Possible involvement of spinal noradrenergic mechanisms in the antiallodynic effect of intrathecally administered 5-HT2C receptor agonists in the rats with peripheral nerve injury

Intrathecal administration of serotonin type 2C (5-HT2C) receptor agonists produces an antiallodynic effect in a rat model of neuropathic pain. In the present study, we characterized this effect pharmacologically. Allodynia was produced by tight ligation of the fifth (L5) and sixth (L6) lumbar spinal nerves on the left side, and was measured by applying von Frey filaments to the left hindpaw. 6-chloro-2-(1-piperazinyl)-pyrazine (MK212; 100 μg) and 1-(m-chlorophenyl)-piperazine (mCPP; 300 μg) were used as 5-HT2C receptor agonists. Intrathecal administration of these agonists resulted in an antiallodynic effect. Intrathecal administration of atropine (30 μg), a muscarinic receptor antagonist, and yohimbine (30 μg), an α2-adrenoceptor antagonist, reversed the effects of 5-HT2C receptor agonists. Intrathecal pretreatment with 6-hydroxydopamine, an adrenergic neurotoxin, inhibited the antiallodynic effect of MK212. These results suggest that spinal noradrenergic mechanisms are involved in the antiallodynic effects of intrathecally administered 5-HT2C receptor agonists. Previously, we demonstrated that intrathecal administration of 5-HT2A receptor agonists also produced antiallodynic effects, and the effects were not reversed by yohimbine. Taken together, these findings suggest that 5-HT2A and 5-HT2C receptors in the dorsal horn of the spinal cord might be involved in alleviating neuropathic pain by different mechanisms.