Dissecting the functional significance of endothelin A receptors in peripheral nociceptors in vivo via conditional gene deletion

The peptide endothelin-1 (ET1), which was originally identified as a vasoconstrictor, has emerged as a critical regulator of a number of painful conditions, including inflammatory pain and tumor-associated pain. There is considerable pharmacological evidence supporting a role for endothelin A receptors (ET_A) in mediating ET1-induced pro-algesic functions. ET_A receptors are expressed in small-diameter nociceptive neurons, but also found in a variety of other cell types in peripheral tissues, including immune cells, keratinocytes, endothelial cells, which have the potential to modulate nociception. To elucidate the functional contribution of ET_A receptors expressed in sensory neurons towards the functions of the ET1 axis in pathological pain states, we undertook a conditional gene deletion approach to selectively deplete expression of ET_A in sensory nerves, preserving expression in non-neural peripheral tissues; the expression of ET_B remained unchanged. Behavioural and pharmacological experiments showed that only late nociceptive hypersensitivity caused by ET1 is abrogated upon a loss of ET_A receptors on nociceptors and further suggest that ET1-induced early nociceptive hypersensitivity involves activation of ET_A as well as ET_B receptors in non-neural peripheral cells. Furthermore, in the context of alleviation of cancer pain and chronic inflammatory pain by ET_A receptor antagonists, we observed in corresponding mouse models that the contribution of ET_A receptors expressed in nociceptors is most significant. These results help understand the role of ET_A receptors in complex biological processes and peripheral cell-cell interactions involved in inflammatory and tumor-associated pain.