Early and Late Contributions of Glutamate and CGRP to Mechanical Sensitization by Endothelin-1

Alla Khodorova, Judith Richter, Michael R. Vasko, Gary Strichartz

Research output: Contribution to journalArticle

18 Scopus citations


Intraplantar injection of endothelin-1 (ET-1) (1.5-10 μM) in the rat produces mechanical allodynia. Here we identify the receptor subtypes for ET-1, glutamate and CGRP critical to such allodynia. Antagonism of ETA or ETB 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 CGRP8-37 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). ETA blockade reduced ET-1's enhancement of basal CGRP release by ∼80%, but basal glutamate release by only ∼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 ETA blockade, nor did blockade of ETB 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.

Original languageEnglish (US)
Pages (from-to)740-749
Number of pages10
JournalJournal of Pain
Issue number7
StatePublished - Jul 1 2009


  • allodynia
  • Endothelin-1
  • mechanical hyperalgesia
  • pain
  • pro-nociception

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine
  • Neurology
  • Clinical Neurology

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