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. 2023 Apr;180(8):1148-1167.
doi: 10.1111/bph.16003. Epub 2022 Dec 29.

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

M Carmen Ruiz-Cantero  1   2   3 , Elsa Cortés-Montero  4 , Aakanksha Jain  5   6 , Ángeles Montilla-García  1   2 , Inmaculada Bravo-Caparrós  1   2 , Jaehoon Shim  5   6 , Pilar Sánchez-Blázquez  4 , Clifford J Woolf  5   6 , José M Baeyens  1   2   3 , Enrique J Cobos  1   2   3   7
Affiliations
Free article

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

M Carmen Ruiz-Cantero et al. Br J Pharmacol. 2023 Apr.
Free article

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+). The sigma-1 receptor (sigma-1R) is a Ca2+ -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.

Keywords: Sigma-1 receptors; TRPV1; endomorphin-2; resiniferatoxin; μ-opioid receptors.

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