@misc{10481/78767,
year = {2022},
month = {12},
url = {https://hdl.handle.net/10481/78767},
abstract = {Background and Purpose: Peripheral sensitization contributes to pathological pain. While prostaglandin E2 (PGE2) and nerve growth factor (NGF) sensitize peptidergic C-nociceptors (TRPV1+), glial cell line-derived neurotrophic factor (GDNF) sensitizes non-peptidergic C-neurons (IB4+). Sigma-1 receptor (σ1R) is a Ca2+-sensing chaperone known to modulate analgesia induced by opioid drugs. This receptor binds both to TRPV1 and the µ-opioid receptor (MOPr), although the functional repercussions of these physical interactions in peripheral sensitization are unknown.
Experimental Approach: We tested the effect 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 MOPr agonist, on dorsal root ganglion (DRG) neurons. Recombinant proteins were used to study the interactions between σ1R, MOPr and TRPV1. We used calcium imaging to study the effects of sigma-1 antagonism on PGE2-induced sensitization of TRPV1+ nociceptors.
Key Results: σ1R 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 σ1R from TRPV1 to MOPr, suggesting that σ1R participate in TRPV1-MOPr crosstalk. Moreover, σ1R 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: σ1R antagonism harnesses endogenous opioids produced by TRPV1+ neurons to reduce hyperalgesia by increasing MOPr activity.},
keywords = {endomorphin-2},
keywords = {resiniferatoxin},
keywords = {Sigma-1 receptors},
keywords = {TRPV1},
keywords = {μ-opioid receptors},
title = {The sigma-1 receptor curtails endogenous opioid analgesia during sensitization of TRPV1 nociceptors},
doi = {10.1111/bph.16003},
author = {Ruiz Cantero, María del Carmen and Cortés-Montero, Elsa and Jain, Aakanksha and Montilla-García, Ángeles and Bravo-Caparrós, Inmaculada and Shim, Jaehoon and Sánchez-Blázquez, Pilar and Woolf, Clifford J. and Baeyens, José M. and Cobos del Moral, Enrique José},
}