Absence of 5-HT3 and cholinergic mechanisms in improgan antinociception

Improgan, an analgesic derived from histamine antagonists, acts in the brain stem to activate descending non-opioid, pain-relieving circuits, but the mechanism of action of this drug remains elusive. Because improgan has a moderate affinity for 5-HT3 receptors, and, since cholinergic and serotonergic drugs can modulate descending analgesic circuits, roles for 5-HT3, nicotinic and muscarinic receptors in improgan antinociception were presently investigated in rats. Improgan (80 μg, icv) induced nearly maximal inhibition of hot plate and tail flick nociceptive responses, and these actions we unaffected by antagonists of muscarinic (atropine, 5.9 mg/kg, i.p.) and nicotinic (mecamylamine, 2 mg/kg, i.p.) receptors. Control experiments verified that these antagonist treatments were maximally effective against muscarinic and nicotinic antinociception in both tests. In addition, improgan antinociception was unaffected by icv pretreatment with a 5-HT3 antagonist (ondansetron, 20 μg). When given alone, icv treatment with neither this antagonist nor a 5-HT3 agonist (m-chlorophenylbiguanide, 1000 nmol, icv) modified thermal nociceptive latencies. These results show no role for supraspinal cholinergic and 5-HT3 receptors in improgan antinociception. The findings help to narrow the search for the relevant mediators of the action of this novel analgesic agent.