Persistent Mu-Opioid Receptor Dysregulation in a Pain-Facilitatory Brain Region Reinstates Hyperalgesia After Resolution of Opioid-Induced Hyperalgesia

Background/Objectives: Opioids paradoxically induce hypersensitivity that typically resolves after discontinuation. Despite normalization of sensitivity, the nociceptive system may remain primed. Descending pathways contribute to opioid-induced hyperalgesia (OIH), and the following latently maintained sensitization. The mechanisms underlying the latter vulnerability remain unknown. We previously showed that the dorsal reticular nucleus (DRt), a key brainstem area involved in pain facilitation, drives OIH through a maladaptation in μ-opioid receptor (MOR) signaling. Whether cellular alterations in the DRt persist after opioids are discontinued and hyperalgesia resolves is unknown. Here, we investigated the long-term effects of morphine on DRt MOR expression, signaling, and function after hyperalgesia has been resolved. Methods: Male Wistar rats received morphine for 7 days either subcutaneously or continuously. Nociceptive sensitivity was evaluated by von Frey and hot-plate tests. MOR and phosphorylated CREB (pCREB) expression in the DRt were quantified during OIH and after hyperalgesia resolution. In the post-OIH phase, we evaluated the effects of MOR activation by DAMGO at DRt, postoperative pain behavior, and systemic morphine dose–response curves. Results: Both morphine regimens induced hypersensitivity that subsided within two weeks. MOR expression in the DRt increased during OIH and normalized in the post-OIH phase, whereas pCREB levels remained elevated in both phases. In the post-OIH phase, DAMGO microinjection at the DRt reinstated robust hypersensitivity and systemic morphine showed reduced antiallodynic potency in postoperative pain. Conclusions: Chronic morphine leaves a lasting molecular imprint in the DRt, sustaining excitatory MOR signaling that can reinstate hyperalgesia and likely diminishes later opioid analgesic efficacy.