title: Antinociceptive effect of the GABAmimetic 4,5,6,7-tetrahydroisoxazolo [5, 4-c]pyridin-3-ol (THIP): chronic treatment increases alpha-2 adrenoceptors in the mouse brain.
abstract: It has been shown that the gamma-aminobutyric acid mimetic THIP (4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol) has an antinociceptive effect in the mouse. Repeated administrations of THIP induced the development of tolerance to its antinociceptive effect. An increased binding of [3H]clonidine to alpha-2 adrenoceptors was found in the cerebral cortex of THIP-tolerant mice, due to an increase of receptor density. This alteration was not present after acute treatment with THIP and was specific for alpha-2 adrenergic receptors, as alpha-1 and beta adrenergic, muscarinic and gamma-aminobutyric acid receptors were unchanged in THIP-tolerant mice. Animals tolerant to THIP were also super-sensitive to the antinociceptive effect of clonidine. The alpha-2 adrenergic receptor antagonist yohimbine antagonized THIP-induced antinociception. These results suggest that the noradrenergic system may be involved in THIP antinociception and in the development of tolerance.
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003000:Clonidine / Q000378:metabolism / Q000494:pharmacology; D004361:Drug Tolerance; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009020:Morphine / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology*; D011942:Receptors, Adrenergic, alpha / Q000032:analysis / Q000187:drug effects*; D011956:Receptors, Cell Surface / Q000187:drug effects; D011963:Receptors, GABA-A
chemical_list: D000700:Analgesics; D007555:Isoxazoles; D010080:Oxazoles; D011942:Receptors, Adrenergic, alpha; D011956:Receptors, Cell Surface; D011963:Receptors, GABA-A; D009020:Morphine; C015542:gaboxadol; D003000:Clonidine