title: Regulation of glutamate release from primary afferents and interneurons in the spinal cord by muscarinic receptor subtypes.
abstract: Activation of spinal muscarinic acetylcholine receptors (mAChRs) produces analgesia and inhibits dorsal horn neurons through potentiation of GABAergic/glycinergic tone and inhibition of glutamatergic input. To investigate the mAChR subtypes involved in the inhibitory effect of mAChR agonists on glutamate release, evoked excitatory postsynaptic currents (eEPSCs) were recorded in lamina II neurons using whole cell recordings in rat spinal cord slices. The nonselective mAChR agonist oxotremorine-M concentration-dependently inhibited the monosynaptic and polysynaptic EPSCs elicited by dorsal root stimulation. Interestingly, oxotromorine-M caused a greater inhibition of polysynaptic EPSCs (64.7%) than that of monosynaptic EPSCs (27.9%). In rats pretreated with intrathecal pertussis toxin, oxotremorine-M failed to decrease monosynaptic EPSCs but still partially inhibited the polysynaptic EPSCs in some neurons. This remaining effect was blocked by a relatively selective M(3) antagonist 4-DAMP. Himbacine, an M(2)/M(4) antagonist, or AFDX-116, a selective M(2) antagonist, completely blocked the inhibitory effect of oxotremorine-M on monosynaptic EPSCs. However, the specific M(4) antagonist MT-3 did not alter the effect of oxotremorine-M on monosynaptic EPSCs. Himbacine also partially attenuated the effect of oxotremorine-M on polysynaptic EPSCs in some cells and this effect was abolished by 4-DAMP. Furthermore, oxotremorine-M significantly decreased spontaneous EPSCs in seven of 22 (31.8%) neurons, an effect that was blocked by 4-DAMP. This study provides new information that the M(2) mAChRs play a critical role in the control of glutamatergic input from primary afferents to dorsal horn neurons. The M(3) and M(2)/M(4) subtypes on a subpopulation of interneurons are important for regulation of glutamate release from interneurons in the spinal dorsal horn.
authors.affiliation: Department of Anesthesiology and Pain Medicine, The University of Texas M.D. Anderson Cancer Center, 1400 Holcombe Blvd., Unit 409, Houston, TX 77030, USA.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Zhang
authors.forename: Shao-Rui
authors.initials: SR
authors.lastname: Chen
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D004347:Drug Interactions / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000187:drug effects / Q000378:metabolism; D043588:Receptor, Muscarinic M4 / Q000187:drug effects / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D018698:Glutamic Acid