1. Modulation of mu opioid receptor desensitization in peripheral sensory neurons by phosphoinositide 3-kinase gamma.
- Author
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König C, Gavrilova-Ruch O, von Banchet GS, Bauer R, Grün M, Hirsch E, Rubio I, Schulz S, Heinemann SH, Schaible HG, and Wetzker R
- Subjects
- Animals, Calcium Channels physiology, Cells, Cultured enzymology, Cells, Cultured physiology, Class II Phosphatidylinositol 3-Kinases deficiency, Class II Phosphatidylinositol 3-Kinases genetics, Drug Tolerance physiology, Ganglia, Spinal cytology, Mice, Mice, Knockout, Morphine administration & dosage, Morphine therapeutic use, Narcotics administration & dosage, Narcotics therapeutic use, Nociceptors drug effects, Nociceptors physiology, Patch-Clamp Techniques, Rats, Rats, Wistar, Reaction Time drug effects, Recombinant Fusion Proteins physiology, Sensory Receptor Cells drug effects, Sensory Receptor Cells physiology, TRPV Cation Channels drug effects, TRPV Cation Channels physiology, Class II Phosphatidylinositol 3-Kinases physiology, Morphine pharmacology, Narcotics pharmacology, Receptors, Opioid, mu drug effects, Sensory Receptor Cells enzymology
- Abstract
G protein-coupled opioid receptors undergo desensitization after prolonged agonist exposure. Recent in vitro studies of mu-opioid receptor (MOR) signaling revealed an involvement of phosphoinositide 3-kinases (PI3K) in agonist-induced MOR desensitization. Here we document a specific role of the G protein-coupled class IB isoform PI3Kgamma in MOR desensitization in mice and isolated sensory neurons. The tail-withdrawal nociception assay evidenced a compromised morphine-induced tolerance of PI3Kgamma-deficient mice compared to wild-type animals. Consistent with a role of PI3Kgamma in MOR signaling, PI3Kgamma was expressed in a subgroup of small-diameter dorsal root ganglia (DRG) along with MOR and the transient receptor potential vanilloid type 1 (TRPV1) receptor. In isolated DRG acute stimulation of MOR blocked voltage-gated calcium currents (VGCC) in both wild-type and PI3Kgamma-deficient DRG neurons. By contrast, following long-term opioid administration the attenuating effect of MOR was strongly compromised in wild-type DRG but not in PI3Kgamma-deficient DRG. Our results uncover PI3Kgamma as an essential modulator of long-term MOR desensitization and tolerance development induced by chronic opioid treatment in sensory neurons., (Copyright (c) 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2010
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