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, but how opioid analgesics modulate this cortical circuit remains unclear<sup>1</sup>. 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 behaviours and is selectively modulated by morphine. Using deep learning behavioural 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 behaviours without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired chemogenetic gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic μ-opioid receptor promoter to drive inhibition<sup>2</sup>. This opioid-mimetic chemogenetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management that targets a key nociceptive cortical opioid circuit with safe, on-demand analgesia.

Authors

Institutions

Publication Details

Journal
Nature
Published
2026-01-07
DOI
https://doi.org/10.1038/s41586-025-09908-w
Citations
1
Primary Topic
Pain Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
32.84
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Mimicking opioid analgesia in cortical pain circuits

K Deisseroth, Blake Kimmey, Gregory Corder, Malaika Mahmood et al.
1 citations
Nature
Pain Mechanisms and Treatments
32.84
article

Mimicking opioid analgesia in cortical pain circuits

K Deisseroth, Blake Kimmey, Gregory Corder, Malaika Mahmood, Samar Nasser Chehimi, Nora M. McCall, Benjamin Reiner, Richard C. Crist, Adrienne Jo, Charu Ramakrishnan, Emily K.W. Lo, Lindsay L. Ejoh, Corinna S. Oswell, Matthew R. Banghart, Sophie A. Rogers, Meghan Wachira, J. Wu, Katherine Beattie, Alex Hsu, R. Ortega, Jessica A. Wojick, Kevin T. Beier, Gregory J. Salimando, Judith A. James, Ghalia Azouz, Sofia A. Farinas, J. G. Vasquez, Eric Allen Yttri, Amrith Rodrigues, Kate Townsend Creasy, Lisa M. Wooldridge
article en
1 citations

Abstract

The anterior cingulate cortex is a key brain region involved in the affective and motivational dimensions of pain, but how opioid analgesics modulate this cortical circuit remains unclear<sup>1</sup>. 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 behaviours and is selectively modulated by morphine. Using deep learning behavioural 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 behaviours without altering sensory detection or reflexive responses, mirroring how opioids alleviate pain unpleasantness in humans. Leveraging these findings, we built a biologically inspired chemogenetic gene therapy that targets opioid-sensitive neurons in the cingulate using a synthetic μ-opioid receptor promoter to drive inhibition<sup>2</sup>. This opioid-mimetic chemogenetic gene therapy recapitulated the analgesic effects of morphine during chronic neuropathic pain, thereby offering a new strategy for precision pain management that targets a key nociceptive cortical opioid circuit with safe, on-demand analgesia.

NatureVol. 649(8098)
Howard Hughes Medical Institute (US), University of San Diego (US), University of California, Irvine (US), University of California San Diego (US), Translational Therapeutics (United States) (US), Carnegie Mellon University (US), University of Pennsylvania (US), Stanford University (US)
Good health and well-being
Openalex Percentile: Top 2%
Pain Mechanisms and Treatments
32.84
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.