The effects of chronic neuropathic pain states on the discriminative stimulus effect of fentanyl and other MOR agonists

Abstract Pleasant subjective effects of drugs (e.g., euphoria) have been demonstrated to contribute to their abuse potential. In humans, there is some evidence that acute pain states may decrease the positive subjective effects of opioids; however, no studies have directly tested the impact of a long-lasting pain state. Therefore, the goal of this study was to directly evaluate the discriminative stimulus of mu opioid receptor (MOR) agonist, fentanyl, or the non-opioid drug of abuse, cocaine, in the presence or absence of spared nerve injury (SNI) induced chronic neuropathic pain. Prior to surgery, MOR agonists (fentanyl, morphine, nalbuphine) dose-dependently increased % fentanyl-like responding, as expected; surprisingly, after surgery, we saw small, significant rightward shifts in the fentanyl and morphine dose response curves in both sham and SNI groups suggesting that the observed shifts were not due to chronic pain. In both sham and SNI groups, there was an increase in the generalization of nalbuphine to the fentanyl-discriminative stimulus. There was no change in the discriminative stimulus of cocaine (or amphetamine substitutions) over 4 months of SNI-induced chronic neuropathic pain or sham states, suggesting that the SNI model failed to alter the discriminative stimuli of fentanyl and cocaine. Following induction of chronic neuropathic pain, there was an observed increase in quinpirole-induced generalization to the cocaine discriminative stimulus. In the future, studies should directly examine the abuse potential of low efficacy MOR agonists and dopaminergic agonists in the presence and absence of chronic pain states. Significance Statement Subjective or interoceptive effects of drugs of abuse are known to contribute to the abuse potential. This study demonstrated that long-lasting neuropathic pain failed to alter the discriminative stimulus of mu opioid receptor agonists or cocaine; however, we observed an increase in quinpirole-induced generalization to the cocaine discriminative stimulus, suggesting the abuse potential of direct dopaminergic agonists should be further evaluated in the presence or absence of pain states. Competing Interest Statement The authors have declared no competing interest. Footnotes Primary lab of origin: Emily M. Jutkiewicz lab at the University of Michigan