Evaluation of THIP in standard tests for analgesic activity: Occurrence of antinociception and hyperalgesia

Abstract

AbstractTHIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol), a structurally rigid analog of the GABA‐agonist muscimol, was investigated for antinociceptive activity in a variety of preclinical tests for analgesic activity. Antinociceptive activity was observed in the mouse writhing, mouse hot plate, rat tail flick, rat inflamed paw, and monkey shock titration tests. In the mouse writhing, mouse hot plate, and rat tail jerk experiments, periods of significant hyperalgesia were noted either prior to or following the occurrence of THIP‐induced antinociception. At those times when an antinociceptive effect of THIP could be demonstrated in the test systems employed in this study, a variety of unfavorable effects were noted including sedation, ataxia, myoclonic jerks, and vomiting. These side‐effects of THIP first appeared near the dose that produced antinociception in 50% of the animals (ED50 value) and became progressively more intense as the dose increased. Neither the narcotic antagonist naloxone, the cholinergic antagonist atropine, nor the GABA‐antagonists bicuculline or picrotoxin blocked the antinociceptive activity of THIP. The synthesis of prostaglandins was not inhibited by THIP. The antinociceptive activity of THIP is an interesting lead in the search for a novel analgesic that lacks the undesirable effects of opiates. However, the occurrence of hyperalgesia and marked side‐effects at doses near the effective analgesic dose may limit THIP's therapeutic potential.