Dual Roles for Endothelin-B Receptors in Modulating Adjuvant-Induced Inflammatory Hyperalgesia in Rats

Alla Khodorova1, Shiping Zou2, Ke Ren2, Ronald Dubner2, Gudarz Davar1, 3, Gary Strichartz1, *
1 Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
2 Department of Biomedical Sciences, Dental School, Program in Neuroscience, University of Maryland, Baltimore, MD, USA
3 Current address: BiogIdec, Inc., 14 Cambridge Center, Cambridge, MA, USA

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© 2009 Khodorova et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

* Address correspondence to this author at the Pain Research Center/ BWH,75 Francis Street, Boston, MA 02115-6110, USA; Tel: (617) 732-7802; Fax: (617) 730-2801; E-mail:


Injection of endothelin-1 (ET-1) into the plantar rat hindpaw causes acute pain at high concentrations and tactile sensitization at low concentrations. The pro-nociceptive actions are driven through ETA receptors for both levels of [ET-1], but the ETB receptors are only pro-nociceptive for allodynia from low [ET-1] and anti-nociceptive for pain from high [ET-1]. The goal of the present work was to discriminate the roles of the ET receptors in the acute hyperalgesia from inflammation by complete Freund’s adjuvant (CFA, 20 mg/paw) into the rat hindpaw. Selective antagonists were injected l0 min before and then together with CFA. An ETA receptor antagonist, BQ-123, reduced CFA-induced thermal hyperalgesia (by up to 50%), as did an ETB receptor antagonist, BQ-788 (by up to 66%). BQ-123 and BQ-788 also delayed the onset (by 1.5 – 2 h) but insignificantly reduced the maximum degree of CFA-induced allodynia (~10%). Surprisingly, an ETB receptor agonist, IRL-1620, also reduced maximum thermal hyperalgesia induced by CFA, suppressed peak allodynia and delayed its occurrence by ~ 3 h. The latter actions of IRL-1620 were reversed by coadministration of BQ-788, naloxone hydrochloride and the peripherally restricted opiate receptor antagonist naloxone methiodide, and by antiserum against β-endorphin. These findings demonstrate an important role for endogenous ET-1 in acute inflammatory pain and a dual action of ETB receptors, including a pro-algesic action along with the important activation of a local analgesic pathway, implying that at least two different ETB receptors contribute to modulation of inflammatory pain.

Keywords: Inflammatory Hyperalgesia, Endothelin-1, Pro-nociception, Anti-nociception, Allodynia, Pain.