Protein kinase C mediates the synergistic interaction between agonists acting at alpha2-adrenergic and delta-opioid receptors in spinal cord. The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] Journal article | | Title | Protein kinase C mediates the synergistic interaction between agonists acting at alpha2-adrenergic and delta-opioid receptors in spinal cord. | | Author(s) | Overland AC, Kitto KF, Chabot-Doré AJ, Rothwell PE, Fairbanks CA, Stone LS, Wilcox GL | | Institution | Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA. | | Source | J Neurosci 2009 Oct 21; 29(42):13264-73. | | MeSH | Adrenergic alpha-Agonists
Anesthetics, Local
Animals
Calcitonin Gene-Related Peptide
Clonidine
Dose-Response Relationship, Drug
Drug Combinations
Drug Synergism
Enzyme Inhibitors
Evoked Potentials
Excitatory Postsynaptic Potentials
Female
Hyperalgesia
Injections, Spinal
Male
Mice
Mice, Inbred C57BL
Mice, Inbred ICR
Oligopeptides
Patch-Clamp Techniques
Posterior Horn Cells
Potassium
Protein Kinase C
Rats
Rats, Sprague-Dawley
Receptors, Adrenergic, alpha-2
Receptors, Opioid, delta
Signal Transduction
Spinal Cord
Substance P
Tetrodotoxin
| | 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. | | Language | eng | | Pub Type(s) | In Vitro
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
| | PubMed ID | 19846714 |
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