Endothelins as pronociceptive mediators of the rat trigeminal system: Role of ETA and ETB receptors

The trigeminal nerve is comprised of three main divisions, ophthalmic, maxillary and mandibular, each providing somatosensory innervation to distinct regions of the head, face and oral cavity. Recently, a role for endothelins in nociceptive signaling in the trigeminal system has been proposed. The present study aimed to gain better insight into the participation of the endothelin system in trigeminal nociceptive transmission. Herein ET-1 and ET-3 mRNA was detected in the rats' trigeminal ganglion (TG). Fluorescent labeling of TG neurons revealed that ETA and ETB receptors are distributed along the entire TG, but ETA receptor expression slightly predominated within the three divisions. TRPV1 receptors were also detected throughout the entire TG, and a significant proportion of TRPV1-positive neurons (∼ 30%) co-expressed either ETA or ETB receptors. Our behavioral data showed that ET-1 (3 to 30 pmol/site) induced overt nociceptive responses after injection into the upper lip or temporomandibular joint (TMJ) and hyperalgesic actions when applied to the eye, while ET-3 and the selective ETB receptor agonist IRL-1620 (each at 3 to 30 pmol/site) showed only the first two effects. Injection of BQ-123, but not BQ-788 (ETA and ETB receptor antagonists, respectively, 10 nmol/site each, 30 min beforehand), into the ipsilateral upper lip abolished ET-1 induced facial grooming, but both antagonists markedly reduced the nociceptive responses induced by ET-1 injected into the TMJ. Taken together, these findings suggest that endothelins, acting through ETA and/or ETB receptors, may play an important role in mediating pain resulting from activation of most trigeminal nerve branches.