The Spinal Muscarinic M₁ Receptors and GABA_A Receptors Contribute to the McN-A-343–Induced Antinociceptive Effects During Thermal Stimulation of Mice

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The present study was undertaken to clarify how spinal muscarinic receptors are involved in the antinociceptive effects in thermal stimulation. Intrathecal (i.t.) injection of the muscarinic agonist McN-A-343 inhibited the tail-flick response to noxious thermal stimulation in a dose-dependent manner (31.5 – 63.0 nmol). This McN-A-343–induced antinociceptive effect was dose-dependently inhibited by intrathecal (i.t.) injection of a nonselective muscarinic receptor antagonist atropine, the selective muscarinic M₁ antagonist pirenzepine, or the M₄ antagonist himbacine. The inhibition of pirenzepine was greater than that of himbacine. In contrast, the selective muscarinic M₂ antagonist methoctramine did not inhibit the antinociceptive effects of McN-A-343. In addition, the McN-A-343–induced antinociceptive effect was attenuated by i.t. injection of the GABA_A antagonist bicuculline, but not by injection of the GABA_B antagonist CGP35348. These results suggest that McN-A-343 produces its antinociceptive effect on the response to thermal stimulation via spinal muscarinic M₁ receptors and, at least in part, through neuronal pathways involving spinal GABA_A receptors in mice.