Cannabidiol reverses mechanical hypersensitivity in a mouse model of apical periodontitis.

Chrepa V.; Murillo J.; Villasenor S.; Tram M.; Ganatra S.; Karakousoglou M.; Kotsakis G.; Barba-Escobedo P.; Ruparel N.; Macpherson L. · Pain · 2026

**Background & Methods** This preclinical study used a mouse behavioral model of apical periodontitis (AP) to evaluate cannabidiol (CBD) as an analgesic for odontogenic pain. Male and female mice underwent pulp exposure of the left maxillary first molar (AP group) or sham surgery, with mechanical hypersensitivity assessed 21 days post-surgery using von Frey filaments on the vibrissal pad. The study investigated CBD's site of action and the involvement of the TRPV1 channel through various administration routes and pharmacological blockade. **Key Findings** - A single oral dose of CBD significantly reduced apical periodontitis-induced mechanical hypersensitivity at 45 and 120 minutes post-administration compared to vehicle control, with a notably greater analgesic effect in male mice than females. - CBD's analgesic effect was mediated through central nervous system action, as intrathecal and intracisternal injections reduced mechanical hypersensitivity in male AP mice, while ipsilateral intraoral CBD injection did not, indicating peripheral administration does not account for the therapeutic effect. - TRPV1 channel involvement was demonstrated by the finding that pretreatment with AMG 517 (a TRPV1 antagonist) administered intraperitoneally or intracisternally blocked the analgesic effect of oral CBD in male mice. **Dosage & Administration** Specific CBD doses were not detailed in the abstract. Administration routes tested included oral (single dose), intrathecal, intracisternal, and ipsilateral intraoral injections. AMG 517 was administered intraperitoneally and intracisternally prior to CBD dosing. **Safety & Adverse Effects** Not reported. **Evidence Quality** This is a preclinical animal model study with significant limitations. The findings are restricted to male and female laboratory mice and cannot be directly extrapolated to human clinical applications. The sex-dependent differences in analgesic response warrant further investigation. The study does not address long-term efficacy, optimal dosing strategies for human use, or potential adverse effects. As a basic science investigation, this work provides proof-of-concept evidence that requires subsequent clinical trials to establish safety and efficacy in human apical periodontitis patients. The involvement of TRPV1 signaling is novel for odontogenic pain but requires validation in human studies.

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