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.

Previous studies have shown that ligands of the sigma-1 receptor chaperone (Sig-1R) regulate pain-related behaviors. Clinical use of chemotherapeutics is often compromised due to their adverse side effects, particularly those related to neuropathy. Previous studies have shown that repeated administration of oxaliplatin and paclitaxel produces neuropathy in rodents. Therefore, the aim of the present study was to clarify the involvement of the Sig-1R in chemotherapeutic-induced neuropathy by examining the effects of oxaliplatin and paclitaxel on the Sig-1R levels in the spinal cord, and by examining the effects of Sig-1R agonist and antagonist on oxaliplatin- and paclitaxel-induced neuropathy in rats. Chemotherapeutic-induced neuropathic pain was accompanied by a significant reduction of the Sig-1R level in the spinal cord. Furthermore, the administration of paclitaxel to CHO cells that stably overexpressed Sig-1Rs induced the clustering of Sig-1Rs. We also found that the Sig-1R agonist SA4503 potently inhibited the neuropathy induced by oxaliplatin- and paclitaxel, whereas this action was abolished by the Sig-1R antagonist NE-100. These results suggest that the reduction of Sig-1R activity is involved in chemotherapeutic-induced neuropathy, and the Sig-1R agonist SA4503 could serve as a potential candidate for the treatment of chemotherapeutic-induced neuropathy.