Differential effects of R-isovaline and the GABA_B agonist, baclofen, in the guinea pig ileum

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• 作者：Timothy Fung^a ; ^{tfung89@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Khalid A. Asseri^a ; ^b ; Yahya I. Asiri^a ; Richard A. Wall^a ; Stephan K.W. Schwarz^a ; ^c ; Ernest Puil^a ; Bernard A. MacLeod^a ; ^{bernard.macleod@gmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Isovaline (PubChem CID ; 94744) ; Baclofen (PubChem CID ; 2284)
• 刊名：European Journal of Pharmacology
• 出版年：2016
• 出版时间：15 November 2016
• 年：2016
• 卷：791
• 期：Complete
• 页码：85-90
• 全文大小：1059 K

文摘

R-isovaline is a non-proteinogenic amino acid which produces analgesia in a range of nociceptive assays. Mediation of this effect by metabotropic receptors for γ-aminobutyric acid (GABA) and glutamate, demonstrated by previous work, may depend on the type of tissue or receptor system. The objective of this study was to assess the activity of R-isovaline acting at GABA_B and group II metabotropic glutamate receptors in guinea pig ileum, which is known to exhibit well-defined responses to GABA_B agonists such as baclofen. The effects of bath-applied R-isovaline and RS-baclofen were examined on electrically evoked contractions of guinea pig ileum and during GABA_B antagonism by CGP52432. In separate experiments, the group II metabotropic glutamate receptor agonist, LY354740 was applied to determine the functional presence of these receptors. R-isovaline (1–100 mM) decreased the amplitude of ileal muscle contractions and increased tension. RS-baclofen reduced contraction amplitude, but decreased tension. CGP52432 did not prevent the effects of R-isovaline on contraction amplitude, but antagonized effects of RS-baclofen on contraction amplitude. The group II metabotropic glutamate receptor agonist, LY354740, produced no detectable effects on evoked contractions. R-isovaline differed significantly from RS-baclofen in its actions in the guinea pig ileum, indicated in particular by the finding that CGP52432 blocked only the effects of RS-baclofen. The ileal tissue did not respond to a group II metabotropic glutamate receptor agonist, previously shown to co-mediate R-isovaline analgesia. These findings raise the possibility of a novel therapeutic target at unknown receptors for R-isovaline-like compounds in the guinea pig ileum.