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Papers of the Week

Papers: 29 May 2021 - 4 Jun 2021

Animal Studies, Pharmacology/Drug Development

2021 Jun 01

J Neurosci Res

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


Leduc-Pessah H, Xu C, Fan CY, Dalgarno R, Kohro Y, Sparanese S, Burke NN, Jacobson KA, Altier C, Salvemini D, Trang T
J Neurosci Res. 2021 Jun 01.
PMID: 34075613.


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