<p>Upregulation of μ-Opioid Receptor in the Rat Spinal Cord Contributes to the α2-Adrenoceptor Agonist Dexmedetomidine-Induced Attenuation of Chronic Morphine Tolerance in Cancer Pain</p>

Abstract

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 α2-adrenergic system is involved in the development of morphine tolerance. Several studies reported that co-administration of α2-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 α2-adrenoceptor agonist dexmedetomidine (10μ/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 α2-adrenoceptor agonist dexmedetomidine enhanced morphine analgesia and attenuated morphine tolerance, which could be blocked by α2-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 α2-adrenoceptor agonist may provide a more versatile analgesia option for morphine treatment for cancer pain.

Involvement of CXCL12/CXCR4 in CB2 receptor agonist-attenuated morphine tolerance in Walker 256 tumor-bearing rats with cancer pain

“…Hyperalgesia due to sustained use of morphine is a causative factor of opioid analgesic tolerance. [38,39] In our study, the combination of CXCL12 with morphine accelerated the development of morphine-induced hyperalgesia, similar to the results of a translational study showing a reduction in the maximal possible antinociceptive effect in rats pretreated with CXCL12 compared with that in those administered morphine alone. [23] Inhibition of CXCL12/CXCR4 by co-administering CXCL12-Ab or AMD3100 attenuated the progression of hyperalgesia.…”

Overexpression of GDNF in Spinal Cord Attenuates Morphine Analgesic Tolerance in Rats with Bone Cancer Pain

“…Given that MOR is the most important opioid receptor responsible for the analgesic effect of morphine, numerous studies have focused on the MOR density and function adaptive changes underlying opioid tolerance and dependence [ 30 , 31 ]. However, studies on the regulation of MOR after chronic opioid treatment have given conflicting results, depending on the experimental conditions [ 32 , 33 , 34 ]. Our present results showed that the expression of MOR was decreased in the spinal cords of BCP rats, and such a decrease was much more obvious in the BM group.…”

The Interplay between Chronic Pain, Opioids, and the Immune System

“…In this study, we did not enroll patients taking opioids. Thus, we can exclude a reduction of the opioid receptor reserve as a consequence of desensitization and/or internalization of MOR ( Zhang and others 2020a ). Still, several questions are open.…”