Antinociception with intrathecal α-Methyl-5-hydroxytryptamine, a 5-hydroxytryptamine2A/2C receptor agonist, in two rat models of sustained pain

Type 2 serotonin (5-hydroxytryptamine [5-HT](2)) receptors in the spinal cord have been reported to mediate antinociception using pain threshold tests, but little is known about the actions of spinal 5-HT2 receptors in sustained pain. In rats, we examined antinociceptive effects of the intrathecal administration of a 5-HT2A/2C receptor agonist, alpha-methyl-5-HT maleate (alpha-m-5-HT), using the formalin test and the chronic constriction injury (CCI) model. An intrathecal catheter was implanted for injection of drugs. In the formalin test, flinches were counted from Minute 1 to 2 and Minute 5 to 6 (Phase 1) and then for 1-min periods at 5-min intervals from 10 to 60 min (Phase 2). In rats with CCI, hind paw withdrawal latency after thermal stimulation was measured. In the formalin test, intrathecal administration of alpha-m-5-HT (1 to 100 mug) dose-dependently suppressed the number of flinches in both Phases 1 and 2. In the CCI model, intrathecally administered alpha-m-5-HT (10 to 100 mug) attenuated thermal hyperalgesia in a dose-dependent manner. These effects were reversed by intrathecal pretreatment with a 5-HT2A/2C antagonist, ketanserin (30 mug), or a muscarinic receptor antagonist, atropine (30 mug). These findings suggest that spinal 5-HT2A/2C receptors mediate antinociception in inflammatory pain and neuropathic pain, and the muscarinic receptors contribute to this action.