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Opposing Functions of Spinal M₂, M₃, and M₄ Receptor Subtypes in Regulation of GABAergic Inputs to Dorsal Horn Neurons Revealed by Muscarinic Receptor Knockout Mice

Department of Anesthesiology, Pennsylvania State University College of Medicine, the Milton S. Hershey Medical Center, Hershey, Pennsylvania (H.-M.Z., S.-R.C., H.-L.P.); Division of Neuronal Network, Institute of Medical Science, University of Tokyo, Tokyo, Japan (M.M.); and Laboratory of Bioorganic Chemistry, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland (D.G., J.W.)

Spinal muscarinic acetylcholine receptors (mAChRs) play an important role in the regulation of nociception. To determine the role of individual mAChR subtypes in control of synaptic GABA release, spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature IPSCs (mIPSCs) were recorded in lamina II neurons using whole-cell recordings in spinal cord slices of wild-type and mAChR subtype knockout (KO) mice. The mAChR agonist oxotremorine-M (3-10 µM) dose-dependently decreased the frequency of GABAergic sIPSCs and mIPSCs in wild-type mice. However, in the presence of the M₂ and M₄ subtype-preferring antagonist himbacine, oxotremorine-M caused a large increase in the sIPSC frequency. In M₃ KO and M₁/M₃ double-KO mice, oxotremorine-M produced a consistent decrease in the frequency of sIPSCs, and this effect was abolished by himbacine. We were surprised to find that in M₂/M₄ double-KO mice, oxotremorine-M consistently increased the frequency of sIPSCs and mIPSCs in all neurons tested, and this effect was completely abolished by 4-diphenylacetoxy-N-methylpiperidine methiodide, an M₃ subtype-preferring antagonist. In M₂ or M₄ single-KO mice, oxotremorine-M produced a variable effect on sIPSCs; it increased the frequency of sIPSCs in some cells but decreased the sIPSC frequency in other neurons. Taken together, these data strongly suggest that activation of the M₃ subtype increases synaptic GABA release in the spinal dorsal horn of mice. In contrast, stimulation of presynaptic M₂ and M₄ subtypes predominantly attenuates GABAergic inputs to dorsal horn neurons in mice, an action that is opposite to the role of M₂ and M₄ subtypes in the spinal cord of rats.

Address correspondence to: Dr. Hui-Lin Pan, Department of Anesthesiology and Pain Medicine, University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Blvd., Unit 409, Houston, TX 77030.

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