BACKGROUND AND PURPOSEBone cancer pain is chronic and often difficult to control with opioids. However, recent studies have shown that several opioids have distinct analgesic profiles in chronic pain. EXPERIMENTAL APPROACHTo clarify the mechanisms underlying these distinct analgesic profiles, functional changes in the m-opioid receptor were examined using a mouse femur bone cancer (FBC) model. KEY RESULTSIn the FBC model, the Bmax of [ CONCLUSION AND IMPLICATIONSThese results show that m-opioid receptor functions are attenuated in several pain-related regions in bone cancer in an agonist-dependent manner, and suggest that modification of the m-opioid receptor is responsible for the distinct analgesic effect of oxycodone and morphine.

Background and Purpose Oxycodone and morphine are μ‐opioid receptor agonists prescribed to control moderate‐to‐severe pain. Previous studies suggested that these opioids exhibit different analgesic profiles. We hypothesized that distinct mechanisms mediate the differential effects of these two opioids and investigated the role of G protein‐gated inwardly rectifying potassium (KIR3 also known as GIRK) channels in their antinociceptive effects. Experimental Approach Opioid‐induced antinociceptive effects were assessed in mice, using the tail‐flick test, by i.c.v. and intrathecal (i.t.) administration of morphine and oxycodone, alone and following inhibition of KIR3.1 channels with tertiapin‐Q (30 pmol per mouse, i.c.v. and i.t.) and KIR3.1‐specific siRNA. The antinociceptive effects of oxycodone and morphine were also examined after tertiapin‐Q administration in the mouse femur bone cancer and neuropathic pain models. Key Results The antinociceptive effects of oxycodone, after both i.c.v. and i.t. administrations, were markedly attenuated by KIR3.1 channel inhibition. In contrast, the antinociceptive effects of i.c.v. morphine were unaffected, whereas those induced by i.t. morphine were attenuated, by KIR3.1 channel inhibition. In the two chronic pain models, the antinociceptive effects of s.c. oxycodone, but not morphine, were inhibited by supraspinal administration of tertiapin‐Q. Conclusion and Implications These results demonstrate that KIR3.1 channels play a primary role in the antinociceptive effects of oxycodone, but not those of morphine, at supraspinal sites and suggest that supraspinal KIR3.1 channels are responsible for the unique analgesic profile of oxycodone.

IntroductionAlthough m-opioid receptor agonists such as morphine, oxycodone, and fentanyl have prominent antinociceptive effects, they also have adverse effects (e.g., emesis, constipation, drowsiness, and psychological dependence). Psychological dependence on opioids is a serious problem worldwide, and one of the triggers for inducing such opioid dependence is the inappropriate use or overdose of prescribed m-opioid receptor agonists (1). It is widely accepted that psychological events such as the reinforcing effects induced by m-opioid receptor agonists can be mimicked in animals as rewarding effects (2 -4), and activation of the mesolimbic dopaminergic system, which projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), plays an important role in the rewarding effects of m-opioid receptor agonists (5 -8).Recently, it has been shown that, as long as m-opioid receptor agonists are used appropriately to control pain, psychological dependence does not occur in clinical situations (9,10 Abstract. The rewarding effects of m-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used m-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of m-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug-induced neuropathic pain. Nevertheless, no information is available regarding whether mreceptor agonists produce psychological dependence under chemotherapeutic drug-induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of m-receptor agonists were not suppressed under oxaliplatin-or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of m-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of m-receptor agonists can still be established under oxaliplatin-or paclitaxelinduced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on m-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain.