Early and late contributions of glutamate and CGRP to mechanical sensitization by endothelin-1.

Abstract

UNLABELLED:

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.

PERSPECTIVE:

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.

• Authors: Alla Khodorova, Judith Richter, Michael R Vasko, Gary Strichartz
• Journal: The journal of pain (J Pain) Vol. 10 Issue 7 Pg. 740-9 (Jul 2009) ISSN: 1528-8447 [Electronic] United States
• PMID: 19559390 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Calcitonin Gene-Related Peptide Receptor Antagonists
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1
• Receptors, Calcitonin Gene-Related Peptide
• Receptors, N-Methyl-D-Aspartate
• Glutamic Acid
• Calcitonin Gene-Related Peptide
• Potassium

Topics

• Animals
• Calcitonin Gene-Related Peptide (antagonists & inhibitors, metabolism)
• Calcitonin Gene-Related Peptide Receptor Antagonists
• Cells, Cultured
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Endothelin-1 (metabolism)
• Ganglia, Spinal (metabolism)
• Glutamic Acid (metabolism)
• Male
• Pain (metabolism)
• Pain Measurement
• Pain Threshold (physiology)
• Physical Stimulation
• Potassium (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Calcitonin Gene-Related Peptide (metabolism)
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)
• Sensory Receptor Cells (metabolism)
• Time Factors