Tonic inhibitory role of α4β2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice

In the spinal dorsal horn, activation of the nicotinic acetylcholine receptors (nAChR) by exogenously applied agonists is known to enhance inhibitory synaptic transmission, and to produce analgesia. However, it is still unknown whether endogenously released acetylcholine exerts a tonic inhibition on nociceptive transmission through the nAChRs in the spinal dorsal horn. Here, we report the presence of such a tonic inhibitory mechanism in the spinal dorsal horn in mice. In behavioral experiments, intrathecal (i.t.) injection of non-selective nAChR antagonist mecamylamine and alpha 4 beta 2 subtype-selective antagonist dihydro-beta-erythroidine (DH beta E) dose-dependently induced thermal and mechanical hyperalgesia in mice while the alpha 7-selective antagonist methyl lycaconitine (MLA) had no effect. Similarly, antisense knock-down of alpha 4 subunit of nAChR, but not alpha 7 subunit, in spinal cord induced thermal and mechanical hyperalgesia. In whole-cell patch-clamp experiments in spinal cord slice preparation from adult mice, the frequency of miniature inhibitory postsynaptic currents (mIPSCs) observed in substantia gelatinosa (SG) neurons was decreased by mecamylamine and DH beta E, but not by MLA. The amplitudes of the mIPSCs were not affected. The nicotinic antagonists decreased the frequency of both GABAergic and glycinergic IPSCs. On the other hand, the nicotinic antagonists had no effect on the excitatory postsynaptic currents (EPSCs). Finally, acetylcholine-esterase inhibitor neostigmine-induced facilitation of IPSO frequencies in SG neurons was inhibited by mecamylamine and DHPE. Altogether these findings suggest that nicotinic cholinergic system in the spinal dorsal horn can tonically inhibit nociceptive transmission through presynaptic facilitation of inhibitory neurotransmission in SG via the alpha 4 beta 2 subtype of nAChR. (c) 2006 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.