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Signaling Mechanisms Responsible for Muscarinic Potentiation of GABAergic Inputs to Spinal Dorsal Horn Neurons
Author(s) -
Zhang Hongmei,
Richardson Timothy E,
Chen Shaorui,
Pan Huilin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1127.10
Subject(s) - oxotremorine , muscarinic acetylcholine receptor , gabaergic , chemistry , neuroscience , muscarinic agonist , long term potentiation , inhibitory postsynaptic potential , acetylcholine , spinal cord , pharmacology , biology , receptor , biochemistry
Activation of muscarinic acetylcholine receptors (mAChRs) potentiates spinal GABAergic tone, which is one of the potential mechanisms of muscarinic analgesia in the spinal cord. Although M 2 , M 3 , and M 4 subtypes are all involved in the potentiation of spinal GABA release, the signaling mechanisms of mAChRs involved in this action are not clear. By whole‐cell recording of GABAergic spontaneous inhibitory postsynaptic current (sIPSCs) in lamina II neurons in the rat spinal cord slice, we found that the stimulating effect of the specific mAChRs agonist oxotremorine‐M on GABAergic sIPSCs was abolished in the Ca 2+ ‐free extracellular solution. Blocking of voltage‐gated Ca 2+ channels with Cd 2+ significantly reduced the effect of oxotremorine‐M on sIPSCs. However, neither the KCNQ channel blocker XE991 nor the adenylate cyclase inhibitor MDL‐12330A affected the effect of oxotremorine‐M on sIPSCs. Blocking of the non‐selective cation channels with SKF96365 or 2‐APB significantly inhibited the effect of oxotremorine‐M on sIPSCs. Treatment with the phosphoinositide‐3‐kinase inhibitor wortmanin or LY‐294002 abolished the stimulating effect of oxotremorine‐M on sIPSCs in 68% neurons tested. In the spinal cord slices from pertussis toxin treated rats (to eliminated M 2 and M 4 subtypes‐mediated effect), wortmanin also blocked the effect of oxotremorine‐M on sIPSCs in 65% neurons. Therefore, this study provides new information that mAChRs stimulate GABAergic neurons by Ca 2+ influx through voltage‐gated Ca 2+ channels and phosphoinositide‐3‐kinase ‐nonselective cation channel pathway in the spinal dorsal horn.