Spinal A3 adenosine receptor activation acutely restores morphine antinociception in opioid tolerant male rats

Heather Leduc-Pessah, Cynthia Xu, Churmy Y. Fan, Rebecca Dalgarno, Yuta Kohro, Sydney Sparanese, Nikita N. Burke, Kenneth A. Jacobson, Christophe Altier, Daniela Salvemini, Tuan Trang

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


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 A3 adenosine receptor (A3AR) in opioid analgesic tolerance. Intrathecal administration of the A3AR 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 A3AR expression was not affected. Collectively, our findings indicate that spinal A3AR activation acutely potentiates morphine antinociception in the opioid tolerant state.

Original languageEnglish
Pages (from-to)251-264
Number of pages14
JournalJournal of Neuroscience Research
Issue number1
Publication statusPublished - Jan 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cellular and Molecular Neuroscience


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