The Contribution of Gi/o Protein to Opioid Antinociception in an Oxaliplatin-Induced Neuropathy Rat Model

Abstract

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 mg/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]-GTPgS binding assay, activation of m-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.

Morphine and oxycodone, but not fentanyl, exhibit antinociceptive effects mediated by G-protein inwardly rectifying potassium (GIRK) channels in an oxaliplatin-induced neuropathy rat model

“…Recent evidence in clinical study suggests that oxycodone is effective in oxaliplatin-induced neuropathy [12]. According to this report, we have previously demonstrated that oxycodone and morphine completely relieved oxaliplatininduced mechanical allodynia while fentanyl antinociception was partial, and these antinociceptive differences may result from differential activation pattern of Gi/o proteins depending on MOR agonists in oxaliplatin-induced neuropathy animal model [13]. In the present study, we investigated further mechanisms underlying different efficacies of MOR agonists in oxaliplatin-induced neuropathy model, focusing on the role of GIRK1 channel function.…”

“…Oxaliplatin-induced peripheral neuropathy was initiated as described previously [13]. Rats were administered oxaliplatin (2 mg/kg, i.p.)…”

“…Mechanical allodynia was assessed using the up-down von Frey monofilament test as described previously [13]. Briefly, the von Frey filaments (0.6, 1, 1.4, 2, 4, 6, 8, 10, 15, and 26 g) were applied to each hind paw for a maximum period of 4 s, and the withdrawal response was observed.…”

“…administration was conducted as described previously [13]. Briefly, rats were anesthetized using 3% isoflurane.…”

Analgesic and Anti–Inflammatory Effects of Oxycodone with Adjuvant Drugs in an Experimental Study of Nociceptive and Neuropathic Pain

“…The dose of OXY used in this study (0.56 mg/kg b.w.) was taken from the Kanbara et al study, wherein after OXY administration (SC), this dose was effective in the treatment of NP in rats [17]. The choice of adjuvants and their doses were based on our earlier studies, in which concurrent analgesic effects of selected adjuvants with tramadol [18] and morphine [19] were explored.…”