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Tonic inhibitory role of alpha4beta2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice.
Pain 2006; 125(1-2):125-35PAIN

Abstract

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 alpha4beta2 subtype-selective antagonist dihydro-beta-erythroidine (DHbetaE) dose-dependently induced thermal and mechanical hyperalgesia in mice while the alpha7-selective antagonist methyllycaconitine (MLA) had no effect. Similarly, antisense knock-down of alpha4 subunit of nAChR, but not alpha7 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 DHbetaE, 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 IPSC frequencies in SG neurons was inhibited by mecamylamine and DHbetaE. 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 alpha4beta2 subtype of nAChR.

Authors+Show Affiliations

Department of Integrative Physiology, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan. mdharunor.rashid@mcgill.caNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16781069

Citation

Rashid, Md Harunor, et al. "Tonic Inhibitory Role of Alpha4beta2 Subtype of Nicotinic Acetylcholine Receptors On Nociceptive Transmission in the Spinal Cord in Mice." Pain, vol. 125, no. 1-2, 2006, pp. 125-35.
Rashid MH, Furue H, Yoshimura M, et al. Tonic inhibitory role of alpha4beta2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice. Pain. 2006;125(1-2):125-35.
Rashid, M. H., Furue, H., Yoshimura, M., & Ueda, H. (2006). Tonic inhibitory role of alpha4beta2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice. Pain, 125(1-2), pp. 125-35.
Rashid MH, et al. Tonic Inhibitory Role of Alpha4beta2 Subtype of Nicotinic Acetylcholine Receptors On Nociceptive Transmission in the Spinal Cord in Mice. Pain. 2006;125(1-2):125-35. PubMed PMID: 16781069.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tonic inhibitory role of alpha4beta2 subtype of nicotinic acetylcholine receptors on nociceptive transmission in the spinal cord in mice. AU - Rashid,Md Harunor, AU - Furue,Hidemasa, AU - Yoshimura,Megumu, AU - Ueda,Hiroshi, Y1 - 2006/06/15/ PY - 2005/11/23/received PY - 2006/04/06/revised PY - 2006/05/03/accepted PY - 2006/6/20/pubmed PY - 2006/11/10/medline PY - 2006/6/20/entrez SP - 125 EP - 35 JF - Pain JO - Pain VL - 125 IS - 1-2 N2 - 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 alpha4beta2 subtype-selective antagonist dihydro-beta-erythroidine (DHbetaE) dose-dependently induced thermal and mechanical hyperalgesia in mice while the alpha7-selective antagonist methyllycaconitine (MLA) had no effect. Similarly, antisense knock-down of alpha4 subunit of nAChR, but not alpha7 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 DHbetaE, 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 IPSC frequencies in SG neurons was inhibited by mecamylamine and DHbetaE. 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 alpha4beta2 subtype of nAChR. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/16781069/Tonic_inhibitory_role_of_alpha4beta2_subtype_of_nicotinic_acetylcholine_receptors_on_nociceptive_transmission_in_the_spinal_cord_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3959(06)00262-4 DB - PRIME DP - Unbound Medicine ER -