RT Journal Article
SR Electronic
T1 M<sub>2</sub>, M<sub>3</sub>, and M<sub>4</sub> Receptor Subtypes Contribute to Muscarinic Potentiation of GABAergic Inputs to Spinal Dorsal Horn Neurons
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 697
OP 704
DO 10.1124/jpet.104.079939
VO 313
IS 2
A1 Zhang, Hong-Mei
A1 Li, De-Pei
A1 Chen, Shao-Rui
A1 Pan, Hui-Lin
YR 2005
UL http://jpet.aspetjournals.org/content/313/2/697.abstract
AB 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 μM) 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 μM 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 M3 subtype antagonist. Furthermore, himbacine (1 μM), a relatively specific antagonist for M2 and M4 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 M4 receptor antagonist MT-3 toxin (100 nM) significantly attenuated the effect of oxotremorine-M on sIPSCs. Collectively, these data suggest that M2 and M4 receptor subtypes play a predominant role in muscarinic potentiation of synaptic GABA release in the spinal cord. The M3 subtype also contributes to increased GABAergic tone in spinal dorsal horn by muscarinic agonists. The American Society for Pharmacology and Experimental Therapeutics