Sci. Signal. 12, eaav0711 (2019)

Injury invokes signaling pathways leading to inflammation and pain modulation (antinociception) that accompany tissue healing. At sites of inflammation, antinociception is generated via endogenous opioids that act through the GPCR MOR in pain-sensing fibers (nociceptors). Meanwhile, TRPV1 channels also found in nociceptors respond to inflammatory mediators and acutely contribute to pain hypersensitivity. Aiming to understand this interplay between inflammation and opioid analgesia and to define the role of TPRV1 in opioid-induced antinociception, Basso et al. found that activation of TRPV1 diverts the GPCR effector β-arrestin2 to the nucleus coincident with enhanced MAPK signaling. When β-arrestin2 is physically separated from cell membrane MOR, the receptor does not bind β-arrestin2 or become internalized for desensitization and recycling. Using a mouse model of chronic inflammatory pain as well as morphine-treated mice, the authors found that TRPV1 knockout blunted endogenous opioid analgesia and led to peripheral opioid desensitization. These results suggest that TRPV1, through its effects on β-arrestin2 traffic, enhances analgesia while maintaining peripheral opioid receptor function and that the interplay between TRPV1 and β-arrestin2 may contribute to the transition from acute to chronic pain.