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bioRxiv · 10.1101/2025.08.05.668770

The effects of chronic neuropathic pain states on MOR-agonist induced antihyperalgesic-like effects and rate suppressant effects

Burgess, G. E.·Rizk, H. Y.·Sanghvi, S. M.·Jutkiewicz, E. M.
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Abstract

Chronic neuropathic pain affects 6.9-10% of the U.S. population. While mu opioid receptor (MOR) agonists are not first-line treatments for chronic pain, previous data suggests that [~]70% of chronic neuropathic pain patients receive MOR agonist treatment. Previous studies demonstrated decreased MOR expression and activity in pain states compared with non-injured or sham controls; however, we know little about how chronic pain states may alter the antinociceptive- and antihyperalgesic-like effects of MOR agonists in vivo. Therefore, the goal of this study was to determine if there were significant differences in MOR agonist-induced antinociceptive- or antihyperalgesic-like effects between SNI and sham groups. MOR agonist-induced antinociceptive- and antihyperalgesic-like effects were evaluated in SNI and sham groups repeatedly over 6 months. MOR agonists induced dose-dependent antinociceptive- and antihyperalgesic-like effects in male and female rats in the expected rank order of potency (fentanyl>morphine[≥]nalbuphine). Over time, there were small rightward shifts in fentanyl- and morphine-induced effects; however, these rightward shifts were observed in sham and SNI groups, suggesting this occurred independent of pain state. Interestingly, in sham and SNI groups, nalbuphine-induced effects were more potent 6 months post-operatively than 3 months, suggesting the potency of nalbuphine changed over time, independent of pain state. Other, non-MOR agonist analgesics were evaluated. Collectively, these data indicate that SNI failed to alter MOR agonist-induced antinociceptive- and antihyperalgesic-like effects. Future studies should evaluate if the SNI-independent increase in sensitivity to nalbuphine is related to the partial KOR agonist activity and if SNI-induced hypersensitivity alters tolerance following repeated administration of MOR agonists. Significance StatementMany chronic pain patients are treated with opioids, but we understand relatively little about how chronic pain may alter the in vivo effects of opioid analgesics. This study demonstrates that, compared to sham groups, SNI-induced hypersensitivity did not alter the potency or efficacy of opioid analgesics, opioid-induced tolerance to analgesic-like effects, or opioid-induced rate suppressant effects in either male or female rats.

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Burgess, G. E., Rizk, H. Y., Sanghvi, S. M., Jutkiewicz, E. M.. 2025-08-07. The effects of chronic neuropathic pain states on MOR-agonist induced antihyperalgesic-like effects and rate suppressant effects. https://doi.org/10.1101/2025.08.05.668770

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