title: The contribution of Gi/o protein to opioid antinociception in an oxaliplatin-induced neuropathy rat model.
abstract: Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3-0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017-0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 μg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [(35)S]-GTPγS binding assay, activation of μ-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model.
authors.affiliation: Pain & Neurology, Discovery Research Laboratories, Shionogi & Co., Ltd., Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Kanbara
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nakamura
authors.forename: Keiko
authors.initials: K
authors.lastname: Takasu
authors.forename: Koichi
authors.initials: K
authors.lastname: Ogawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shibasaki
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kanemasa
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005283:Fentanyl / Q000494:pharmacology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D020645:Mediodorsal Thalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects*; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010098:Oxycodone / Q000494:pharmacology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D037342:Pertussis Toxin / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D009944:Organoplatinum Compounds; D017450:Receptors, Opioid, mu; D000077150:Oxaliplatin; D009020:Morphine; D010098:Oxycodone; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005283:Fentanyl