Possible involvement of prolonging spinal µ-opioid receptor desensitization in the development of antihyperalgesic tolerance to µ-opioids under a neuropathic pain-like state

• Published in: Addiction biology Vol. 18; no. 4; pp. 614 - 622
• Main Authors: Narita, Minoru, Imai, Satoshi, Nakamura, Atsushi, Ozeki, Ayumi, Asato, Megumi, Rahmadi, Mahardian, Sudo, Yuka, Hojo, Minoru, Uezono, Yasuhito, Devi, Lakshmi A., Kuzumaki, Naoko, Suzuki, Tsutomu
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2013; John Wiley & Sons, Inc
• Subjects: Addiction; Analgesics, Opioid - administration & dosage; Analgesics, Opioid - pharmacology; Animals; beta-Endorphin - genetics; beta-Endorphin - physiology; Dose-Response Relationship, Drug; Drug Tolerance - physiology; Female; Fentanyl; Fentanyl - administration & dosage; Fentanyl - pharmacology; GTP-Binding Proteins - drug effects; GTP-Binding Proteins - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Hot Temperature; Hyperalgesia - drug therapy; Injections, Subcutaneous; Ligation; Male; Mice; Mice, Knockout; Morphine - administration & dosage; Morphine - pharmacology; mouse; Neuralgia - drug therapy; Neuralgia - metabolism; neuropathic pain; opioid tolerance; Oxycodone - administration & dosage; Oxycodone - pharmacology; Pain Measurement - methods; Pain Threshold - drug effects; Radioligand Assay; Receptors, Opioid, mu - agonists; Receptors, Opioid, mu - physiology; Sciatic Nerve - surgery; Sodium Chloride - administration & dosage; spinal cord; Spinal Cord - metabolism; μ-opioid receptor
• ISSN: 1355-6215; 1369-1600
• DOI: 10.1111/j.1369-1600.2011.00354.x

ABSTRACT In the present study, we investigated the possible development of tolerance to the antihyperalgesic effect of µ‐opioid receptor (MOR) agonists under a neuropathic pain‐like state. Repeated treatment with fentanyl, but not morphine or oxycodone, produced a rapid development of tolerance to its antihyperalgesic effect in mice with sciatic nerve ligation. Like the behavioral study, G‐protein activation induced by fentanyl was significantly reduced in membranes obtained from the spinal cord of nerve‐ligated mice with in vivo repeated injection of fentanyl. In β‐endorphin‐knockout mice with nerve ligation, developed tolerance to the antihyperalgesic effect of fentanyl was abolished, and reduced G‐protein activation by fentanyl after nerve ligation with fentanyl was reversed to the normal level. The present findings indicate that released β‐endorphin within the spinal cord may be implicated in the rapid development of tolerance to fentanyl under a neuropathic pain‐like state.