title: Differences in tolerance to anti-hyperalgesic effects between chronic treatment with morphine and fentanyl under a state of pain.
abstract: The present study was undertaken to investigate the possible change in anti-hyperalgesic effect following repeated treatment with morphine or fentanyl using the dose to improve the thermal hyperalgesia under an inflammatory pain-like state. The anti-hyperalgesic effect induced by fentanyl in complete Freund's adjuvant (CFA)-pretreated mice rapidly disappeared during the consecutive administration of fentanyl, whereas morphine preserved its potency of anti-hyperalgesic effect. In addition, repeated treatment with fentanyl, but not morphine, resulted in the increase in levels of phosphorylated-mciro-opioid receptor (MOR) associated with the enhanced inactivation of protein phosphatase 2A and the reduction in Rab4-dependent MOR resensitization. Next, we investigated the specific involvement of the opioid receptor types and MOR subtypes in analgesic properties of morphine and fentanyl in the mouse spinal cord. In the competitive displacement binding assay with [1H]DAMGO, no significant difference in the binding affinity to MOR between morphine and fentanyl was noted in membranes obtained from the mouse spinal cord. Furthermore, there was no significant difference between morphine and fentanyl in either antinociceptive effect or G-protein activation in mice partially lacking MOR-1B, which shows a greater resistance to agonist-induced desensitization than for other MOR subtypes. These findings point out the possibility that the chronic treatment with fentanyl may cause the different modulation from chronic treatment with morphine on either the internalization or resensitization of MORs in the spinal cord under a pain-like state. The present data provide the first evidence for the mechanism underlying the development of tolerance to fentanyl-induced anti-hyperalgesic effect under chronic pain.
authors.affiliation: Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8501 Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Imai
authors.forename: Minoru
authors.initials: M
authors.lastname: Narita
authors.forename: Seiko
authors.initials: S
authors.lastname: Hashimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Kan
authors.initials: K
authors.lastname: Miyoshi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nozaki
authors.forename: Nana
authors.initials: N
authors.lastname: Hareyama
authors.forename: Tomoe
authors.initials: T
authors.lastname: Takagi
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Michiko
authors.initials: M
authors.lastname: Narita
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005620:Freund's Adjuvant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054648:Protein Phosphatase 2; D017450:Receptors, Opioid, mu / Q000145:classification / Q000378:metabolism; D012996:Solutions; D013116:Spinal Cord / Q000378:metabolism; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D012996:Solutions; D009020:Morphine; D005620:Freund's Adjuvant; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D020695:rab4 GTP-Binding Proteins; D005283:Fentanyl