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Role of presynaptic muscarinic and GABA(B) receptors in spinal glutamate release and cholinergic analgesia in rats.
J Physiol. 2002 Sep 15; 543(Pt 3):807-18.JP

Abstract

Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce effective pain relief. However, the analgesic mechanisms and the site of actions of cholinergic agents in the spinal cord are not fully understood. In this study, we investigated the mechanisms underlying cholinergic presynaptic regulation of glutamate release onto spinal dorsal horn neurons. The role of spinal GABA(B) receptors in the antinociceptive action of muscarine was also determined. Whole-cell voltage-clamp recordings were performed on visualized dorsal horn neurons in the lamina II in the spinal cord slice preparation of rats. The miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) were recorded in the presence of tetrodotoxin. The evoked EPSCs (eEPSCs) were obtained by electrical stimulation of the dorsal root entry zone or the attached dorsal root. Nociception in rats was measured using a radiant heat stimulus and the effect of intrathecal administration of drugs tested. Acetylcholine (10-100 microM) reduced the amplitude of monosynaptic eEPSCs in a concentration-dependent manner. Acetylcholine also significantly decreased the frequency of non-NMDA receptor-mediated mEPSCs, which was antagonized by atropine but not mecamylamine. The frequency of GABA(A) receptor-mediated mIPSCs was significantly increased by acetylcholine and this excitatory effect was abolished by atropine. Existence of presynaptic M(2) muscarinic receptors in the spinal dorsal horn was further demonstrated by immunocytochemistry staining and dorsal rhizotomy. CGP55845, a GABA(B) receptor antagonist, significantly attenuated the inhibitory effect of acetylcholine on the frequency of mEPSCs and the amplitude of monosynaptic eEPSCs in lamina II neurons. Furthermore, the antinociceptive action produced by intrathecal muscarine was significantly reduced by CGP55845 pretreatment in rats. Therefore, data from this integrated study provide new information that acetylcholine inhibits the glutamatergic synaptic input to lamina II neurons through presynaptic muscarinic receptors. Inhibition of glutamate release onto lamina II neurons by presynaptic muscarinic and GABA(B) heteroreceptors in the spinal cord probably contributes to the antinociceptive action of cholinergic agents.

Authors+Show Affiliations

Department of Anesthesiology, Penn State University College of Medicine, Hershey, PA 17033, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12231640

Citation

Li, De-Pei, et al. "Role of Presynaptic Muscarinic and GABA(B) Receptors in Spinal Glutamate Release and Cholinergic Analgesia in Rats." The Journal of Physiology, vol. 543, no. Pt 3, 2002, pp. 807-18.
Li DP, Chen SR, Pan YZ, et al. Role of presynaptic muscarinic and GABA(B) receptors in spinal glutamate release and cholinergic analgesia in rats. J Physiol (Lond). 2002;543(Pt 3):807-18.
Li, D. P., Chen, S. R., Pan, Y. Z., Levey, A. I., & Pan, H. L. (2002). Role of presynaptic muscarinic and GABA(B) receptors in spinal glutamate release and cholinergic analgesia in rats. The Journal of Physiology, 543(Pt 3), 807-18.
Li DP, et al. Role of Presynaptic Muscarinic and GABA(B) Receptors in Spinal Glutamate Release and Cholinergic Analgesia in Rats. J Physiol (Lond). 2002 Sep 15;543(Pt 3):807-18. PubMed PMID: 12231640.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of presynaptic muscarinic and GABA(B) receptors in spinal glutamate release and cholinergic analgesia in rats. AU - Li,De-Pei, AU - Chen,Shao-Rui, AU - Pan,Yu-Zhen, AU - Levey,Allan I, AU - Pan,Hui-Lin, PY - 2002/9/17/pubmed PY - 2003/2/26/medline PY - 2002/9/17/entrez SP - 807 EP - 18 JF - The Journal of physiology JO - J. Physiol. (Lond.) VL - 543 IS - Pt 3 N2 - Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce effective pain relief. However, the analgesic mechanisms and the site of actions of cholinergic agents in the spinal cord are not fully understood. In this study, we investigated the mechanisms underlying cholinergic presynaptic regulation of glutamate release onto spinal dorsal horn neurons. The role of spinal GABA(B) receptors in the antinociceptive action of muscarine was also determined. Whole-cell voltage-clamp recordings were performed on visualized dorsal horn neurons in the lamina II in the spinal cord slice preparation of rats. The miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) were recorded in the presence of tetrodotoxin. The evoked EPSCs (eEPSCs) were obtained by electrical stimulation of the dorsal root entry zone or the attached dorsal root. Nociception in rats was measured using a radiant heat stimulus and the effect of intrathecal administration of drugs tested. Acetylcholine (10-100 microM) reduced the amplitude of monosynaptic eEPSCs in a concentration-dependent manner. Acetylcholine also significantly decreased the frequency of non-NMDA receptor-mediated mEPSCs, which was antagonized by atropine but not mecamylamine. The frequency of GABA(A) receptor-mediated mIPSCs was significantly increased by acetylcholine and this excitatory effect was abolished by atropine. Existence of presynaptic M(2) muscarinic receptors in the spinal dorsal horn was further demonstrated by immunocytochemistry staining and dorsal rhizotomy. CGP55845, a GABA(B) receptor antagonist, significantly attenuated the inhibitory effect of acetylcholine on the frequency of mEPSCs and the amplitude of monosynaptic eEPSCs in lamina II neurons. Furthermore, the antinociceptive action produced by intrathecal muscarine was significantly reduced by CGP55845 pretreatment in rats. Therefore, data from this integrated study provide new information that acetylcholine inhibits the glutamatergic synaptic input to lamina II neurons through presynaptic muscarinic receptors. Inhibition of glutamate release onto lamina II neurons by presynaptic muscarinic and GABA(B) heteroreceptors in the spinal cord probably contributes to the antinociceptive action of cholinergic agents. SN - 0022-3751 UR - https://www.unboundmedicine.com/medline/citation/12231640/Role_of_presynaptic_muscarinic_and_GABA_B__receptors_in_spinal_glutamate_release_and_cholinergic_analgesia_in_rats_ L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0022-3751&date=2002&volume=543&spage=807 DB - PRIME DP - Unbound Medicine ER -