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M2, M3, and M4 receptor subtypes contribute to muscarinic potentiation of GABAergic inputs to spinal dorsal horn neurons.
J Pharmacol Exp Ther. 2005 May; 313(2):697-704.JP

Abstract

The spinal cholinergic system and muscarinic receptors are important for regulation of nociception. Activation of spinal muscarinic receptors produces analgesia and inhibits dorsal horn neurons through potentiation of GABAergic inputs. To determine the role of receptor subtypes in the muscarinic agonist-induced synaptic GABA release, spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in lamina II neurons using whole-cell voltage-clamp recordings in rat spinal cord slices. The muscarinic receptor agonist oxotremorine-M dose-dependently (1-10 microM) increased GABAergic sIPSCs but not miniature IPSCs. The potentiating effect of oxotremorine-M on sIPSCs was completely blocked by atropine. In rats pretreated with intrathecal pertussis toxin to inactive inhibitory G (i/o) proteins, 3 microM oxotremorine-M had no significant effect on sIPSCs in 31 of 55 (56%) neurons tested. In the remaining 24 (44%) neurons in pertussis toxin-treated rats, oxotremorine-M caused a small increase in sIPSCs, and this effect was completely abolished by subsequent application of 25 nM 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), a relatively selective M(3) subtype antagonist. Furthermore, himbacine (1 microM), a relatively specific antagonist for M(2) and M(4) subtypes, produced a large reduction in the stimulatory effect of oxotremorine-M on sIPSCs, and the remaining effect was abolished by 4-DAMP. Additionally, the M(4) receptor antagonist MT-3 toxin (100 nM) significantly attenuated the effect of oxotremorine-M on sIPSCs. Collectively, these data suggest that M(2) and M(4) receptor subtypes play a predominant role in muscarinic potentiation of synaptic GABA release in the spinal cord. The M(3) subtype also contributes to increased GABAergic tone in spinal dorsal horn by muscarinic agonists.

Authors+Show Affiliations

Department of Anesthesiology, Pennsylvania State University College of Medicine, Hershey, 17033, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15640398

Citation

Zhang, Hong-Mei, et al. "M2, M3, and M4 Receptor Subtypes Contribute to Muscarinic Potentiation of GABAergic Inputs to Spinal Dorsal Horn Neurons." The Journal of Pharmacology and Experimental Therapeutics, vol. 313, no. 2, 2005, pp. 697-704.
Zhang HM, Li DP, Chen SR, et al. M2, M3, and M4 receptor subtypes contribute to muscarinic potentiation of GABAergic inputs to spinal dorsal horn neurons. J Pharmacol Exp Ther. 2005;313(2):697-704.
Zhang, H. M., Li, D. P., Chen, S. R., & Pan, H. L. (2005). M2, M3, and M4 receptor subtypes contribute to muscarinic potentiation of GABAergic inputs to spinal dorsal horn neurons. The Journal of Pharmacology and Experimental Therapeutics, 313(2), 697-704.
Zhang HM, et al. M2, M3, and M4 Receptor Subtypes Contribute to Muscarinic Potentiation of GABAergic Inputs to Spinal Dorsal Horn Neurons. J Pharmacol Exp Ther. 2005;313(2):697-704. PubMed PMID: 15640398.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - M2, M3, and M4 receptor subtypes contribute to muscarinic potentiation of GABAergic inputs to spinal dorsal horn neurons. AU - Zhang,Hong-Mei, AU - Li,De-Pei, AU - Chen,Shao-Rui, AU - Pan,Hui-Lin, Y1 - 2005/01/07/ PY - 2005/1/11/pubmed PY - 2005/7/6/medline PY - 2005/1/11/entrez SP - 697 EP - 704 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 313 IS - 2 N2 - The spinal cholinergic system and muscarinic receptors are important for regulation of nociception. Activation of spinal muscarinic receptors produces analgesia and inhibits dorsal horn neurons through potentiation of GABAergic inputs. To determine the role of receptor subtypes in the muscarinic agonist-induced synaptic GABA release, spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in lamina II neurons using whole-cell voltage-clamp recordings in rat spinal cord slices. The muscarinic receptor agonist oxotremorine-M dose-dependently (1-10 microM) increased GABAergic sIPSCs but not miniature IPSCs. The potentiating effect of oxotremorine-M on sIPSCs was completely blocked by atropine. In rats pretreated with intrathecal pertussis toxin to inactive inhibitory G (i/o) proteins, 3 microM oxotremorine-M had no significant effect on sIPSCs in 31 of 55 (56%) neurons tested. In the remaining 24 (44%) neurons in pertussis toxin-treated rats, oxotremorine-M caused a small increase in sIPSCs, and this effect was completely abolished by subsequent application of 25 nM 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), a relatively selective M(3) subtype antagonist. Furthermore, himbacine (1 microM), a relatively specific antagonist for M(2) and M(4) subtypes, produced a large reduction in the stimulatory effect of oxotremorine-M on sIPSCs, and the remaining effect was abolished by 4-DAMP. Additionally, the M(4) receptor antagonist MT-3 toxin (100 nM) significantly attenuated the effect of oxotremorine-M on sIPSCs. Collectively, these data suggest that M(2) and M(4) receptor subtypes play a predominant role in muscarinic potentiation of synaptic GABA release in the spinal cord. The M(3) subtype also contributes to increased GABAergic tone in spinal dorsal horn by muscarinic agonists. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/15640398/M2_M3_and_M4_receptor_subtypes_contribute_to_muscarinic_potentiation_of_GABAergic_inputs_to_spinal_dorsal_horn_neurons_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15640398 DB - PRIME DP - Unbound Medicine ER -