Intrathecal RGS4 inhibitor, CCG50014, reduces nociceptive responses and enhances opioid-mediated analgesic effects in the mouse formalin test

Cited 10 time in webofscience Cited 0 time in scopus
253 Viewed 36 Downloaded
Title
Intrathecal RGS4 inhibitor, CCG50014, reduces nociceptive responses and enhances opioid-mediated analgesic effects in the mouse formalin test
Author(s)
Seo-Yeon Yoon; Jiwan Woo; Joon-Oh Park; Eui-Ju Choi; Hee-Sup Shin; Dae-Hyun Roh; Key-Sun Kim
Publication Date
2015-03
Journal
ANESTHESIA AND ANALGESIA, v.120, no.3, pp.671 - 677
Publisher
LIPPINCOTT WILLIAMS & WILKINS
Abstract
BACKGROUND: The regulator of G-protein signaling protein type 4 (RGS4) accelerates the guanosine triphosphatase activity of Gαi and Gαo, resulting in the inactivation of G-protein–coupled receptor signaling. An opioid receptor (OR), a Gαi-coupled receptor, plays an important role in pain modulation in the central nervous system. In this study, we examined whether (1) spinal RGS4 affected nociceptive responses in the formalin pain test, (2) this RGS4-mediated effect was involved in OR activation, and (3) the μ-OR agonist–induced antinociceptive effect was modified by RGS4 modulation. METHODS: Formalin (1%, 20 μL) was injected subcutaneously into the right hindpaws of male 129S4/SvJae×C57BL/6J (RGS4+/+ or RGS4−/−) mice, and the licking responses were counted for 40 minutes. The time periods (seconds) spent licking the injected paw during 0 to 10 minutes (early phase) and 10 to 40 minutes (late phase) were measured as indicators of acute nociception and inflammatory pain response, respectively. An RGS4 inhibitor, CCG50014, and/ or a μ-OR agonist, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), were intrathecally injected 5 minutes before the formalin injection. A nonselective OR antagonist, naloxone, was intraperitoneally injected 30 minutes before the CCG50014 injection. RESULTS: Mice that received the formalin injection exhibited typical biphasic nociceptive behaviors. The nociceptive responses in RGS4-knockout mice were significantly decreased during the late phase but not during the early phase. Similarly, intrathecally administered CCG50014 (10, 30, or 100 nmol) attenuated the nociceptive responses during the late phase in a dose-dependent manner. The antinociceptive effect of the RGS4 inhibitor was totally blocked by naloxone (5 mg/kg). In contrast, intrathecal injection of DAMGO achieved a dose-dependent reduction of the nociceptive responses at the early and late phases. This analgesic effect of DAMGO was significantly enhanced by the genetic depletion of RGS4 or by coadministration of CCG50014 (10 nmol). CONCLUSIONS: These findings demonstrated that spinal RGS4 inhibited the endogenous or exogenous OR-mediated antinociceptive effect in the formalin pain test. Thus, the inhibition of RGS4 activity can enhance OR agonist–induced analgesia. The enhancement of OR agonist– induced analgesia by coadministration of the RGS4 inhibitor suggests a new therapeutic strategy for the management of inflammatory pain. (Anesth Analg 2015;120:671–7) © 2015 International Anesthesia Research Society
URI
https://pr.ibs.re.kr/handle/8788114/3833
ISSN
0003-2999
Appears in Collections:
Center for Cognition and Sociality(인지 및 사회성 연구단) > Journal Papers (저널논문)
Files in This Item:
166. Intrathecal RGS4 Inhibitor, CCG50014.pdfDownload

qrcode

  • facebook

    twitter

  • Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.
해당 아이템을 이메일로 공유하기 원하시면 인증을 거치시기 바랍니다.

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse