biostudies-literatureUnknownOswell CSNIDA NIH HHSNINDS NIH HHSNIGMS NIH HHSThe 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 dynamics 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 unpleasant, 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. This opioid-mimetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management targeting a key nociceptive cortical opioid circuit with safe, on-demand analgesia.bioRxiv : the preprint server for biology2024.04.26.591113https://www.ebi.ac.uk/biostudies/studies/S-EPMC11092437biostudies-literatureMimicking opioid analgesia in cortical pain circuits.PMC11092437T32 DA028874F32 DA053099F32 DA055458R00 DA043609R21 DA055846F31 DA057795R34 DA059509R01 DA056599RF1 NS126073DP2 GM140923R01 NS130044F31 NS125927R01 DA054374F31 DA062445Beier KTBanghart MRWachira MCreasy KTVasquez JJWojick JAOrtega RASBeattie KFarinas SAWu JKWooldridge LMJo ADeisseroth KMahmood MRamakrishnan CYttri EACorder GLo EJames JGAzouz GReiner BCRogers SARodrigues AOswell CSHsu AIEjoh LLSalimando GJKimmey BACrist RCMcCall NMChehimi SNfalseMimicking 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 dynamics 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 unpleasant, 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. This opioid-mimetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management targeting a key nociceptive cortical opioid circuit with safe, on-demand analgesia.2025-01-01T00:00:00Z2025 Apr2026-06-22T03:15:38.072Z2026-06-22T03:08:08.866ZS-EPMC110924373874609010.1101/2024.04.26.591113