期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 100, 期 1, 页码 251-264出版社
WILEY
DOI: 10.1002/jnr.24869
关键词
adenosine; analgesia; opioids; opioid tolerance; RRID; AB_10711040; RRID; AB_10751536; RRID; AB_141844; RRID; AB_2039711; RRID; AB_2535792; RRID; AB_2636996; RRID; AB_449329; RRID; AB_476743; RRID; AB_521594; spinal cord
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [ZIADK31117]
- Canada Research Chairs
- Canadian Institutes for Health Research [CIHR PJ8-169697]
- Natural Sciences and Engineering Research Council of Canada [NSERC RGPIN06289-2019]
The activation of spinal A(3) adenosine receptor acutely potentiates morphine antinociception in the opioid tolerant state, suggesting a potential therapeutic strategy to enhance the pain-relieving effects of opioids despite tolerance development.
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-naive 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.
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