Identification and evaluation of a pinocembrin analog as a TRPV1 inhibitor with analgesic properties in murine pain models

TL;DR

A new TRPV1 inhibitor called PINO was found to reduce pain in multiple mouse models, offering a potential alternative to opioids and NSAIDs.

Contribution

A novel TRPV1 antagonist derived from natural sources was identified and shown to have analgesic effects in various pain models.

Findings

PINO reduced pain responses in acetic acid-induced, inflammatory, and bone cancer pain models in mice.

PINO suppressed pro-inflammatory cytokine production and inhibited NF-κB and MAPK signaling pathways.

PINO showed superior stability in TRPV1 interactions through virtual screening and molecular dynamics simulations.

Abstract

Pain is a complex phenomenon involving physiological and psychological responses to noxious stimuli. Long-term opioid or NSAID use leads to reduced efficacy and tolerance. Initially a thermosensitive receptor, TRPV1 is increasingly recognized as a target for analgesic intervention.

Our investigation is focused on the exploration of novel TRPV1 antagonists derived from natural sources through computational screening methodologies, aiming to assess their efficacy as analgesic agents.

Among the compounds screened, a promising TRPV1 antagonist named pinocembrin-7-o-3-o-galloyl-4-6-hexahydroxydiphenoyl-beta-d-glucoside (PINO) has exhibited superior stability in its interaction with TRPV1 through virtual screening and molecular dynamics simulation. A dosage of 20 mg/kg of PINO had been shown to reduce the writhing response in acetic acid-induced mice, elevate the thermal pain threshold in the hot water tail-flick and hot plate assays, and concurrently increase the mechanical pain threshold in CFA-induced inflammatory pain models in mice. Moreover, in a murine Lewis lung carcinoma cell line LL-induced bone cancer pain model, PINO also effectively raised the thermal and mechanical pain thresholds in mice. Furthermore, PINO had been found to attenuate the production and gene expression of pro-inflammatory cytokines. The underlying mechanism was attributed to the suppression of NF-κB and MAPK signaling cascades.

This innovative compound represents a prospective avenue for the management of acute, chronic, and bone cancer pain, providing a viable alternative analgesic option for individuals suffering from such conditions.

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