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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.
Mol Pharmacol. 2006 Mar; 69(3):1048-55.MP

Abstract

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 microM) 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.

Authors+Show Affiliations

Department of Anesthesiology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16365281

Citation

Zhang, Hong-Mei, et al. "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." Molecular Pharmacology, vol. 69, no. 3, 2006, pp. 1048-55.
Zhang HM, Chen SR, Matsui M, et al. 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. Mol Pharmacol. 2006;69(3):1048-55.
Zhang, H. M., Chen, S. R., Matsui, M., Gautam, D., Wess, J., & Pan, H. L. (2006). 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. Molecular Pharmacology, 69(3), 1048-55.
Zhang HM, et al. 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. Mol Pharmacol. 2006;69(3):1048-55. PubMed PMID: 16365281.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Zhang,Hong-Mei, AU - Chen,Shao-Rui, AU - Matsui,Minoru, AU - Gautam,Dinesh, AU - Wess,Jürgen, AU - Pan,Hui-Lin, Y1 - 2005/12/19/ PY - 2005/12/21/pubmed PY - 2006/4/20/medline PY - 2005/12/21/entrez SP - 1048 EP - 55 JF - Molecular pharmacology JO - Mol Pharmacol VL - 69 IS - 3 N2 - 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 microM) 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16365281/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_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16365281 DB - PRIME DP - Unbound Medicine ER -