title: Differential effects of R-isovaline and the GABABagonist, baclofen, in the guinea pig ileum.
abstract: 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 GABABand group II metabotropic glutamate receptors in guinea pig ileum, which is known to exhibit well-defined responses to GABABagonists 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 GABABantagonism 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 (1-100mM) 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.
authors: Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Electronic address: tfung89@gmail.com.
authors: Timothy
authors: T
authors: Fung
authors: Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3; Department of Pharmacology, College of Pharmacy, King Khalid University, Abha 62529, Asir, Saudi Arabia.
authors: Khalid A
authors: KA
authors: Asseri
authors: Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors: Yahya I
authors: YI
authors: Asiri
authors: Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors: Richard A
authors: RA
authors: Wall
authors: Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3; Department of Anesthesiology, Perioperative Medicine & Pain Management, Providence Health Care/St. Paul's Hospital, Vancouver, British Columbia, Canada V6Z 1Y6.
authors: Stephan K W
authors: SKW
authors: Schwarz
authors: Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.
authors: Ernest
authors: E
authors: Puil
authors: Hugill Anesthesia Research Centre, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Electronic address: bernard.macleod@gmail.com.
authors: Bernard A
authors: BA
authors: MacLeod
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018080:Receptors, GABA-B / Q000378:metabolism*; D013237:Stereoisomerism; D014633:Valine / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001643:Bridged Bicyclo Compounds; D058786:GABA-B Receptor Agonists; D018080:Receptors, GABA-B; C032737:isovaline; D001418:Baclofen; D014633:Valine; C104753:eglumetad
keywords: Baclofen; Baclofen (PubChem CID: 2284); GABAB; Glutamate; Isovaline; Isovaline (PubChem CID: 94744); Metabotropic