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, *
Identifiers and Pagination:Year: 2009
First Page: 30
Last Page: 40
Publisher Id: TOPAINJ-2-30
Article History:Received Date: 17/12/2008
Revision Received Date: 15/01/2009
Acceptance Date: 16/03/2009
Electronic publication date: 24/3/2009
Collection year: 2009
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: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.