Endothelin Receptor-mediated Responses in Trigeminal Ganglion Neurons

Abstract

Recent evidence implicates endothelin in nociception, but it is unclear how endothelin activates trigeminal ganglion (TRG) neurons. In the present study, we investigated the expression of the endothelin receptors ETA and ETB and endothelin-induced responses in rat TRG neurons. Double-immunofluorescence studies demonstrated that ETA and ETB were expressed in TRG neurons and that 26% of ETA- or ETB-expressing neurons expressed both receptors. During whole-cell patch-clamp recording, endothelin-1 enhanced an induced current in response to capsaicin, a TRPV1 agonist, in approximately 20% of dissociated neurons. The enhancement was blocked by the PKC inhibitor chelerythrine and by the ETA antagonist BQ-123, but not by the ETB antagonist BQ-788. Ca(2+)-imaging showed that endothelin-1 increased the intracellular Ca(2+) concentration in more than 20% of the dissociated neurons. Importantly, unlike the effect of endothelin-1 on capsaicin-induced current, the Ca(2+) response was largely suppressed by BQ-788 but not by BQ-123. These results suggest that ETA-mediated TRPV1 hyperactivation via PKC activation and ETB-mediated Ca(2+) mobilization occurs in different subsets of TRG neurons. These endothelin-induced responses may contribute to the induction of orofacial pain. The ETB-mediated function in TRG neurons is a special feature in the trigeminal system because of no ETB expression in dorsal root ganglion neurons.

Cold hypersensitivity increases with age in mice with sickle cell disease

“…Endothelin 1 may act indirectly, possibly by sensitizing vascular endothelial cells to mechanical stimulation and ATP release [22]. It may also act directly at sensory neurons by activating both endothelin receptors ET A and ET B to sensitize TRP channels; ET A and ET B are each co-expressed on ∼30% of TRPV1-immunopositive neurons [10], and endothelin 1 modulates TRPV1 through the ET A receptor [46,60]. TRPA1 may also be involved in the pain-like behavior induced by ET1 [34].…”

Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

“…[73,74] The interaction of ET-1 and ETA receptors can induce nociceptor activation in pre-clinical studies of normal subjects. [71,75] ET-1 subcutaneous administration was found to activate C-fibers and A TMfibers in rat sciatic nerve in a dose-dependent manner. [67] This activation was blocked when an ETA receptor antagonist was administered in conjunction with ET-1.…”

“…In addition, ET-1-induced increases in intracellular calcium were found to contribute to the activation of sensory neurons through activation of PKCε, [82] which phosphorylates TRPV1 receptors. [75,76,82] Indeed, in a mouse model of SCD, PKCε was ETA receptor activation initiates a G-protein linked signaling cascade, in which the production of diacyl-glycerol (DAG) activates protein kinase C (PKC) ε. The latter phosphorylates TRPV1 channels.…”

Peripheral Scaffolding and Signaling Pathways in Inflammatory Pain

“…[48][49][50] Of clinical importance, ETAR sensitization of TRPV1 in trigeminal sensory neurons has also been reported. 51 Trigeminal sensory neurons innervate the orofacial cavity, a tissue that is sometimes populated by oral squamal cell carcinomas (OSCCs), one of leading oral cancers with the highest mortality rate. OSCCs produce significant amounts of ET, 52 consequentially supporting inflammatory hyperalgesia 53 in one of the most sensitive tissues of the body.…”