In this study, we have investigated
serotonin hyperalgesia employing the mechanical paw withdrawal nociceptive threshold test in the rat. Intradermally injected
serotonin was found to produce a dose-dependent
hyperalgesia that was not attenuated by procedures which eliminate the known indirect mechanisms of
hyperalgesia such as
sympathectomy, polymorphonuclear leukocyte depletion or
cyclooxygenase inhibition. In addition, the latency to onset of
serotonin hyperalgesia is extremely short, with maximal
hyperalgesia observed in less than 1 min, a similar temporal onset to direct-acting hyperalgesic agents such as
prostaglandin E2. The results suggest, therefore, that the hyperalgesic effects of
serotonin in our animal model are exerted by direct action on primary afferent neurons. Only the
intradermal injection of selective
serotonin (
5-hydroxytryptamine;
5-HT) agonists for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide and N,N-dipropyl-5-carboxamido-tryptamine
maleate, produced dose-dependent
hyperalgesia. No
hyperalgesia was seen after 5-HT1B,
CGS-12066B maleate and m-trifluoromethylphenyl-
piperazine hydrochloride; 5-HT2+IC, alpha methyl 5HT and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl; or 5-HT3,
2-methyl-5-hydroxytryptamine maleate and
phenylbiguanide, agonists. Similarly, only the 5-HT1A antagonists,
spiroxatrine and
spiperone, attenuated the
hyperalgesia induced by intradermally injected
serotonin. 5-HT2+IC antagonists,
mesulergine and
ketanserin, and
5-HT3 antagonists,
quipazine and
3-tropanyl-indole-3-carboxylate, did not significantly attenuate
5-HT hyperalgesia. We conclude that
serotonin produces
hyperalgesia by a direct action on the primary afferent neuron via the 5-HT1A subset of
serotonin receptors.