Abstract
The purpose of this article is to summarize recent findings on the role of serotonin in pain processing in the peripheral nervous system. Serotonin (5-hydroxtryptamine [5-HT]) is present in central and peripheral serotonergic neurons, it is released from platelets and mast cells after tissue injury, and it exerts algesic and analgesic effects depending on the site of action and the receptor subtype. After nerve injury, the 5-HT content in the lesioned nerve increases. 5-HT receptors of the 5-HT3 and 5-HT2A subtype are present on C-fibers. 5-HT, acting in combination with other inflammatory mediators, may ectopically excite and sensitize afferent nerve fibers, thus contributing to peripheral sensitization and hyperalgesia in inflammation and nerve injury.
Similar content being viewed by others
References
Eide P. K., Hole K. (1993). The role of 5-hydroxytryptamine (5-HT) receptor subtypes and plasticity in the 5-HT systems in the regulation of nociceptive sensitivity. Cephalalgia 13, 75–85.
Yaksh T., Tyce G. (1979). Mkcroinjections of morphine into the periaqueductal gray evokes the release of serotonin from spinal cord. Brain Res. 171, 176–181.
Yaksh T. L., Wilson P. R. (1979). Spinal serotonin terminal system mediates antinociception. J. Pharmacol. Exp. Ther. 208, 446–453.
Peng Y. B., Lin Q., Willis W. D. (1996). The role of 5-HT3 receptors in periaqueductal gray-induced inhibition of nociceptive dorsal horn neurons in rats. J. Pharmacol. Exp. Ther. 276, 116–124.
Liu M. Y., Su C. F., Lin M. T. (1988). The antinociceptive role of a bulbospinal serotonergic pathway in the rat brain. Pain 33, 123–129.
Kiefel J. M., Cooper M. L., Bodnar R. J. (1992). Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. Brain Res. 597, 331–338.
Lin Q., Peng Y. B., Willis W. D. (1996). Antinociception and inhibition from the periaqueductal gray are mediated in part by spinal 5-hydroxytryptamine(1A) receptors. J. Pharmacol. Exp. Ther. 276, 958–967.
Stamford J. A. (1995). Descending control of pain. Br. J. Anaesth. 75, 217–227.
Sorkin L., McAdoo D., Willis W. (1993). Raphe magnus stimulation-induced antinociception in the cat is associated with the release of amino acids as well as serotonin in the lumbar dorsal horn. Brain Res. 618, 95–108.
McQuay H. J., Tramer M., Nye B. A., Carroll D., Wiffen P. J., Moore R. A. (1996). A systematic review of antidepressants in neuropathic pain. Pain 68, 217–227.
Ansari A. (2000). The efficacy of newer antidepressants in the treatment of chronic pain: a review of current literature. Harv. Rev. Psychiatry 7, 257–277.
Sindrup S. H., Gram L. F., Brosen K., Eshoj O., Mogensen E. F. (1990). The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 42, 135–144.
Sindrup S. H., Bjerre U., Dejgaard A., Brosen K., Aaes-Jorgensen T., Gram L. F. (1992). The selective serotonin reuptake inhibitor citalopram relieves the symptoms of diabetic neuropathy. Clin. Pharmacol. Ther. 52, 547–552.
Ferrari M. D., Odink J., Tapparelli C., Van Kempen G. M., Pennings E. J., Bruyn G. W. (1989). Serotonin metabolism in migraine. Neurology 39, 1239–1242.
Johnson K. W., Phebus L. A., Cohen M. L. (1998). Serotonin in migraine: theories, animal models and emerging therapies. Prog. Drug Res. 51, 219–244.
Goadsby P. J., Hargreaves R. J. (2000). Mechanisms of action of serotonin 5-HT1B/D agonists: insights into migraine pathophysiology using rizatriptan. Neurology 55, S8–14.
Marziniak M., Mössner R., Schmitt A., Lesch K.-P., Sommer C. (2001). A functional serotonin transporter gene polymorphism is associated with migraine with aura. Neurology, in press.
Dray A. (1995). Inflammatory mediators of pain. Br. J. Anaesth. 75, 125–131.
Lehtosalo J. I., Uusitalo H., Laakso J., Palkama A., Harkonen M. (1984). Biochemical and immunohistochemical determination of 5-hydroxytryptamine located in mast cells in the trigeminal ganglion of the rat and guinea pig. Histochemistry 80, 219–223.
Anden N. E., Olsson Y. (1967). 5-hydroxytryptamine in normal and sectioned rat sciatic nerve. Acta. Pathol. Microbiol. Scand. 70, 537–540.
Maeno Y., Takabe F., Mori Y., Iwasa M., Inoue H. (1991). Simultaneous observation of catecholamine, serotonin and their metabolites in incised skin wounds of guinea pig. Forensic Sci. Int. 51, 51–63.
Anden N. E., Olsson Y. (1967). 5-hydroxytryptamine in normal and sectioned rat sciatic nerve. Acta. Pathol. Microbiol. Scand. 70, 537–540.
Vogel C., Mossner R., Gerlach M., et al. (2003). Absence of thermal hyperalgesia in serotonin transporter-deficient mice. J. Neurosci. 23, 708–715.
Satoh O., Omote K. (1996). Roles of monoaminergic, glycinergic and GABAergic inhibitory systems in the spinal cord in rats with peripheral mononeuropathy. Brain Res. 728, 27–36.
Lovell J. A., Novak J. C., Stuesse S. L., Cruce W. L., Crisp T. (2000). Changes in spinal serotonin turnover mediate age-related differences in the behavioral manifestations of peripheral nerve injury. Pharmacol. Biochem. Behav. 66, 873–878.
Sorkin L. S., McAdoo D. J. (1993). Amino acids and serotonin are released into the lumbar spinal cord of the anesthetized cat following intradermal capsaicin injections. Brain Res. 607, 89–98.
Liu D. X., Valadez V., Sorkin L. S., McAdoo D. J. (1990). Norepinephrine and serotonin release upon impact injury to rat spinal cord. J. Neurotrauma 7, 219–227.
Busto R., Dietrich W. D., Globus M. Y., Alonso O., Ginsberg M. D. (1997). Extracellular release of serotonin following fluid-percussion brain injury in rats. J. Neurotrauma 14, 35–42.
Lundberg C., Gerdin B. (1984). The role of histamine and serotonin in the inflammatory reaction in an experimental model of open wounds in the rat. Scand. J. Plast. Reconstr. Surg. 18, 175–180.
Di Rosa M., Giroud J. P., Willoughby D. A. (1971). Studies on the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. J. Pathol. 104, 15–29.
Zhang Y. Q., Gao X., Zhang L. M., Wu G. C. (2000). The release of serotonin in rat spinal dorsal horn and periaqueductal gray following carrageenan inflammation. Neuroreport 11, 3539–3543.
Ernberg M., Hedenberg-Magnusson B., Alstergren P., Kopp S. (1999). The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia. Life Sci. 65, 313–325.
Kopp S. (1998). The influence of neuropeptides, serotonin, and interleukin 1beta on temporomandibular joint pain and inflammation. J. Oral Maxillofac. Surg. 56, 189–191.
Pierce P. A., Xie G. X., Levine J. D., Peroutka S. J. (1996). 5-Hydroxytryptamine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: a polymerase chain reaction study. Neuroscience 70, 553–559.
Fozard J. R. (1984). Neuronal 5-HT receptors in the periphery. Neuropharmacology 23, 1473–1486.
Carlton S. M., Coggeshall R. E. (1997). Immunohistochemical localization of 5-HT2A receptors in peripheral sensory axons in rat glabrous skin. Brain Res. 763, 271–275.
Yoder E. J., Tamir H., Ellisman M. H. (1997). Serotonin receptors expressed by myelinating Schwann cells in rat sciatic nerve. Brain Res. 753, 299–308.
Fjallbrant N., Iggo A. (1961). The effect of histamine, 5-hydroxytryptamine and acetylcholine on cutaneous afferent fibres. J. Physiol. 156, 578–590.
Beck P. W., Handwerker H. O. (1974). Bradykinin and serotonin effects on various types of cutaneous nerve fibers. Pflugers Arch. 347, 209–222.
Fock S., Mense S. (1976). Excitatory effects of 5-hydroxytryptamine, histamine and potassium ions on muscular group IV afferent units: a comparison with bradykinin. Brain Res. 105, 459–469.
Kessler W., Kirchhoff C., Reeh P. W., Handwerker H. O. (1992). Excitation of cutaneous afferent nerve endings in vitro by a combination of inflammatory mediators and conditioning effect of substance P. Exp. Brain. Res. 91, 467–476.
Davis K. D., Meyer R. A., Campbell J. N. (1993). Chemosensitivity and sensitization of nociceptive afferents that innervate the hairy skin of monkey. J. Neurophysiol. 69, 1071–1081.
Taiwo Y. O., Levine J. D. (1992). Serotonin is a directly-acting hyperalgesic agent in the rat. Neuroscience 48, 485–490.
Sufka K. J., Schomburg F. M., Giordano J. (1992). Receptor mediation of 5-HT-induced inflammation and nociception in rats. Pharmacol. Biochem. Behav. 41, 53–56.
Parada C. A., Tambeli C. H., Cunha F. Q., Ferreira S. H. (2001). The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience 102, 937–944.
Babenko V., Svensson P., Graven-Nielsen T., Drewes A. M., Jensen T. S., Arendt-Nielsen L. (2000). Duration and distribution of experimental muscle hyperalgesia in humans following combined infusions of serotonin and bradykinin. Brain Res. 853, 275–281.
Lischetzki G., Rukwied R., Handwerker H. O., Schmelz M. (2001). Nociceptor activation and protein extravasation induced by inflammatory mediators in human skin. Eur. J. Pain 5, 49–57.
Schmelz M., Schmidt R., Weidner C., Hilliges M., Torebjork H. E., Handwerker H. O. (2003). Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J. Neurophysiol. 89, 2441–2448.
Ernberg M., Lundeberg T., Kopp S. (2000). Effect of propranolol and granisetron on experimentally induced pain and allodynia/hyperalgesia by intramuscular injection of serotonin into the human masseter muscle. Pain 84, 339–346.
Ernberg M., Lundeberg T., Kopp S. (2000). Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals. Pain 85, 31–39.
Herbert M. K., Schmidt R. F. (1992). Activation of normal and inflamed fine articular afferent units by serotonin. Pain 50, 79–88.
Grubb B. D., McQueen D. S., Iggo A., Birrell G. J., Dutia M. B. (1988). A study of 5-HT-receptors associated with afferent nerves located in normal and inflamed rat ankle joints. Agents Actions 25, 216–218.
Song X. J., Zhang J. M., Hu S. J., LaMotte R. H. (2003). Somata of nerve-injured sensory neurons exhibit enhanced responses to inflammatory mediators. Pain 104, 701–709.
Aley K. O., Messing R. O., Mochly-Rosen D., Levine J. D. (2000). Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J. Neurosci. 20, 4680–4685.
Abbott F. V., Hong Y., Blier P. (1996). Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators. Neuropharmacology 35, 99–110.
Lang E., Novak A., Reeh P. W., Handwerker H. O. (1990). Chemosensitivity of fine afferents from rat skin in vitro. J. Neurophysiol. 63, 887–901.
Michaelis M., Vogel C., Blenk K. H., Janig W. (1997). Algesics excite axotomised afferent nerve fibres within the first hours following nerve transection in rats. Pain 72, 347–354.
Michaelis M., Vogel C., Blenk K. H., Arnarson A., Janig W. (1998). Inflammatory mediators sensitize acutely axotomized nerve fibers to mechanical stimulation in the rat. J. Neurosci. 18, 7581–7587.
Kress M., Reeh P. W., Vyklicky L. (1997). An interaction of inflammatory mediators and protons in small diameter dorsal root ganglion neurons of the rat. Neurosci. Lett. 224, 37–40.
Coelho A. M., Fioramonti J., Bueno L. (1998). Mast cell degranulation induces delayed rectal allodynia in rats: role of histamine and 5-HT. Dig. Dis. Sci. 43, 727–737.
Bingham S., Davey P. T., Sammons M., Raval P., Overend P., Parsons A. A. (2001). Inhibition of inflammation-induced thermal hypersensitivity by sumatriptan through activation of 5-HT(1B/1D) receptors. Exp. Neurol. 167, 65–73.
Zochodne D. W., Ho L. T. (1994). Sumatriptan blocks neurogenic inflammation in the peripheral nerve trunk. Neurology 44, 161–163.
Tokunaga A., Saika M., Senba E. (1998). 5-HT2A receptor subtype is involved in the thermal hyperalgesic mechanism of serotonin in the periphery. Pain 76, 349–355.
Abbott F. V., Hong Y., Blier P. (1997). Persisting sensitization of the behavioural response to formalin-induced injury in the rat through activation of serotonin2A receptors. Neuroscience 77, 575–584.
Obata H., Saito S., Ishizaki K., Goto F. (2000). Antinociception in rat by sarpogrelate, a selective 5-HT(2A) receptor antagonist, is peripheral. Eur. J. Pharmacol. 404, 95–102.
Okamoto K., Imbe H., Morikawa Y., et al. (2002). 5-HT2A receptor subtype in the peripheral branch of sensory fibers is involved in the potentiation of inflammatory pain in rats. Pain 99, 133–143.
Doak G. J., Sawynok J. (1997). Formalin-induced nociceptive behavior and edema: involvement of multiple peripheral 5-hydroxytryptamine receptor subtypes. Neuroscience 80, 939–949.
Giordano J., Dyche J. (1989). Differential analgesic actions of serotonin 5-HT3 receptor antagonists in the mouse. Neuropharmacology 28, 423–427.
Giordano J., Rogers L. V. (1989). Peripherally administered serotonin 5-HT3 receptor antagonists reduce inflammatory pain in rats. Eur. J. Pharmacol. 170, 83–86.
Eschalier A., Kayser V., Guilbaud G. (1989). Influence of a specific 5-HT3 antagonist on car-rageenan-induced hyperalgesia in rats. Pain 36, 249–255.
Espejo E. F., Gil E. (1998). Antagonism of peripheral 5-HT4 receptors reduces visceral and cutaneous pain in mice, and induces visceral analgesia after simultaneous inactivation of 5-HT3 receptors. Brain Res. 788, 20–24.
Giordano J., Daleo C., Sacks S. M. (1998). Topical ondansetron attenuates nociceptive and inflammatory effects of intradermal capsaicin in humans. Eur. J. Pharmacol. 354, R13–14.
Ernberg M., Lundeberg T., Kopp S. (2003). Effects on muscle pain by intramuscular injection of granisetron in patients with fibromyalgia. Pain 101, 275–282.
Stratz T., Varga B., Muller W. (2002). Treatment of tendopathies with tropisetron. Rheumatol. Int. 22, 219–221.
Stratz T., Muller W. (2003). Lokalbehandlung rheumatischer Erkrankungen mit dem 5-HT3-Rezeptor-Antagonisten Tropisetron. Schmerz 17, 200–203.
Stratz T., Samborski W., Hrycaj P., et al. (1993). Die Serotoninkonzentration im Serum bei Patienten mit generalisierter Tendomyopathie (Fibromyalgie) und chronischer Polyarthritis. Med. Klin. 88, 458–462.
Abdi S., Lee D. H., Chung J. M. (1998). The anti-allodynic effects of amitriptyline, gabapentin, and lidocaine in a rat model of neuropathic pain. Anesth. Analg. 87, 1360–1366.
Sawynok J., Esser M. J., Reid A. R. (1999). Peripheral antinociceptive actions of desipramine and fluoxetine in an inflammatory and neuropathic pain test in the rat. Pain 82, 149–158.
Sawynok J. (2003). Topical and peripherally acting analgesics. Pharmacol. Rev. 55, 1–20.
Sudoh Y., Cahoon E. E., Gerner P., Wang G. K. (2003). Tricyclic antidepressants as long-acting local anesthetics. Pain 103, 49–55.
Zeitz K. P., Guy N., Malmberg A. B., et al. (2002). The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J. Neurosci. 22, 1010–1019.
Bengel D., Murphy D. L., Andrews A. M., et al. (1998). Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4- methylene-dioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol. Pharmacol. 53, 649–655.
Fabre V., Beaufour C., Evrard A., et al. (2000). Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur. J. Neurosci. 12, 2299–2310.
Rioux A., Fabre V., Lesch K. P., et al. (1999). Adaptive changes of serotonin 5-HT2A receptors in mice lacking the serotonin transporter. Neurosci. Lett. 262, 113–116.
Palm F., Zelenka M., Moessner R., Gerlach M., Lesch K.-P., Sommer C. (2003). Serotonin transporter deficient mice have reduced thermal hyperalgesia. J. Neurol. 250, II/91.
Gold M. S., Reichling D. B., Shuster M. J., Levine J. D. (1996). Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors. Proc. Natl. Acad. Sci. USA 93, 1108–1112.
Aley K. O., Levine J. D. (1999). Role of protein kinase A in the maintenance of inflammatory pain. J. Neurosci. 19, 2181–2186.
Aley K. O., McCarter G., Levine J. D. (1998). Nitric oxide signaling in pain and nociceptor sensitization in the rat. J. Neurosci. 18, 7008–7014.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sommer, C. Serotonin in pain and analgesia. Mol Neurobiol 30, 117–125 (2004). https://doi.org/10.1385/MN:30:2:117
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1385/MN:30:2:117