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Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in μ-opioid receptor (MOR)–G protein coupling from G_i/o to G_s that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L₅/L₆ spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G_s in the damaged (ipsilateral) spinal dorsal horn. This MOR-G_s coupling occurred without changing G_i/o coupling levels and without changing the expression of MOR or Gα proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G_s coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone …