Mimicking opioid analgesia in cortical pain circuits

The anterior cingulate cortex is a key brain region involved in the affective and motivational dimensions of pain, yet how opioid analgesics modulate this cortical circuit remains unclear. Uncovering how opioids alter nociceptive neural computations to produce pain relief is essential for developing safer and more targeted treatments for chronic pain. Here we show that a population of cingulate neurons encodes spontaneous pain-related behaviors and is selectively modulated by morphine. Using deep-learning behavioral analyses combined with longitudinal neural recordings in mice, we identified a persistent shift in cortical activity patterns following nerve injury that reflects the emergence of an affective chronic pain state. Morphine reversed these neuropathic neural dynamics and reduced affective-motivational behaviors without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic mu-opioid receptor promoter to drive chemogenetic inhibition in opioid-responsive ACC neurons. This targeted neuromodulation recapitulated the analgesic effects of morphine during chronic neuropathic pain. This opioid-mimetic gene therapy offers a new strategy for precision pain management by targeting a key nociceptive cortical circuit with safe, on-demand analgesia.