The contribution of Gi/o protein to opioid antinociception in an oxaliplatin-induced neuropathy rat model

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 [35s]-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. © the japanese pharmacological society.