Endothelin Receptors and Pain

Abstract

In this paper we review the biochemistry, second messenger pathways and hetero-receptor coupling that are activated by ET receptors, the cellular physiological responses to ET receptor activation, and the contribution to pain of such mechanisms occurring in the periphery and the CNS. Our goal is to frame the subject of endothelin and pain for a broad readership, and to present the generally accepted as well as the disputed concepts, including important unanswered questions.

Bosentan, an endothelin receptor antagonist, ameliorates collagen-induced arthritis: the role of TNF-α in the induction of endothelin system genes

“…One gene was Mitogen-activated protein kinase 1 (Mapk1), a signaling molecule that regulates the production of cytokines and cytotoxic enzymes that have been implicated in RA pathogenesis. In agreement with our results, Mapk1 is induced through ETA and ETB receptors, and it mediates important peripheral functions of ETs, including DNA synthesis, mitogenesis, and the activation of vascular smooth muscle [40,41]. Chemokine (C-C motif) receptor 2 (Ccr2) and chemokine (C-C motif) receptor 5 (Ccr5), which along Fig.…”

UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling

“…For the inducible null mice this finding is highly surprising because it suggests that ET1's proalgesic/algogenic effect is fully dependent on TRPV4 in keratinocytes. Although previous studies had shown that ET1 is sufficient to elicit nocifensive behavior (66,67), the elimination of ET1's proalgesic/algogenic effect in iKO mice was completely unexpected given that both ET(R)s and TRPV4 are expressed by sensory afferents (63), all of them unaffected in tam-treated iKO mice.…”

“…ET(R)s were suitable candidates because they are known to function in pain signaling (63) and because their cognate peptide ligand, endothelin-1 (ET1), is elevated when keratinocytes are exposed to UVB (64). When 1°MK were exposed to ET1, they exhibited a significant increase in UVB-induced Ca 2+ signaling (Fig.…”

Updated Mechanisms of Sickle Cell Disease-Associated Chronic pain

“…The painful effects of ET-1 administration are linked to its binding to the endothelintype A receptor found on nociceptors. [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.…”