Work

The sigma‐1 receptor curtails endogenous opioid analgesia during sensitization of TRPV1 nociceptors

Year: 2022

Type: article

Abstract: BACKGROUND AND PURPOSE: -sensing chaperone known to modulate opoid analgesia. This receptor binds both to TRPV1 and the μ opioid receptor, although the functional repercussions of these physical interactions in peripheral sensitization are unknown. EXPERIMENTAL APPROACH: We tested the effects of sigma-1 antagonism on PGE2-, NGF-, and GDNF-induced mechanical and heat hyperalgesia in mice. We used immunohistochemistry to determine the presence of endomorphin-2, an endogenous μ receptor agonist, on dorsal root ganglion (DRG) neurons. Recombinant proteins were used to study the interactions between sigma-1R, μ- receptor, and TRPV1. We used calcium imaging to study the effects of sigma-1 antagonism on PGE2-induced sensitization of TRPV1+ nociceptors. KEY RESULTS: Sigma1 antagonists reversed PGE2- and NGF-induced hyperalgesia but not GDNF-induced hyperalgesia. Endomorphin-2 was detected on TRPV1+ but not on IB4+ neurons. Peripheral opioid receptor antagonism by naloxone methiodide or administration of an anti-endomorphin-2 antibody to a sensitized paw reversed the antihyperalgesia induced by sigma-1 antagonists. Sigma-1 antagonism transfers sigma-1R from TRPV1 to μ receptors, suggesting that sigma-1R participate in TRPV1-μ receptor crosstalk. Moreover, sigma-1 antagonism reversed, in a naloxone-sensitive manner, PGE2-induced sensitization of DRG neurons to the calcium flux elicited by capsaicin, the prototypic TRPV1 agonist. CONCLUSION AND IMPLICATIONS: Sigma-1 antagonism harnesses endogenous opioids produced by TRPV1+ neurons to reduce hyperalgesia by increasing μ receptor activity.

Source: British Journal of Pharmacology

DOI: 10.1111/bph.16003