The sigma-1 receptor curtails endogenous opioid analgesia during sensitization of TRPV1 nociceptors.
Br J Pharmacol
; 180(8): 1148-1167, 2023 04.
Article
en En
| MEDLINE
| ID: mdl-36478100
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. EXPERIMENTALAPPROACH:
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. KEYRESULTS:
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.Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Nociceptores
/
Analgesia
Límite:
Animals
Idioma:
En
Revista:
Br J Pharmacol
Año:
2023
Tipo del documento:
Article
País de afiliación:
España