The Role of TRPA1 and TRPV1 Channels in Orofacial Pain

Inflammation of the trigeminal nerve is considered one of the most painful conditions known to humankind. The diagnosis is often difficult moreover, safe and effective pharmacological treatments are lacking. Transient receptor potential (TRP) channels are a large family of non-selective cation channels. Several TRP channel family members, including TRP cation channel subfamily V member 1 (TRPV1), subfamily A member 1 (TRPA1) and TRP channel melastatin 8 (TRPM8), are expressed in TG somatosensory neurons, which also project within the oral and nasal cavities and are deputed to detect a great deal of external stimuli, including pressure, temperature, and chemicals. In recent years many efforts have been dedicated to the discovery of better and safer analgesics. However the medical need for this type of drugs remains substantially unmet. In particular, compounds capable of targeting both inflammatory and neuropathic pain are lacking. Thus, capitalizing on recent results [1] about the ability of the synthetic TRPA1 antagonist ADM_09 to revert oxaliplatin-induced neuropatic pain, and given the evident role of TRP channels in TG-related pain, we report herein on the synthesis of a new lipoic-containing antagonist namely ADM_12. This water-soluble small molecule, structurally simpler and more stable than ADM_09, showed: i) a remarkable safe profile; ii) a high binding constant vs. TRPA1; iii) an intriguing behaviour vs. TRPV1 and iv) the ability to significantly and persistently reduce mechanical facial allodynia in rats. Noteworthy, testing ADM_12 we shed light on the unprecedented involvement of both TRPA1 and TRPV1 channels in orofacial pain.