Establishment of Opioid-Induced Rewarding Effects Under Oxaliplatin- and Paclitaxel-Induced Neuropathy in Rats

Abstract

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.

Effects of paclitaxel on mechanical sensitivity and morphine reward in male and female C57Bl6 mice.

“…In the CPP experiments, paclitaxel-induced allodynia failed to alter significantly the effects of morphine relative to saline-treated control male and female mice. Our observation that the susceptibility to morphine’s conditioned rewarding effects remains unaltered as a function of paclitaxel treatment is consistent with a recent report in male rats where the conditioned rewarding effects of opioids such as 4 mg/kg morphine, 0.056 mg/kg oxycodone, and 0.017 mg/kg fentanyl, administered subcutaneously, were not altered in the presence of paclitaxel- and oxaliplatin-induced treatment (Mori, et al, 2014). However, our results are in contrast to the reports indicating either an increase (Cahill CM, 2013; Sufka, 1994) or a decrease (Suzuki, Kishimoto, & Misawa, 1996) (Niikura, Kobayashi, et al, 2008; Niikura, Narita, et al, 2008; Ozaki, et al, 2003; Ozaki, et al, 2002; Ozaki, et al, 2004) in opioid reward using alternative chronic pain models such as persistent inflammatory pain and neuropathic pain from nerve injury in male rats and mice.…”

Repeated Morphine Produces Sensitization to Reward and Tolerance to Antiallodynia in Male and Female Rats with Chemotherapy-Induced Neuropathy

“…Second, paclitaxel also failed to alter the trajectory of increasing morphine reward produced by repeated morphine administration. This supports a previous study that found no effect of paclitaxel on morphine-induced conditioned place preference in rats (Mori et al, 2014) and extends these studies by showing a failure of paclitaxel to alter the changes in morphine reward that occur with initial exposure to a regimen of repeated morphine treatment. It is especially relevant to note that repeated morphine administration produced increasing expression of reward while producing decreased expression of (i.e., tolerance to) antiallodynia.…”

The Effect of Anakinra on Paclitaxel-Induced Peripheral Neuropathic Pain in Rats

“…After the normal paw pain threshold of the animal groups was measured using a Basile ® algesimeter (18), a daily single dose of 2 mg kg −1 paclitaxel was intraperitoneally administered to the rats in the PAC, PAC-50 and PAC-100 groups for a total of four times on days 1, 3, 5 and 7, with a twoday interval between each administration (17,19). At the end of day 7, 50 mg kg −1 and 100 mg kg −1 doses of anakinra were intraperitoneally injected to the rats in the PAC-50 and PAC-100 groups, respectively.…”