Research article summary (published 19 Oct 2009):

Protein kinase C mediates the synergistic interaction between agonists acting at alpha2-adrenergic and delta-opioid receptors in spinal cord.

Full Abstract

Coactivation of spinal alpha(2)-adrenergic receptors (ARs) and opioid receptors produces antinociceptive synergy. Antinociceptive synergy between intrathecally administered alpha(2)AR and opioid agonists is well documented, but the mechanism underlying this synergy remains unclear. The delta-opioid receptor (DOP) and the alpha(2A)ARs are coexpressed on the terminals of primary afferent fibers in the spinal cord where they may mediate this phenomenon. We evaluated the ability of the DOP-selective agonist deltorphin II (DELT), the alpha(2)AR agonist clonidine (CLON) or their combination to inhibit calcitonin gene-related peptide (CGRP) release from spinal cord slices. We then examined the possible underlying signaling mechanisms involved through coadministration of inhibitors of phospholipase C (PLC), protein kinase C (PKC) or protein kinase A (PKA). Potassium-evoked depolarization of spinal cord slices caused concentration-dependent release of CGRP. Coadministration of DELT and CLON inhibited the release of CGRP in a synergistic manner as confirmed statistically by isobolograpic analysis. Synergy was dependent on the activation of PLC and PKC, but not PKA, whereas the effect of agonist administration alone was only dependent on PLC. The importance of these findings was confirmed in vivo, using a thermal nociceptive test, demonstrating the PKC dependence of CLON-DELT antinociceptive synergy in mice. That inhibition of CGRP release by the combination was maintained in the presence of tetrodotoxin in spinal cord slices suggests that synergy does not rely on interneuronal signaling and may occur within single subcellular compartments. The present study reveals a novel signaling pathway underlying the synergistic analgesic interaction between DOP and alpha(2)AR agonists in the spinal cord.

Author information

Author/s: Overland, Aaron C (AC); Kitto, Kelley F (KF); Chabot-Doré, Anne-Julie (AJ); Rothwell, Patrick E (PE); Fairbanks, Carolyn A (CA); Stone, Laura S (LS); Wilcox, George L (GL);

Affiliation: Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Grants: R01DA015438 (Agency:NIDA NIH HHS) ; T32DA07234 (Agency:NIDA NIH HHS)

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Oct; vol 29 (issue 42) : pp 13264-73

Dates: Created 2009/10/22; Completed 2009/11/06;

PMID: 19846714, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Adrenergic alpha-Agonists - pharmacology Anesthetics, Local - pharmacology Animals Calcitonin Gene-Related Peptide - metabolism Clonidine - pharmacology Dose-Response Relationship, Drug Drug Combinations Drug Synergism Enzyme Inhibitors - pharmacology Evoked Potentials - drug effects; physiology Excitatory Postsynaptic Potentials - drug effects Female Hyperalgesia - metabolism Injections, Spinal - methods Male Mice

Mice Mice, Inbred C57BL Mice, Inbred ICR Oligopeptides - pharmacology Patch-Clamp Techniques - methods Posterior Horn Cells - drug effects; metabolism Potassium - pharmacology Protein Kinase C - metabolism Rats Rats, Sprague-Dawley Receptors, Adrenergic, alpha-2 - agonists; metabolism Receptors, Opioid, delta - agonists; metabolism Signal Transduction - drug effects; physiology Spinal Cord - cytology; metabolism Substance P - metabolism Tetrodotoxin - pharmacology

Associated Chemicals: Adrenergic alpha-Agonists (0) ; Anesthetics, Local (0) ; Drug Combinations (0) ; Enzyme Inhibitors (0) ; Oligopeptides (0) ; Receptors, Adrenergic, alpha-2 (0) ; Receptors, Opioid, delta (0) ; deltorphin II, Ala(2)- (122752-16-3) ; Substance P (33507-63-0) ; Clonidine (4205-90-7) ; Tetrodotoxin (4368-28-9) ; Potassium (7440-09-7) ; Calcitonin Gene-Related Peptide (83652-28-2) ; Protein Kinase C (EC 2.7.11.13)

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