuation of morphine analgesia in rats with lesions of the locus coeruleus and dorsal raphe nucleus. Europ J Pharmacol 42:53-62, Yeung J C and Rudy T A Multiplicative interaction between narcotic agonisms expressed at spinal and supraspinal sites of antinociceptive action as revealed by concurrent intrathecal and intracerebro-ventricular injections of morphine. J Pharmacol Exp Ther 215: , Yaksh T L and Reddy S V R Studies in the primate on the analgetic effects associated with intrathecal actions of opiates, adrenergic agonists and baclofen. Anesthesiology 54: , 29. McCleary P E and Leander J D Clonidine analgesia and suppression of operant responding: dissociation of mechanism. Europ J Pharmacol 69:63-69, ANESTHESIA PROGRESS

5 30. Kuraishi Y Harada Y and Takagi H Noradrenaline regulation of transmission in the spinal cord mediated by x-adrenoceptors. Brain Res 174: , Johansson F von Knorring L Sedvall G and Terenius L Changes in endorphins and 5-hydroxyindoleacetic acid in cerebrospinal fluid as a result of treatment with a serotonin reuptake inhibitor (Zimelidine) in chronic patients. Psychiatry Res 2: , Bayer D B and Stenger T G Trigeminal neuralgia: an overview. Oral Surg 48: , Simmonds M A Distinction between the effects of barbiturates, benzodiazepines and phenytoin on responses to -aminobutyric acid receptor activation and antagonism by bicuculline and picrotoxin. Brit J Pharmacol 73: , 34. Hill R C Maurer R Buescher H H and Roemer D Analgesic properties of the GABA-minetic THIP. Europ J Pharmacol 69: , 35. Fromm G H Chattha A S Terrence C F and Glass J D Role of inhibitory mechanisms in trigeminal neuralgia. Neurol 31: , 36. Davies J Selective depression of synaptic excitation in cat spinal neurones by baclofen: an iontophoretic study. Brit J Pharmacol 72: , 37. Torrens Y Beaujouan J C Besson M J Michelot R and Glowinski J Inhibitory effects of GABA, L-glutamic acid and nicotine on the potassium-evoked release of substance P in substantia nigra slices of the rat. Europ J Pharmacol 71: , 38. Bowery N G Hill D R Hudson A L Doble A Middlemniss D N Shaw J and Turnbull M (-) Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283:92-94, Yang J C Clark W C and Ngai S H Antagonism of nitrous oxide analgesia by naloxone in man. Anesthesiology 52: , Berkowitz B A Finck A D and Ngai S H Nitrous oxide analgesia: reversal by naloxone and development of tolerance. J Pharmacol Exp Ther 203: , Chung S H and Dickenson A Pain, enkephalin and acuptuncture. Nature 283: , Olness K Wain H J and Ng L A pilot study of blood endorphin levels in children using self-hypnosis to control. Devel Behav Ped 1:187, Sjolund B H and Erksson M B E The influence of nialoxone on analgesia produced by peripheral conditioninig stimulation. Brain Res 173: , Frid M and Singer G Hypnotic analgesia in conditions of stress is partially reversed by naloxone. Psychopharmacol 63: , Folkers K Horig J Rosell S and Bjorkroth U Chemical design of antagonists of substance P Acta Phvsiol Scand 111: , 46. Holmdahl G. Hakanson R Leanders S Rosell S Folkers K and Sundler F A substance P antagonist [D-Pro2, D-Trp79] SP, inhibits inflammatory responses in the rabbit eve. Science 214: , SCIENTIA OM DOLOBEM VINCII JULY-AUGUST

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