Characterization of the antinociception produced by intrathecally administered muscarinic agonists in rats.
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.
Iwamoto
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Department of Pharmacology, University of Kentucky College of Medicine, Lexington.
Marion
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D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000698:Analgesia; D000818:Animals; D002217:Carbachol / Q000031:analogs & derivatives / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology; D004148:Dioxolanes / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007278:Injections, Spinal; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009116:Muscarine / Q000494:pharmacology; D009292:Narcotic Antagonists; D009619:Nociceptors / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D010277:Parasympathomimetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D010890:Pirenzepine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors; D014018:Tissue Distribution
D000317:Adrenergic alpha-Antagonists; D003959:Diamines; D004148:Dioxolanes; D009292:Narcotic Antagonists; D010277:Parasympathomimetics; D011942:Receptors, Adrenergic, alpha; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; C053765:N-methylcarbamylcholine; D010890:Pirenzepine; C024310:2-methyldioxolane; D008464:Mecamylamine; D009116:Muscarine; D002217:Carbachol; C054938:methoctramine