Targeting TRPA1 antagonists for nociplastic pain: systematic review and meta-analysis of preclinical evidence.

Nociplastic pain results from altered nociceptive processing without apparent tissue damage. Effective treatment remains challenging due to limited biomarker availability and poor response to conventional analgesics. Transient receptor potential ankyrin 1 (TRPA1) is a promising molecular target because of its role in pain hypersensitivity and neuroinflammatory signaling. Preclinical studies indicate that TRPA1 antagonists reduce nociception in various nociplastic pain models. However, their therapeutic significance has not been systematically evaluated. This systematic review and meta-analysis summarize preclinical evidence regarding TRPA1 antagonists as modulators of nociplastic pain hypersensitivity. The protocol was registered in PROSPERO (CRD42025629227). A systematic search of PubMed, Scopus, and Web of Science identified studies published from 2011 to 2024. Twelve in vivo rodent studies met the inclusion criteria, assessing TRPA1 antagonists in migraine-like nociception, chronic post-ischemia pain (CPIP), and reserpine-induced fibromyalgia models. Mechanical allodynia was the primary outcome. Data were pooled using a random-effects model, and heterogeneity was quantified using the I2. Study quality ranged from low to moderate, with recent publications revealing improved reporting standards and reduced risk of bias. Meta-analysis showed that TRPA1 antagonists produced consistent antinociceptive effects across nociplastic pain models, reducing mechanical and cold allodynia, with high-quality evidence for CPIP and migraine models. Consistent effects were observed across doses, administration routes, and antagonist types. No publication bias was detected, and sensitivity analyses validated the robustness of the findings. Despite variability in study quality, methodological limitations, and incomplete behavioral characterization, the evidence supports TRPA1 as an advantageous therapeutic target for prospective translational research.