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Spinal A 3 adenosine receptor activation acutely restores morphine antinociception in opioid tolerant male rats
Author(s) -
LeducPessah Heather,
Xu Cynthia,
Fan Churmy Y.,
Dalgarno Rebecca,
Kohro Yuta,
Sparanese Sydney,
Burke Nikita N.,
Jacobson Kenneth A.,
Altier Christophe,
Salvemini Daniela,
Trang Tuan
Publication year - 2022
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.24869
Subject(s) - morphine , nociception , pharmacology , opioid , analgesic , adenosine , agonist , medicine , adenosine receptor , drug tolerance , receptor , anesthesia
Opioids are potent analgesics, but their pain‐relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A 3 adenosine receptor (A 3 AR) in opioid analgesic tolerance. Intrathecal administration of the A 3 AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7 days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine‐naïve rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine‐induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A 3 AR expression was not affected. Collectively, our findings indicate that spinal A 3 AR activation acutely potentiates morphine antinociception in the opioid tolerant state.