• Imai Satoshi, Minoru Narita, Ayumi Ozeki, Atsushi Nakamura, Seiko Hashimoto, Michiko Narita, Naoko Kuzumaki, Yasuhito Uezono, and Tsutomu Suzuki.
• Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
• Nihon Shinkei Seishin Yakurigaku Zasshi. 2008 Nov 1; 28 (5-6): 169-76.

AbstractIn the present study, we demonstrated that repeated treatment with fentanyl, but not morphine or oxycodone, causes a rapid desensitization to its ability to block the hyperalgesia associated with the attenuation of mu-opioid receptor resensitization in mice in a chronic pain-like state. In contrast, no such effect was noted in beta-endorphin knockout mice under the chronic pain-like conditions. On the assumption that beta-endorphin might be released within the spinal cord under pain-like conditions, we further examined whether beta-endorphin could be responsible for a desensitization and resensitization of fentanyl under the chronic pain. In cultured cells, unlike morphine, fentanyl and oxycodone induced a robust mu-opioid receptor internalization and, in turn, its resensitization. In the presence of beta-endorphin, the internalized mu-opioid receptor induced by fentanyl, but not oxycodone, remained within the cytosolic component even after washing out. The findings suggest that beta-endorphin could attenuate the resensitization of mu-opioid receptors. This phenomenon may explain the high degree of tolerance to fentanyl that develops with hyperalgesia caused by a chronic pain-like state.

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