CHARACTERIZATION OF THE ANTINOCICEPTION PRODUCED BY INTRATHECALLY ADMINISTERED MUSCARINIC AGONISTS IN RATS

The present study was designed to characterize the antinociception pro duced by the administration of a potent muscarinic agonist into the in trathecal space of the lumbar spinal cord of male Sprague-Dawley rats. Seven days after surgical implantation of intrathecal catheters, anim als were injected with graded doses of (+)-cis-methyldioxolane. (+)-ci s-Methyldioxolane produced hot-plate and tail-flick antinociception fo r up to 90 min, peaking 5 to 30 min after injection. The dose of (+)-c is-methyldioxolane that inhibited nociception by 50% was 12 nmol in bo th the hot-plate and tail-flick tests. This antinociception was not ac companied by a general depression of other spontaneous motor responses . The tissue concentration of (+)-cis-methyldioxolane in the lumbar sp inal cord present at the time of maximal hot-plate and tail-flick anti nociception was approximately 12 muM. In similarity to (+)-cis-methyld ioxolane, intrathecally administered (+)-muscarine also produced stron g hot-plate and tail-flick antinociceptive responses. In contrast, int rathecally administered N-methylcarbachol, a nicotinic agonist, had no effect on nociception. Five-minute pretreatment with graded doses of pirenzepine, methoctramine, idazoxan, LY53857, or S-(-)-zacopride each significantly antagonized hot-plate and tail-flick antinociception pr oduced by 37.5 nmol of (+)-cis-methyldioxolane in a dose-related manne r with median effective antagonist doses in the range of 0.4 to 2.2 nm ol. Intrathecal pretreatment with graded doses of prazosin or naloxone enhanced the antinociception produced by (+)-cis-methyldioxolane in t he tail-flick but not the hot-plate tests. Intrathecal vehicle, S(-)-p ropranolol or mecamylamine did not alter (+)-cis-methyldioxolane-induc ed antinociception. The data suggest that the antinociceptive response s produced by intrathecally administered (+)-cis-methyldioxolane invol ve the stimulation of muscarinic M1 and/or M2 cholinergic receptors, a nd may also involve activation of alpha-2 adrenergic, 5-hydroxytryptam ine1c/2 and 5-hydroxytryptamine3 serotonergic receptor systems at the level of the lumbar cord.