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.

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.