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The efficiency of descending pain modulation, commonly assessed with the conditioned pain modulation (CPM) procedure, is diminished in patients with chronic pain. We hypothesized that the efficiency of pain modulation is controlled by cortical opioid circuits. We evaluated the effects of mu opioid receptor (MOR) activation in the anterior cingulate cortex (ACC) on descending control of nociception (DCN), a preclinical correlate of CPM, in male Sprague Dawley rats with spinal nerve ligation-induced chronic pain or in sham-operated controls. Additionally, we explored the consequences of respective activation or inhibition of kappa opioid receptor in the ACC of naïve rats or animals with neuropathic pain. DCN was measured as the hindpaw withdrawal response to noxious pressure (test stimulus) in the absence or presence of capsaicin injection in the forepaw (conditioning stimulus). DCN was diminished in the ipsilateral, but not contralateral, hindpaw of rats with spinal nerve ligation. Bilateral administration of morphine in the ACC had no effect in shams but restored diminished DCN without altering hypersensitivity in rats with neuropathic pain. Bilateral ACC microinjection of kappa opioid receptor antagonists, including norbinaltrexamine or NMRA-140 (Navacaprant), also re-established DCN in rats with neuropathic pain without altering hypersensitivity and with no effect in shams. Conversely, bilateral injection of a kappa opioid receptor agonist, U69,593, in the ACC of naïve rats inhibited DCN without altering withdrawal thresholds. ACC kappa opioid receptor activation therefore diminishes descending control of nociception both in naïve animals and as an adaptive response to chronic pain likely by enhancing net descending facilitation. DCN can be restored by activation of mu opioid receptors in the ACC, but also by kappa opioid receptor antagonists, providing a nonaddictive alternative to opioid analgesics. NMRA-140 is now in advanced clinical trials. Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.


Edita Navratilova, Chaoling Qu, Guangchen Ji, Volker Neugebauer, Miguel Guerrero, Hugh Rosen, Ed Roberts, Frank Porreca. Opposing effects on descending control of nociception by mu and kappa opioid receptors in the anterior cingulate cortex. Anesthesiology. 2023 Sep 19

PMID: 37725756

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