[Difference in tolerance to anti-hyperalgesic effect and its molecular mechanisms between chronic treatment with morphine, fentanyl and oxycodone in a chronic pain-like state].
In 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.
Satoshi
Imai
I
Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Narita
Minoru
M
Ozeki
Ayumi
A
Nakamura
Atsushi
A
Hashimoto
Seiko
S
Narita
Michiko
M
Kuzumaki
Naoko
N
Uezono
Yasuhito
Y
Suzuki
Tsutomu
T
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000235:genetics*; D005283:Fentanyl / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000627:therapeutic use*; D010098:Oxycodone / Q000008:administration & dosage / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy*; D017450:Receptors, Opioid, mu / Q000502:physiology*; D001615:beta-Endorphin / Q000378:metabolism / Q000502:physiology*
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D001615:beta-Endorphin; D009020:Morphine; D010098:Oxycodone; D005283:Fentanyl