Capsaicin and cinnamaldehyde as topical transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 agonists in humans: Formulation, stability, and pharmacodynamic evaluation.

Transient receptor potential (TRP) vanilloid 1 and TRP ankyrin 1 channels mediate nociceptive and neurovascular signaling and can be activated experimentally by capsaicin and cinnamaldehyde, respectively. We characterized the physicochemical stability, in vitro permeation, and human pharmacodynamic effects of topical capsaicin and cinnamaldehyde formulations. Solutions underwent six-month stability testing at 4 °C and permeation studies in Franz diffusion cells using Strat-M and lauryl alcohol-impregnated cellulose nitrate membranes. The formulations were then applied to the forearm skin of 15 women with migraine, and dermal blood flow was measured for 90 minutes using laser speckle contrast imaging. Both formulations remained stable for 6 months. No active compound was detected in the receptor chamber with Strat-M, whereas low but pharmacologically relevant permeation occurred across the cellulose nitrate membrane. Capsaicin produced a robust and sustained vasodilatory response, with dermal blood flow increasing by 264.7% at 30 minutes and peaking at 291.0% at 45 minutes; the response remained elevated at 90 minutes. Cinnamaldehyde produced a rapid but transient response, increasing dermal blood flow by 231.6% at 30 minutes and progressively returning toward baseline by 90 minutes. No local or systemic adverse events were reported. These findings support topical capsaicin and cinnamaldehyde as complementary experimental probes for studying TRP vanilloid 1- and TRP ankyrin 1-mediated cutaneous neurovascular responses in humans. SIGNIFICANCE STATEMENT: This study establishes a reproducible human model integrating physicochemical validation and in vivo pharmacodynamic assessment of transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 agonists, demonstrating that minimal topical permeation is sufficient to elicit robust, receptor-specific vascular responses without systemic exposure. The distinct temporal profiles of capsaicin and cinnamaldehyde provide a translational framework for probing neurogenic inflammation and for early-phase evaluation of targeted therapies.