TRPV1 regulates opioid analgesia during inflammation

Abstract

Acute inflammation in humans or mice enhances the analgesic properties of opioids. However, the inflammatory transducers that prime opioid receptor signaling in nociceptors are unknown. We found that TRPV1-/- mice are insensitive to peripheral opioid analgesia in an inflammatory pain model. We report that TRPV1 channel activation drives a MAPK signaling pathway accompanied by the shuttling of {beta}-arrestin2 to the nucleus. This shuttling in turn prevents: {beta}-arrestin2-receptor recruitment, subsequent internalization of agonist-bound mu opioid receptor (MOR), and suppression of DAMGO-induced inhibition of N-type calcium current observed upon desensitization. Consequently, inflammation-induced activation of TRPV1 preserves opioid analgesic potency in a mouse model of opioid receptor desensitization. Overall, our work reveals a TRPV1-mediated signaling mechanism, involving {beta}-arrestin2 nuclear translocation, that underlies the peripheral opioid control of inflammatory pain. Our data single out TRPV1 channels as modulators of opioid analgesia.