Mu opioid receptor (MOR) agonist‐induced antihyperalgesic effects following spared nerve injury in male and female rats

In most preclinical models of neuropathic pain, hypersensitivity to pain often resolves after a few weeks. However, spared nerve injury (SNI) produces a persistent pain state that lasts at least 18 months. The goal of the current study was to evaluate antihyperalgesic effects of mu-opioid receptor (MOR) agonists varying in potency and efficacy in the SNI model. We hypothesized that the MOR agonists, fentanyl, morphine, and nalbuphine, would produce antihyperalgesic effects in both male and female rats. Mechanical hypersensitivity was evaluated by measuring responses to increasing pressure (g) applied to each paw (paw pressure test or Randall-Selitto test) with a maximum cut-off of 300 g. Using a within-subjects design, responses were evaluated before and after SNI or sham surgery in male and female rats, and cumulative dose effects curves for fentanyl (0.01-0.1 mg/kg), morphine (0.3-10 mg/kg), and nalbuphine (0.3-10 mg/kg) were determined. Both male and female sham rats demonstrated an initial hypersensitivity on their ipsilateral paw following surgery that dissipated within 7 d. Following SNI surgery, paw pressure thresholds on the injured paw were lower as compared with the pre-surgical response and with the contralateral paw for at least 20 wks in male and female rats. In male rats, fentanyl, morphine, and nalbuphine dose-dependently alleviated SNI-induced hypersensitivity, with EC50 values of 0.03 (± 0.007), 3.9 (± 0.8), and 5.3 (± 0.8) mg/kg, respectively. In female rats, fentanyl, morphine, and nalbuphine also alleviated SNI-induced hypersensitivity in a dose-dependent manner, with EC50 values of 0.01 (± 0.002), 4.1 (± 0.8), and 5.5 (± 0.8) mg/kg, respectively. Naltrexone (0.3 mg/kg) produced rightward shifts in the fentanyl and morphine dose effect curves. Interestingly, fentanyl and morphine also increased paw pressure thresholds in the uninjured, contralateral paws and sham-treated ipsilateral paws in male and female rats. In contrast, gabapentin produced anti-hyperalgesic effects in both male and female rats at 180 mg/kg as demonstrated by a return to pre-surgical, paw pressure thresholds without altering thresholds in the non-injured paw. These results demonstrate MOR agonists produce dose-dependent increases in paw pressure thresholds following SNI surgery in both male and female rats. As expected, MOR agonists demonstrated a rank order in potency with fentanyl > morphine > nalbuphine in both sexes, and only fentanyl was slightly more potent in females. Fentanyl and morphine also increased paw pressure thresholds in non-injured paws, suggesting that large doses inhibited responses to mechanical stimulation perhaps due to sedation and/or behavioral suppression. Overall, these findings demonstrate that MOR agonists produce antihyperalgesic effects in male and female rats potentially with narrow therapeutic indices. Future studies will investigate other behavioral effects of MOR agonists, such as reinforcing and interoceptive effects, in this chronic neuropathic pain model.