Journal Article

G‐protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal

Lowe, Janet, Cheong, Young‐Pyo, Terman, Gregory W, Chavkin, Charles, Jin, Wenzhen, Lefkowitz, Robert J, Caron, Marc G

2004

Overview

Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor desensitization by G‐protein receptor kinase mediated receptor phosphorylation and subsequent β‐arrestin binding. To define the role of this regulatory mechanism in the control of the electrophysiological and behavioral responses to opioids, we used mice having a targeted disruption of the G‐protein receptor kinase 3 (GRK3) gene. Mice lacking GRK3 did not differ from wild‐type littermates neither in their response latencies to noxious stimuli on the hot‐plate test nor in their acute antinociceptive responses to fentanyl or morphine. Tolerance to the electrophysiological response to the opioid fentanyl, measured in vitro in the hippocampus, was blocked by GRK3 deletion. In addition, tolerance to the antinociceptive effects of fentanyl was significantly reduced in GRK3 knockouts compared to wild‐type littermate controls. Tolerance to the antinociceptive effects of morphine was not affected by GRK3 deletion although morphine tolerance in hippocampal slices from GRK3 knockout mice was significantly inhibited. Tolerance developed more slowly in vitro to morphine than fentanyl supporting previous work in in vitro systems showing a correlation between agonist efficacy and GRK3‐mediated desensitization. The results of these studies suggest that GRK3‐mediated mechanisms are important components of both electrophysiologic and behavioral opioid tolerance. Fentanyl, a high efficacy opioid, more effectively produced GRK3‐dependent effects than morphine, a low efficacy agonist. British Journal of Pharmacology (2004) 141, 55–64. doi:10.1038/sj.bjp.0705595

• Publisher: Blackwell Publishing Ltd,Nature Publishing
• Subject: Analgesics, Opioid - adverse effects / Analgesics, Opioid - metabolism / Analgesics, Opioid - pharmacology / Animals / Biological and medical sciences / Dose-Response Relationship, Drug / Drug Implants / Drug Tolerance / Electrophysiology - methods / Evoked Potentials - drug effects / Evoked Potentials - physiology / fentanyl / Fentanyl - administration & dosage / Fentanyl - antagonists & inhibitors / Fentanyl - pharmacokinetics / G-Protein-Coupled Receptor Kinase 3 / GRK3 / Hippocampus - cytology / Hippocampus - drug effects / Hippocampus - physiology / Homozygote / Hot Temperature - adverse effects / Infusion Pumps, Implantable / Injections, Subcutaneous / Male / Medical sciences / Mice / Mice, Knockout / morphine / Morphine - administration & dosage / Morphine - antagonists & inhibitors / Morphine - pharmacokinetics / Naloxone - administration & dosage / Naloxone - pharmacokinetics / opioid receptor / Pain Measurement - methods / Pharmacology. Drug treatments / phosphorylation / Protein Serine-Threonine Kinases - drug effects / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Reaction Time - drug effects / Reaction Time - genetics / receptor desensitization / Receptors, Opioid - drug effects / Receptors, Opioid - genetics / Receptors, Opioid - metabolism / Substance Withdrawal Syndrome - genetics / Substance Withdrawal Syndrome - metabolism / Substance Withdrawal Syndrome - physiopathology / tolerance / Up-Regulation - drug effects / Up-Regulation - genetics / withdrawal