title: 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.
authors: Department of Medicine, Division of Neuroscience, University of California at San Francisco, San Francisco, California 94143-0440, USA.
authors: Elizabeth K
authors: EK
authors: Joseph
authors: Paul G
authors: PG
authors: Green
authors: Oliver
authors: O
authors: Bogen
authors: Pedro
authors: P
authors: Alvarez
authors: Jon D
authors: JD
authors: Levine
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004715:Endometriosis / Q000503:physiopathology; D042783:Endothelial Cells / Q000502:physiology*; D016232:Endothelins; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005260:Female; D006614:Hindlimb / Q000502:physiology; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D018482:Muscle, Skeletal / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects*; D017830:Octoxynol / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D010147:Pain Measurement; D017288:Pain Threshold; D005082:Physical Exertion / Q000502:physiology; D010812:Physical Stimulation; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000187:drug effects; D058476:Receptors, Purinergic P2X2 / Q000187:drug effects*; D014732:Vibration
chemical_list: D016232:Endothelins; D020319:Oligodeoxyribonucleotides, Antisense; D058911:Purinergic P2X Receptor Agonists; D044022:Receptor, Endothelin A; D058476:Receptors, Purinergic P2X2; D017830:Octoxynol