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Vascular endothelial cells mediate mechanical stimulation-induced enhancement of endothelin hyperalgesia via activation of P2X2/3 receptors on nociceptors.

Abstract
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.
AuthorsElizabeth K Joseph, Paul G Green, Oliver Bogen, Pedro Alvarez, Jon D Levine
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 33 Issue 7 Pg. 2849-59 (Feb 13 2013) ISSN: 1529-2401 [Electronic] United States
PMID23407944 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Endothelins
  • Oligodeoxyribonucleotides, Antisense
  • Purinergic P2X Receptor Agonists
  • Receptor, Endothelin A
  • Receptors, Purinergic P2X2
  • Octoxynol
Topics
  • Animals
  • Blotting, Western
  • Endometriosis (physiopathology)
  • Endothelial Cells (physiology)
  • Endothelins
  • Endothelium, Vascular (cytology, physiology)
  • Female
  • Hindlimb (physiology)
  • Hyperalgesia (chemically induced, physiopathology)
  • Laser-Doppler Flowmetry
  • Male
  • Muscle, Skeletal (physiology)
  • Nociceptors (drug effects)
  • Octoxynol (pharmacology)
  • Oligodeoxyribonucleotides, Antisense (pharmacology)
  • Pain Measurement
  • Pain Threshold
  • Physical Exertion (physiology)
  • Physical Stimulation
  • Purinergic P2X Receptor Agonists (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A (drug effects)
  • Receptors, Purinergic P2X2 (drug effects)
  • Vibration

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