Early and late contributions of glutamate and CGRP to mechanical sensitization by endothelin-1.
Intraplantar injection of endothelin-1 (ET-1) (1.5-10 muM) in the rat produces mechanical allodynia. Here we identify the receptor subtypes for ET-1, glutamate and CGRP critical to such allodynia. Antagonism of ET(A) or ET(B) receptors alone, by BQ123 or BQ788, respectively, only partially suppressed allodynia; the combined antagonists prevented allodynia, showing the involvement of both receptor subtypes. Co-injection of NMDA receptor antagonists, (+)MK-801 or D-AP5, with ET-1 also prevented allodynia. In contrast, co-injection of the CGRP1 antagonist CGRP(8-37) attenuated only the later phase of allodynia (>30 min). A mechanistic basis for these effects is shown by ET-1's ability to enhance basal release from cultured sensory neurons of glutamate and CGRP (2.4-fold and 5.7-fold, respectively, for 10 nM ET-1). ET(A) blockade reduced ET-1's enhancement of basal CGRP release by approximately 80%, but basal glutamate release by only approximately 30%. ET-1 also enhanced the capsaicin-stimulated release of CGRP (up to 2-fold for 0.3 nM ET-1), but did not change capsaicin-stimulated glutamate release. Release stimulated by elevated K+ was not altered by ET(A) blockade, nor did blockade of ET(B) reduce any type of release. Thus, ET-1 may induce release of glutamate and CGRP from nerve terminals innervating skin, thereby sensitizing primary afferents, accounting for ET-1-dependent tactile allodynia.


CONCLUSIONS
The endogenous endothelin peptides participate in a remarkable variety of pain-related processes. The present results provide evidence for the participation of ionotropic glutamatergic receptors and CGRP receptors in the hyperalgesic responses to exogenous ET-1 and suggest clinically relevant targets for further study of elevated pain caused by release of endogenous ET-1.
Khodorova
Alla
A
Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Boston, Massachusetts 02115-6110, USA.
Richter
Judith
J
Vasko
Michael R
MR
Strichartz
Gary
G
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002478:Cells, Cultured; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D010146:Pain / Q000378:metabolism*; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D010812:Physical Stimulation; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011984:Sensory Receptor Cells / Q000378:metabolism; D013997:Time Factors
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D018015:Receptors, Calcitonin Gene-Related Peptide; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D015740:Calcitonin Gene-Related Peptide; D011188:Potassium