Opioids are widely used medications for the relief of moderate to severe pain. While they remain one of the strongest analgesics for pain associated with cancer, trauma, or surgery, prolonged treatment often comes with undesirable side effects, including analgesic tolerance that causes dose escalation and addiction.
Three opioid receptors: mu-, delta-, and kappa-opioid receptors (MOR, DOR, and KOR, respectively) are found in the afferent pain pathway and participate in opioid-induced analgesia . These receptors respond to exogenous (i.e morphine) and endogenous opioids (β-endorphin, enkephalins, and the dynorphins) that exert efficient inhibitory control of pain at sites of inflammation and in the central nervous system. The endogenous opioid system represents an evolutionarily important pain-coping strategy during tissue healing and several studies have shown that opioid receptors on afferent nociceptors respond to peripherally acting endogenous opioids released by immune cells, including CD4+T cells that are recruited in the later phase of inflammation . Overall, pain sensitization and opioid signaling appear intertwined in the establishment of chronic inflammatory pain. Activation of the mu-opioid receptor (MOR) by opioids results in the binding of β-arrestin2 to the receptor. This interaction prevents receptor signaling, and elicits desensitization, which in turn reduces the pain-relieving effect and requires increased opioid administration, enhancing the unwanted side effects of MOR activation . Previous work reported an improvement of the opioid therapeutic window in acute inflammation, suggesting a mechanism by which inflammation renders opioid receptors to be more responsive . We recently identified the transient receptor potential vanilloid type 1 (TRPV1), a main target of inflammatory mediators, as a central hub protein that primes pain-relieving effects of opioids. MOR is predominantly expressed in TRPV1+ nociceptors and chemical stimulation of the TRPV1 channel was found to prevent G protein-coupled receptor kinase 5-dependent phosphorylation of agonist-bound MOR . We found that activation of TRPV1 diverts the MOR effector β-arrestin2 to the nucleus, and this process coincides with enhanced mitogen-activated protein kinases (MAPK) signaling. With β-arrestin2 removed from the membrane-anchored MOR, the receptor is free of β-arrestin2 and hence unable to desensitize and internalize. We next used the complete Freund’s adjuvant (CFA) model of chronic inflammatory pain to show that TRPV1 knockout mice do not exhibit endogenous opioid analgesia during resolution of inflammation. Finally, using morphine-treated animals, we found that absence of TRPV1 expression promotes peripheral opioid receptor desensitization. Altogether, our findings suggest that agonists of TRPV1 prevent β arrestin2-biased signaling of MOR, which enhances analgesia by maintaining peripheral opioid receptor function (Fig. 1) . As chronic inflammatory conditions like arthritis or inflammatory bowel diseases are often associated with persistent pain, further studies will reveal whether the dysregulated interplay between TRPV1 and β-arrestin2 contributes to the transition from acute to chronic pain.
With current research efforts focused on optimizing new types of opioids that circumvent the adverse side effects, these findings could lead to new combination therapies using TRPV1 agonists like vanilloids and cannabinoids as effective analgesics that may also be useful to prevent opioid tolerance.
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Funding and disclosure
The senior author is a Canada Research Chair in Inflammatory pain. C.A. is supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC). The authors declare no competing interests.
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Abdullah, N., Altier, C. TRPV1 and MOR working in tandem: implications for pain and opioids use. Neuropsychopharmacol. 45, 225–226 (2020). https://doi.org/10.1038/s41386-019-0516-3