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The Journal of Neuroscience, October 21, 2009, 29(42):13264-13273; doi:10.1523/JNEUROSCI.1907-09.2009

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Cellular/Molecular
Protein Kinase C Mediates the Synergistic Interaction Between Agonists Acting at ₂-Adrenergic and Delta-Opioid Receptors in Spinal Cord

Aaron C. Overland,^1,3 Kelley F. Kitto,^2,3,4 Anne-Julie Chabot-Doré,⁹ Patrick E. Rothwell,^1,3 Carolyn A. Fairbanks,^1,2,3,4 Laura S. Stone,^6,7,8 and George L. Wilcox^1,3,4,5

¹Graduate Program in Neuroscience, ²Department of Pharmaceutics, College of Pharmacy, and Departments of ³Neuroscience, ⁴Pharmacology, and ⁵Dermatology, Medical School, University of Minnesota, Minneapolis, Minnesota 55455, and ⁶Faculty of Dentistry, Alan Edwards Centre for Research on Pain, Departments of ⁷Pharmacology and Toxicology and ⁸Anesthesia, Faculty of Medicine, and ⁹Alan Edwards Centre for Research on Pain, McGill University, Montreal, Quebec H3A 1A4, Canada

Correspondence should be addressed to George L. Wilcox, University of Minnesota, Department of Neuroscience, 6-145 Jackson Hall, Minneapolis, MN 55455. Email: george{at}umn.edu

Coactivation of spinal ₂-adrenergic receptors (ARs) and opioid receptors produces antinociceptive synergy. Antinociceptive synergy between intrathecally administered ₂AR and opioid agonists is well documented, but the mechanism underlying this synergy remains unclear. The delta-opioid receptor (DOP) and the _2AARs 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 ₂AR 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 ₂AR agonists in the spinal cord.

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Received April 21, 2009; revised Sept. 8, 2009; accepted Sept. 14, 2009.

Correspondence should be addressed to George L. Wilcox, University of Minnesota, Department of Neuroscience, 6-145 Jackson Hall, Minneapolis, MN 55455. Email: george{at}umn.edu

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