Endothelin-1 (ET-1) is unique among a broad range of hyperalgesic agents in that it induces
hyperalgesia in rats that is markedly enhanced by repeated mechanical stimulation at the site of administration. Antagonists to the ET-1 receptors, ET(A) and ET(B), attenuated both initial as well as stimulation-induced enhancement of
hyperalgesia (SIEH) by
endothelin. However, administering antisense
oligodeoxynucleotide to attenuate ET(A) receptor expression on nociceptors attenuated ET-1
hyperalgesia but had no effect on SIEH, suggesting that this is mediated via a non-neuronal cell. Because vascular endothelial cells are both stretch sensitive and express ET(A) and ET(B) receptors, we tested the hypothesis that SIEH is dependent on endothelial cells by impairing vascular endothelial function with
octoxynol-9 administration; this procedure eliminated SIEH without attenuating ET-1
hyperalgesia. A role for
protein kinase Cε (PKCε), a second messenger implicated in the induction and maintenance of
chronic pain, was explored. Intrathecal antisense for PKCε did not inhibit either ET-1
hyperalgesia or SIEH, suggesting no role for neuronal PKCε; however, administration of a PKCε inhibitor at the site of testing selectively attenuated SIEH. Compatible with endothelial cells releasing
ATP in response to mechanical stimulation, P2X(2/3) receptor antagonists eliminated SIEH. The endothelium also appears to contribute to
hyperalgesia in two ergonomic
pain models (eccentric exercise and hindlimb vibration) and in a model of
endometriosis. We propose that SIEH is produced by an effect of ET-1 on vascular endothelial cells, sensitizing its release of
ATP in response to mechanical stimulation;
ATP in turn acts at the nociceptor P2X(2/3) receptor.