Upregulation of [micro]-Opioid Receptor in the Rat Spinal Cord Contributes to the a2-Adrenoceptor Agonist Dexmedetomidine-lnduced Attenuation of Chronic Morphine Tolerance in Cancer Pain

Background: Sustained morphine treatment for cancer pain has been limited due to analgesic tolerance. Opioid receptor internalization and desensitization mediated by downregulation of mu-opioid receptor (MOR) expression have been confirmed as one of the mechanisms of chronic morphine tolerance. In a...

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Published in:Journal of pain research 2020-10, Vol.13, p.2617
Main Authors: Zhang, Pinyi, Bu, Jianlong, Wu, Xiaohong, Deng, Lin, Chi, Meng, Ma, Chao, Shi, Xiaoding, Wang, Guonian
Format: Article
Language:English
Subjects:
Cancer
Cancer pain
Cancer treatment
Dexmedetomidine
Morphine
Pain management
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Summary:Background: Sustained morphine treatment for cancer pain has been limited due to analgesic tolerance. Opioid receptor internalization and desensitization mediated by downregulation of mu-opioid receptor (MOR) expression have been confirmed as one of the mechanisms of chronic morphine tolerance. In addition to the opiate system, the a2-adrenergic system is involved in the development of morphine tolerance. Several studies reported that co-administration of a2-adrenoceptor agonist dexmedetomidine inhibits morphine tolerance in normal or neuropathic pain animals. However, the effect of dexmedetomidine on morphine tolerance has not been studied in cancer pain. Therefore, we investigated the effect of intrathecal injection of dexmedetomidine on the development of morphine tolerance in cancer pain and on the expression of MOR in the spinal cord of morphine-tolerant cancer pain rats. Methods: The model was established using a rat's right hind paw injection of Walker 256 cancer cells. Subcutaneous morphine (10mg/kg) was administrated twice daily for 7 days; meanwhile, the rats received intrathecal [alpha]2-adrenoceptor agonist dexmedetomidine (10[micro]/kg) or antagonist MK-467 (0.25mg/kg) in test groups. Rats receiving drug vehicle served as the control group. Antinociception was detected by von Frey filaments and hot-plate tests. The expression of MOR in the spinal cord was examined through real-time reverse transcription polymerase chain reaction and Western blotting. The data were analyzed via analysis of variance followed by Student t-test with Bonferroni correction. Results: Seven-day chronic morphine administration elicited notable analgesic tolerance in the rats with cancer pain. Co-administration of a2-adrenoceptor agonist dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance, which could be blocked by a2-adrenoceptor antagonist MK-467. Furthermore, pre-treatment of dexmedetomidine significantly upregulated MOR protein expression without a notable change in MOR mRNA expression in the spinal cord. Conclusion: Our findings suggest that intrathecal injection of dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance in cancer pain, potentially by upregulating MOR expression in the spinal cord. The a2-adrenoceptor agonist may provide a more versatile analgesia option for morphine treatment for cancer pain. Keywords: [micro]-opioid receptor, MOR, [alpha]2-adrenoceptor, [alpha]2-AR, dexmedetomidine, DEX, morphine to
ISSN:1178-7090
1178-7090
DOI:10.2147/JPR.S274225