Behavioral Effects of Opioid Analgesics in the Presence or Absence of Chronic Neuropathic Pain

Abstract

Chronic neuropathic pain affects ~6.9-10% of the American population. Previous research suggested that chronic pain conditions may increase the susceptibility to developing an opioid use disorder (OUD). Opioid analgesics, or mu-opioid receptor (MOR) agonists, are often used to treat chronic neuropathic pain, such that more than half (~69%) of patients are treated with MOR agonists at some point during their condition. Thus, the goal of these studies was to examine the effect of a neuropathic chronic pain state on the antinociceptive, antihyperalgesic, response rate decreasing, subjective, and reinforcing effects produced by opioid analgesics in both male and female rats. These behavioral effects of the MOR agonists, fentanyl, morphine, and nalbuphine, were evaluated before and after the induction of spared nerve injury (or sham surgery), which produces long-lasting hypersensitivity to noxious stimuli. To evaluate potential pain-relieving effects of MOR agonists, paw withdrawal thresholds were measured in response to increasing mechanical pressure applied to the hind paws. Rates of responding was measured in schedule-controlled responding assays under a fixed ratio (FR)10 schedule of reinforcement. Subjective or discriminative stimulus effects were evaluated in animals trained to discriminate experimenter-administered injections of fentanyl from saline under a fixed ratio (FR) 10 schedule of reinforcement for sucrose pellets. To measure reinforcing effects, animals responded on a FR5 schedule of reinforcement to produce intravenous infusions of fentanyl. Fentanyl, morphine, and nalbuphine produced dose-dependent increases in paw withdrawal thresholds and increases in fentanyl-like discriminative stimulus effects in both male and female rats. Following surgery, small, but significant, decreases in sensitivity to antinociceptive- and antihyperalgesic-like effects, discriminative stimulus effects, and rate suppressant effects of fentanyl and morphine were observed over time; however, these changes were independent of the presence or absence of nerve injury. While decreases in sensitivity to the rate suppressant effects of nalbuphine were also found in discrimination and schedule controlled responding assays, nalbuphine was more potent and/or effective in producing antinociceptive, antihyperalgesic, and fentanyl-appropriate responding over time. Similar to that observed with fentanyl and morphine, the changes in the effects of nalbuphine were independent of nerve injury. Finally, in self-administration experiments, fentanyl maintained responding in male and female rats. Following surgery, there was a significant decrease in fentanyl self-administration on post-operative day 4 that was resolved/restored by post-operative day 9. Over the remaining 4 weeks of post-surgical evaluation, independent of injury, there was an increased intake of specifically the 10 μg/kg dose in both groups. Collectively, these data indicate that chronic neuropathic pain produced few, if any changes, in the behavioral effects of high efficacy MOR agonists, such as fentanyl and morphine. Interestingly, there were changes in the behavioral effects of the partial MOR agonist, nalbuphine, over time that were also independent of nerve injury. The work presented in this dissertation provides novel evidence that chronic neuropathic pain does not alter the behavioral effects of MOR agonists or increase susceptibility to the abuse liability of opioid analgesics. Therefore, increased incidences of OUD diagnoses in chronic pain patients are more likely explained by frequent use of opioids or increased access to opioid prescriptions rather than chronic pain itself.