5-HT acts on nociceptive primary afferents through an indirect mechanism to induce hyperalgesia in the subcutaneous tissue.
We have recently demonstrated that s.c.-injected 5-hydroxytryptamine (5-HT) induces nociception by an indirect action on the primary afferent nociceptor in addition to its previously described direct action. Although the mechanisms mediating hyperalgesia can be quite separate and distinct from those mediating nociception, the aim of this study was to test the hypothesis that 5-HT induces mechanical hyperalgesia by mechanisms similar to those mediating nociception. s.c. injection of 5-HT induced a dose-dependent mechanical hyperalgesia measured by the mechanical paw withdrawal nociceptive threshold test in the rat. 5-HT-induced hyperalgesia was significantly reduced by local blockade of the 5-HT(3) receptor by tropisetron, by the nonspecific selectin inhibitor fucoidan, by the cyclooxygenase inhibitor indomethacin, by guanethidine depletion of norepinephrine in the sympathetic terminals, and by local blockade of the beta(1)- or beta(2)-adrenergic receptor by atenolol or ICI 118,551, respectively. Taken together, these findings indicate that like nociception, hyperalgesia induced by the injection of 5-HT in the s.c. tissue is also mediated by an indirect action of 5-HT on the primary afferent nociceptor. This indirect hyperalgesic action of 5-HT is mediated by a combination of mechanisms involved in inflammation such as neutrophil migration and the local release of prostaglandin and norepinephrine. However, in contrast to nociception, hyperalgesia induced by 5-HT in the s.c. tissue is mediated by a norepinephrine-dependent mechanism that involves the activation of peripheral beta(2) adrenoceptors.
Oliveira
M C G
MC
Department of Physiology, Laboratory of Orofacial Pain, Faculty of Dentistry of Piracicaba, University of Campinas, UNICAMP, Av. Limeira, 901, Zip Code 13414-900, Piracicaba, São Paulo, Brazil.
Pelegrini-da-Silva
A
A
Parada
C A
CA
Tambeli
C H
CH
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009638:Norepinephrine / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D019087:Selectins / Q000187:drug effects / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D012867:Skin / Q000294:innervation* / Q000503:physiopathology; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D016861:Cyclooxygenase Inhibitors; D011453:Prostaglandins; D018343:Receptors, Adrenergic, beta-2; D044406:Receptors, Serotonin, 5-HT3; D019087:Selectins; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D009638:Norepinephrine