Activation of mu opioid receptors sensitizes transient receptor potential vanilloid type 1 (TRPV1) via β-arrestin-2-mediated cross-talk

PLoS One. 2014 Apr 2;9(4):e93688. doi: 10.1371/journal.pone.0093688. eCollection 2014.


The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that β-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of β-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in β-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates β-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven β-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / metabolism*
  • Cells, Cultured
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Fluorescence Resonance Energy Transfer
  • Furans / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morphine / pharmacology
  • Pyrones / pharmacology
  • Receptors, Opioid, mu / agonists*
  • TRPV Cation Channels / metabolism*
  • beta-Arrestin 2
  • beta-Arrestins


  • 9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho(2,1-c)pyran-7-carboxylic acid methyl ester
  • Arrb2 protein, mouse
  • Arrestins
  • Furans
  • Pyrones
  • Receptors, Opioid, mu
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • beta-Arrestin 2
  • beta-Arrestins
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Morphine