Pharmacological antagonism of the antinociceptive effects of serotonin in the rat spinal cord

Abstract

Serotonin creatinine sulfate (5-HT) administered via chronically implanted intrathecal catheters produced a dose-dependent increase in the rat hot plate and tail flick response latencies. To characterize the nature of the spinal receptor system through which this effect is mediated, putative serotonin antagonists were co-administered with 200 μg of 5-HT. In these experiments, methysergide (12–48 nmol), 2-bromolysergic acid diethylamide (BOL 6–48 nmol) and ketanserin (12–73 nmol) produced a dose-dependent antagonism of the effects of intrathecally administered 5-HT on the tail flick; with the IC 50 values being: methysergide 17.5±2.5 nmol; BOL 26.5±6.5 nmol; ketanserin 34.5±5.1 nmol The effects of spiroperidol (12–44 nmol) and metergoline (6–32 nmol) were not dose-dependent, although a measurable antagonism did occur at the highest dose. In contrast to the results obtained with the tail flick test, none of the 5-HT antagonists attenuated the elevation of hot plate latency produced by 5-HT. With the exception of spiroperidol, none of these agents showed any effect on the baseline response latencies. Sacrifice and dissection of rat brain and cord at 5, 15 and 45 min after intrathecal [ 14C]5-HT revealed that significant quantities of radioactivity appeared in brain only at the longest interval, at a time when the magnitude of the analgesia was significantly diminished, indicating that these spinal drug effects were likely produced by a local action on spinal receptors. The ability of methysergide and BOL (agents with measurable 5-HT 1 binding activity) to readily antagonize the effects of intrathecal 5-HT versus the relative inactivity of spiroperidol and ketanserin, used to characterize the 5-HT 2 binding site, suggests the likely role of 5-HT 1 receptors in mediating the spinnal effects of 5-HT in the tail flick, but not the hot plate test of nociception.