Significance of GABAergic systems in the action of improgan, a non-opioid analgesic

Improgan is the prototype drug from a new class of non-opioid analgesics ch emically related to histamine and histamine antagonists, but the mechanism of action of these compounds has not been identified. Because several class es of analgesics act in the brain by reducing GABAergic inhibition of endog enous pain-relieving circuits; and because the activity of these substances is abolished by the GABA(A) agonist muscimol, the present study assessed t he effects of muscimol on improgan antinociception in rats. Intracerebroven tricular (icv) improgan (80 mug) and morphine (20 mug) both induced 80-100% of maximal analgesic responses on the tail flick test 10 to 30 min later. However, muscimol pretreatment (0.5 mug, icy) completely eliminated the ant inociceptive activity of both compounds. Since improgan in vitro lacks acti vity at opioid and GABA, receptors, these findings: 1) confirm earlier lite rature showing that muscimol inhibits morphine analgesia, and 2) suggest th at improgan activates a supraspinal, descending analgesic pathway, possibly via inhibition of GABAergic transmission. Since muscimol is the first comp ound discovered which inhibits improgan analgesia, muscimol will be a usefu l tool for the further characterization of this new class of pain-relieving substances. (C) 2001 Elsevier Science Inc. All rights reserved.