The Journal of pharmacology and experimental therapeutics

Characterization of the antinociception produced by intrathecally administered muscarinic agonists in rats.

PMID 8101218


The present study was designed to characterize the antinociception produced by the administration of a potent muscarinic agonist into the intrathecal space of the lumbar spinal cord of male Sprague-Dawley rats. Seven days after surgical implantation of intrathecal catheters, animals were injected with graded doses of (+)-cis-methyldioxolane. (+)-cis-Methyldioxolane produced hot-plate and tail-flick antinociception for up to 90 min, peaking 5 to 30 min after injection. The dose of (+)-cis-methyldioxolane that inhibited nociception by 50% was 12 nmol in both the hot-plate and tail-flick tests. This antinociception was not accompanied by a general depression of other spontaneous motor responses. The tissue concentration of (+)-cis-methyl-dioxolane in the lumbar spinal cord present at the time of maximal hot-plate and tail-flick antinociception was approximately 12 microM. In similarity to (+)-cis-methyldioxolane, intrathecally administered (+)-muscarine also produced strong hot-plate and tail-flick antinociceptive responses. In contrast, intrathecally 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 produced by 37.5 nmol of (+)-cis-methyldioxolane in a dose-related manner with median effective antagonist doses in the range of 0.4 to 2.2 nmol. Intrathecal pretreatment with graded doses of prazosin or naloxone enhanced the antinociception produced by (+)-cis-methyldioxolane in the tail-flick but not the hot-plate tests. Intrathecal vehicle, S(-)-propranolol or mecamylamine did not alter (+)-cis-methyldioxolane-induced antinociception. The data suggest that the antinociceptive responses produced by intrathecally administered (+)-cis-methyldioxolane involve the stimulation of muscarinic M1 and/or M2 cholinergic receptors, and may also involve activation of alpha-2 adrenergic, 5-hydroxytryptamine1c/2 and 5-hydroxytryptamine3 serotonergic receptor systems at the level of the lumbar cord.

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2-Methyl-1,3-dioxolane, 97%