Abstract
During the past fifteen years, a variety of evidence has accumulated which is consistent with the Brodie and Shore (1957) hypothesis that serotonergic neurons in the central nervous system serve a tropotrophic role (Hess, 1954) in inhibiting an animal’s response to diverse arousing stimuli (Harvey et al., 1975). This role for serotonin is, perhaps, most thoroughly documented in studies dealing with an animal’s responsé to painful stimuli. The results of numerous studies suggest that decreases in serotonergic activity result in hyperalgesia while increases produce analgesia (Harvey et al., 1975; Mayer and Price, 1976; Messing and Lytle, 1977). Thus one can assume that painful stimuli normally lead to increased activity within the serotonergic system which partially inhibits or diminishes the intensity of the nociceptive reflex. This view of the role of serotonin in determining an animal’s response to painful stimuli has resulted from the application of a wide variety of techniques for altering serotonergic function in the central nervous system and for assessing pain sensitivity. Such a convergent approach is important, since no single technique can be relied on to produce an alteration in serotonergic function without also having additional effects, some of which are known and others yet to be discovered. Similarly, since pain is not a unitary phenomenon, there is no a priori reason for assuming that serotonin should have an equivalent inhibitory effect on all nociceptive reflexes. In fact, since different nociceptive reflexes involve different portions of the central nervous system, it would be more surprising if some form of selectivity did not exist. Most investigators, including ourselves, have sometimes ignored these caveats by placing too great a reliance on a single procedure for altering serotonergic function or for assessing pain sensitivity. As a result the precise role of serotonin in determining an animal’s response to painful stimuli has recently been obscured by conflicting conclusions and apparently contradictory data. Accordingly, this paper will review the evidence concerning the role of serotonin in nociception, with special attention given to the means employed for altering serotonergic function and assessing pain sensitivity.
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References
Agid, Y., Javoy, F., Glowinski, J., Bouvet, D., and Sotelo, C., 1973, Injection of 6-hydroxydopamine into the substantia nigra of the rat. II. Diffusion and specificity, Brain Research, 58: 291–301.
Björklund, A., Baumgarten, H. G., and Rensch, A., 1975, 5,7dihydroxytryptamine: improvement of its selectivity for serotonin neurons in the CNS by treatment with desipramine, Journal of Neurochemistry, 24:833–835.
Bläsig, J., Reinhold, K., and Herz, A., 1973, Effect of 6-hydroxydopamine, 5,6-dihydroxytryptamine and raphe lesions on the entinoceceptive actions of morphine in rats, Psychopharmacologia, 31: 111–119.
Breese, G. R., and Mueller, R. A., 1978, Alterations in the neurocytoxicity of 5,7-dihydroxytryptamine by pharmacologic agents in adult and developing rats, Annals of the New York Academy of Sciences, 305: 160–174.
Brodie, B. B., and Shore, P. A., 1957, A concept for the role of serotonin and norepinephrine as chemical mediators in the brain, Annals of the New York Academy of Sciences, 66: 631–642.
Buxbaum, D. M., Yarbrough, G. G., and Carter, M. E., 1973, Biogenic amines narcotic effects. I. Modification of morphine-induced analgesia and motor activity after alteration of cerebral amine levels, Journal of Pharmacology and Experimental Therapeutics, 185: 317–327.
Carnegie, P. R., 1971, Properties, structure and possible neuro-receptor role of the encephalitogenic protein of human brain, Nature (London), 229: 25–28.
Cheney, D. L., and Goldstein, A., 1971, The effect of -chlorophenylalanine on opiate-induced running, analgesia, tolerance, and physical dependence in mice, Journal of Pharmacology and Experimental Therapeutics, 177: 309–315.
Christenson, J. G., Dairman, W., and Udenfriend, S., 1972, On the identity of DOPA decarboxylase and 5-hydroxytryptophan de-carboxylase, Proceedings of the National Academy of Science (USA), 69: 343–347.
Corrodi, H., Fuxe, K., and Schou, M., 1969, The effect of prolonged lithium administration on cerebral monoamine neurons in the rat, Life Science, (Part I), 8: 643–651.
Coscina, D. V., Warsh, J. J., Godse, D. P., and Stancer, H. S., 1974, Nonspecifícity of 5-hydroxytryptophan in repleting brain serotonin in rats with MFB lesions, Research Communications in Chemistry, Pathology, and Pharmacology, 1: 617–620.
Dennis, M., 1972, Sex-dependent and sex-independent neural control of reactivity to electric foot shock in the rat. Experimental Neurology, 37: 256–268.
Evans, W. O., 1961, A new technique for the investigation of some analgesic drugs on a reflexive behavior in the rat. Psychopharmacologia, 2: 318–325.
Fíbiger, H. C., Mertz, P. H., and Campbell, B. A., 1972, The effect of para-chlorophenylalanine on aversive thresholds and reactivity to foot shock, Physiology and Behavior, 8: 259–263.
Fuller, R. W., Perry, K. W., Snoddy, H. D., and Molloy, B. B., 1974, Comparison of the specificity of 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine and chlorimipramine as amine uptake inhibitors in mice, European Journal of Pharmacology, 28: 233–236.
Fuller, R. W., Snoddy, H. D., and Molloy, B. B., 1975, Blockade of amine depletion by nísoxetine in comparison to other uptake inhibitors, Psychopharmacology Communications, 1: 455–464.
Fuller, R. W., and Wong, D. T., 1977, Inhibition of serotonin reuptake, Federation Proceedings, 36: 2154–2158.
Fuxe, K., 1965, Evidence for the existence of monoamine neurons in the central nervous systems. IV. Distribution of monoamine nerve terminals in the central nervous system. Acta Physiologica Scandinavica, Supplementum 247: 39–85.
Fuxe, K., Butcher, L. L., and Engel, J., 1971, DL-5-hydroxytryptophan-induced changes in central monoamine/neurons after peripheral decarboxylase inhibition, Journal of Pharmacy and Pharmacology, 23: 420–424.
Fuxe, K., and Jonsson, G., 1974, Further mapping of central 5-hydroxytryptamine neurons: studies with the neurotoxic dihydroxytryptamines, Advances in Biochemical Psychopharmacology, 10: 1–12.
Fuxe, K.A Ogren, S.-E., Agnati, L. F., Jonsson, G., and Gustafsson, J.-X., 1978, I5,7-dihydroxytryptamine as a tool to study the functional role of central 5-hydroxytryptamine neurons, Annals of the New York Academy of Sciences, 305: 346–369.
Gallager, D. W., and Aghajanian, G. K., 1976, Inhibition of firing of raphe neurones by tryptophan and 5–hydroxytryptophan: blockade by inhibiting serotonin synthesis with R0–4–4602, Neuropharmacology, 15: 149 – 156.
Garau, L., Mulas, M. L., and Pepeu, G., 1975, The influence of raphe lesions on the effect of morphine on nociception and cortical Ach output, Neuropharmacology, 14: 259–263.
Gerson, S., and Baldessarini, R. J., 1975, Selective destruction of serotonin terminals in rat forebrain by high doses of 5,7dihydroxytryptamine, Brain Research, 85: 140–145.
Gerson, S., Baldessarini, R. J., and Wheeler, S. C., 1974, Biochemical effects of dihydroxylated tryptamines on central indoleamine neurones, Neuropharmacology, 13: 987–1004.
Geyer, M. A., Puerto, A., Dansey, W. J., Knapp, S., Bullard, W. P., and Mandell, A. J., 1976, Histologic and enzymatic studies of the mesolimbic and mesostriatal serotonergic pathways, Brain Research, 106: 241–256.
Grahame-Smith, D. G., 1973, Does the total turnover of brain 5-HT reflect the functional activity of 5-HT in brain?, in: “Serotonin and Behavior,” J. Barchas and E. Usdin, eds., Academic Press, New York.
Haigler, H. J., and Aghajanian, G. K., 1974, Peripheral serotonin antagonists: failure to antagonize serotonin in brain areas receiving a prominent serotonergic input, Journal of Neural Transmission, 35: 257–273.
Haigler, H. J., and Aghajanian, G. K., 1977, Serotonin receptors in the brain, Federation Proceedings, 36: 2159–2164.
Halaris, A. E., Jones, G. G., and Moore, R. Y., 1976, Axonal transport in serotonin neurons of the midbrain raphe, Brain Research, 107, 555–574.
Harrison-Read, P. E., and Steinberg, H., 1971, Lithium-induced hypersensitivity to foot shock in rats and the role of 5hydroxytryptophan, Nature (New Biology), 232: 120–121.
Harvey, J. A., and Gal, E. M., 1974, Septal tryptophan-5-hydroxylase: divergent response to raphe lesions and para-chlorophenylalanine, Science (Washington), 183: 869–871.
Harvey, J. A., Heller, A., and Moore, R. Y., 1963, The effect of unilateral and bilateral medial forebrain bundle lesions on brain serotonin, Journal of Pharmacology and Experimental Therapeutics, 140: 103–110.
Harvey, J. A., and Lints, C. E., 1965, Lesions in the medial forebrain bundle: delayed effects on sensitivity to electric shock, Science, 148: 250–252.
Harvey, J. A., and Lints, C. E., 1971, Lesions in the medial fore- brain bundle: relationship between pain sensitivity and telencephalic content of serotonin, Journal of Comparative and Physiological Psychology, 74: 28–36.
Harvey, J. A., Schlosberg, A. J., and Yunger, L. M., 1974, Effect of p-chlorophenylalanine and brain lesions on pain sensitivity and morphine analgesia in the rat, Advances in Biochemical Psychopharmacology, 10: 233–245.
Harvey, J. A., Schlosberg, A. J., and Yunger, L. M., 1975, Behavioral correlates of serotonin depletion, Federation Proceedings, 34: 1796–1801.
Harvey, J. A., and Yunger, L. M., 1973, Relationship between terencephalic content of serotonin and pain sensitivity, in: “Serotonin and Behavior,” J. Barchas and E. Usdin, eds., Academic Press, New York.
Headley, P. M., Duggan, A. W., and Griersmith, B. T., 1978, Selective reduction by noradrenaline and 5-hydroxytryptamine of nociceptive responses of cat dorsal horn neurons, Brain Research, 145: 185–189.
Heller, A., and Harvey, J. A., 1963, Effect of CNS lesions on brain norepinephrine, Pharmacologist, 5: 264.
Heller, A., and Moore, R. Y., 1968, Control of brain serotonin and norepinephrine by specific neural systems, Advances in Pharmacology, 6A: 191–206.
Hess, W. R., 1954, “Diencephalon, Autonomic and Extraphyramidal Functions,” Grune and Stratton, New York.
Ho, A. K. S., Loh, H. H., Craves, F., Hitzemann, R. J., and Gershon, S., 1970, The effect of prolonged lithium treatment on the synthesis rate and turnover of monoamines in brain regions of rats, European Journal of Pharmacology, 10: 72–78.
Hókfelt, T., Fuxe, K., and Goldstein, M., 1973, Immunohistochemical localization of aromatic L-amino acid decarboxylase (DOPA de-carboxylase) in central dopamine and 5-hydroxytryptamine nerve cell bodies of the rat, Brain Research, 53: 175–180.
Hole, K., Fuxe, K., and Jonsson, G., 1976, Behavioral effects of 5,7-dihycroxytryptamine lesions of ascending 5-hydroxytryptamine pathways, Brain Research, 107: 385–399.
Hole, K., and Lorens, S. A., 1975, Response to electric shock in rats: effects of selective midbrain raphe lesions, Pharmacology, Biochemistry, and Behavior, 3: 95–102.
Hole, K., and Marsden, C. A., 1975, Unchanged sensitivity to electric shock in L-tryptophan treated rats, Pharmacology, Biochemistry, and Behavior, 3: 307–309.
Jonsson, G., Einarsson, P., Fuxe, K., and Hallman, H., 1975, Micro- spectrofluorimetric analysis of the formaldehyde induced fluorescence in midbrain raphe neurons, Medical Biology, 53: 25–39.
Koe, K., 1976, Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain, Journal of Pharmacology and Experimental Therapeutics, 199: 649–661.
Koe, B. K., and Weissman, A., 1966, p-Chlorophenylalanine: a specific depletor of brain serotonin, Journal of Pharmacology and Experimental Therapeutics, 154:499-516.
Kuhar, M. J., Aghajanian, G. K., and Roth, R. H., 1972, Tryptophan hydroxylase activity and synaptosomal uptake of serotonin in discrete brain regions after midbrain raphe lesions: correlations with serotonin levels and histochemical fluorescence, Brain Research, 44: 165–176.
Kuraishi, Y., Harada, Y., and Takagi, H., 1979, Noradrenaline regulation of pain-transmission in the spinal cord mediated by alpha-adrenoleptors, Brain Research, 174: 333–336.
Lints, C. E., and Harvey, J. A., 1969, Altered sensitivity to foot shock and decreased brain content of serotonin following brain lesions in the rat, Journal of Comparative and Physiological Psychology, 67: 23–31.
Lints, C. E., and Harvey, J. A., 1969, Drug induced reversal of brain damage in the rat, Physiology and Behavior, 4: 29–31.
Lints, C. E., Nenja, L. H., and Miller, J. F., 1979, Stimulusdependent changes in footshock sensitivity following medial forebrain bundle lesions in the rat, Neuroscience Abstracts, 5: 613.
Lorens, S. A., Köhler, C., and Guldberg, H. C., 1975, Lesions in Gudden’s tegmental nuclei produce behavioral and 5-HT effects similar to those after raphe lesions, Pharmacology, Biochemistry, and Behavior, 3: 653–659.
Lorens, S. A., Sorenson, J. P., and Harvey, J. A., 1970, Lesions in the nuclei accumbens septi of the rat: behavioral and neurochemical effects, Journal of Comparative and Physiological Psychology, 73: 284–290.
Lorenz, H. P., Pieri, L., and Richards, J. G., 1975, Disappearance of supra-ependymal 5-HT axons in the rat forebrain after electrolytic and 5,6-DHT-induced lesions of the medial forebrain bundle, Brain Research, 100: 1–12.
Lubar, J. F., Brener, J. M., Deagle, J. H., Numan, R., and Clemens, W. J., 1970, Effect of septal lesions on detection threshold and unconditioned response to shock, Physiology and Behavior, 5: 459–463.
Lytle, L. D., Messing, R. B., Fisher, L., and Phebus, L., 1975, Effects of long-term corn consumption on brain serotonin and the response to electric shock, Science, 190: 692–694.
Margalit, D., and Segal, M., 1979, A pharmacologic study of analgesia produced by stimulation of the nucleus locus coeruleus, Psychopharmacology, 62: 169–173.
Mayer, D. J., and Price, D. D., 1976, Central nervous system mechanisms of analgesia, Pain, 2: 379–404.
Melzack, R., Stotler, W. A., and Livingston, W. K., 1958, Effects of discrete brainstem lesions in cats on perception of noxious stimulation, Journal of Neurophysiology, 21: 353–367.
Messing, R. B., Fisher, L. A., Phebus, L., and Lytle, L. D., 1976, Interaction of diet and drugs in the regulation of brain 5hydroxyindoles and the response to painful electric shock, Life Sciences, 18: 707–714.
Messing, R. B., and Lytle, L. A., 1977, Serotonin-containing neurons: their possible role in pain and analgesia, Pain, 4: 1–21.
Messing, R. B., Phebus, L., Fisher, L. A., and Lytle, L. D., 1975, Analgesic effect of fluoxetine hydrochloride (Lilly 110140), a specific inhibitor of serotonin uptake, Psychopharmacplogy Communications, 1: 511–521.
Miczek, K. A., Kelsey, J. E., and Grossman, S. P., 1972, Time course of effects of septal lesions on avoidance, response suppression and reactivity to shock, Journal of Comparative and Physiological Psychology, 79: 318–327.
Misantone, L. J., 1976, Effects of damage to the monoamine axonal constituents of the medial forebrain bundle on reactivity to foot shock and ingestive behavior in the rat, Experimental Neurology, 50: 448–464.
Moir, A. T. B., and Eccleston, D., 1968, The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles, Journal of Neurochemistry, 15: 1093–1108.
Nauta, W. J. H., 1958, Hippocampal projections and related neural pathways to the midbrain in the cat, Brain, 81: 319–340.
Nobin, A., and Björklund, A., 1978, Degenerative effects of various neurotoxic indoleamines on central monoamine neurons, Annals of the New York Academy of Sciences, 305: 305–327.
Owman, C., and Rosengren, E., 1967, Dopamine formation in blood capillariesan enzymatic blood-brain barrier mechanism, Journal of Neurochemistry, 14: 547–550.
Palkovits, M., Saavedra, J. M., Jacobowitz, D. M., Kizer, J. S., Zaborszky, L., and Brownstein, M. J., 1977, Serotonergic innervation of the forebrain: effect of lesions on serotonin and tryptophan hydroxylase levels, Brain Research, 130: 121–134.
Persip, G. L., and Hamilton, L. W., 1973, Behavioral effects of serotonin or a blocking agent applied to the septum of the rat, Pharmacology, Biochemistry, and Behavior, 1: 139–147.
Rodgers, R. J., 1977, The medial amygdala: serotonergic inhibition of shock-induced aggression and pain sensitivity in rats, Aggressive Behavior, 3: 277–288.
Schmitt, H., LeDouarec, J.-C., and Petillot, N., 1974, Antinociceptive effects of some alpha-sympathomimetic agents, Neuro-pharmacology, 13: 289–294.
Segal, D. S., 1976, Differential effects of para-chlorophenylalanine on amphetamine-induced locomotion and stereotypy, Brain Research, 116: 267–276.
Segal, M., and Sandberg, D., 1977, Analgesia produced by electrical stimulation of catecholamine nuclei in the rat brain, Brain Research, 123: 369–372.
Shaskan, E. G., and Snyder, S. H., 1970, Kinetics of serotonin accumulation into slices from rat brain: relationship to catecholamine uptake, Journal of Pharmacology and Experimental Therapeutics, 175: 404–418.
Simansky, K. J., and Harvey, J. A., 1978, Stimulus-dependent changes in pain-sensitivity after central monoamine depletion: hyperalgesia on the hot-plate associated with norepinephrine depletion and in flinch-jump with serotonin depletion, Neuroscience Abstracts, 4: 283.
Simansky, K. J., and Harvey, J. A., 1979, Stimulus-dependent analgesic action of monoamine uptake inhibitors: relationship to 5-HT and NE function in CNS, Neuroscience Abstracts, 5: 353.
Slater, P., 1974, Effect of 6-hydroxydopamine on some actions of tremoríne and oxotremorine, European Journal of Pharmacology, 25: 130–137.
Slater, P., and Blundell, C., 1978, The effect of 6-hydroxydopamine on the antinociceptive action of morphine, European Journal of Pharmacology, 48: 237–247.
Smith, R. F., 1979, Mediation of footshock sensitivity by serotonergic projection to hippocampus, Pharmacology, Biochemistry, and Behavior, 10: 381–388.
Sugrue, M. F., and Mclndewar, I., 1976, Effect of blockade of 5hydroxytryptamine reuptake on drug-induced antinociception in the rat, Journal of Pharmacy and Pharmacology, 28: 447–448.
Tagliamonte, A., Tagliamonte, P., Corsini, G. U., Mereu, G. P., and Gessa, G. L., 1973, Decreased conversion of tyrosine to catecholamines in the brain of rats treated with p-chlorophenylalanine, Journal of Pharmacy and Pharmacology, 25: 101–103.
Telner, J., Lepore, F., and Guillemot, J.-P., 1979, Effects of serotonin content on pain sensitivity in the rat, Pharmacology, Biochemistry, and Behavior, 10: 657–661.
Tenen, S. S., 1967, The effects of p-chlorophenylalanine, a serotonin depletor, on avoidance acquisition, pain sensitivity and related behavior in the rat, Psychopharmacologia, 10: 204–219.
White, S. R., White, F. P., Barnes, C. D., and Albright, J. F., 1973, Increased shock sensitivity in rats with experimental allergic encephalomyelitis and reversal by 5-hydroxytryptophan, Brain Research, 58: 251–254.
Wong, D. T., Bymaster, F. P., Horng, J. S., and Molloy, B. B., 1975, A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-Trifluoromethylphenoxy)-Nmethyl-3-phenylpropylamine, Journal of Pharmacology and Experimental Therapeutics, 193: 804–811.
Wong, D. T., Horng, J. S., Bymaster, F. P., Hauser, K. L., and Molloy, B. B., 1974, A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p trifluoromethylphenoxy)-N-methyl-3phenylpropylamine, Life Sciences, 15: 471–479.
Yaksh, T. L., and Wilson, P. R., 1979, Spinal serotonin system mediates antinociception, Journal of Pharmacology and Experimental Therapeutics, 208: 446–453.
Yunger, L. M., and Harvey, J. A., 1973, Effect of lesions in the medial forebrain bundle on three measures of pain sensitivity and noise-elicited startle, Journal of Comparative and Physiological Psychology, 83, 173–183.
Yunger, L. M., and Harvey, J. A., 1976, Kinetic analysis of 3Hserotonin accumulation in four regions of rat brain after lesions in the medial forebrain bundle, Life Sciences, 19: 105–116.
Yunger, L. M., and Harvey, J. A., 1976, Behavioral effects of L-5hydroxytryptophan after destruction of ascending serotonergic pathways in the rat: the role of catecholaminergic neurons, Journal of Pharmacology and Experimental Therapeutics, 196: 307–315.
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Harvey, J.A., Simansky, K.J. (1981). The Role of Serotonin in Modulation of Nociceptive Reflexes. In: Haber, B., Gabay, S., Issidorides, M.R., Alivisatos, S.G.A. (eds) Serotonin. Advances in Experimental Medicine and Biology, vol 133. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-3860-4_7
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