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

Abstract

Archer: Evaluation of THlP in standard tests for analgesic activity: Occurrence of antinociception and hyperalgesia. Drug Dev. Res. 4:405-419, 1984. THlP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a structurally rigid analog of the GABAagonist 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 THlP 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 THlP first appeared near the dose that produced antinociception in 50% of the animals (EDs0 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 THlP 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.

Analgesia and motor activity following administration of THIP into the periaqueductal gray and lateral ventricle of rats

“…Also, the correlation between percent maximum possible analgesia and percent failure on the rotorod following baclofen is less than that observed following THIP [Vaught et al, 19851. However, by contrast with the expectations for GABAA agonists, bicuculline does not antagonize THIP-induced analgesia [Christensen et al, 1982;Grognet et al, 1983;Hill et al, 1981;Hynes et al, 1984;Kendall et al, 1982;Vaught et al, 19851. Thus, it is not yet possible to state whether analgesia produced by THIP is due to events occurring at GABAA, GABAB, or perhaps other receptors.…”

“…The many reports that naloxone fails appreciably to antagonize THIP-induced analgesia [Christensen et al, 1982;Grognet et al, 1983;Hill et al, 1981;Hynes et al, 1984;Kendall et al, 1982;Vaught et al, 19851 strongly suggest that the analgesia produced by THIP may involve some nonopioid components. However, the cross-tolerance that exists between morphine and THIP in analgesimetric tests of animals receiving chronic THIP would imply that it is premature to rule out the occurrence of opioid-mediated events in THIP-induced analgesia [Andree et al, 1983;Vaught et al, 19851.…”

“…THIP is believed to be an agonist at GABA, sites, and baclofen is thought to be an agonist at GABAB sites. Baclofen is itself analgesic [Levy and Proudfit, 1977;Hynes et al, 1984;Vaught et al, 19851 and differs from THIP in that intrathecal administration of baclofen produces analgesia Wilson and Yaksh, 19781, whereas intrathecal administration of THIP does not [Hammond and Drower, 19831. Also, the correlation between percent maximum possible analgesia and percent failure on the rotorod following baclofen is less than that observed following THIP [Vaught et al, 19851.…”

“…Third, in studies using GABAergic agonists, muscimol has been reported to potentiate morphine analgesia in some but not all preparations [Biggio et al, 1977;Christensen et al, 1978;Mantegazza et al, 1979;Zambotti et al, 1982;Zonta et al, 19811. More recently, the muscimol congeners THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and kojic amine (2-aminomethyl-5-hydroxy-4H-pyran-4-one), were found to produce analgesia that was not antagonized by naloxone or bicuculline [Christensen et al, 1982;Grognet et al, 1983;Hill et al, 1981;Hynes et al, 1984;Kendall et al, 1982;Vaught et al, 19851. However, several investigators report that analgesia produced by THIP is antagonized by atropine [Grognet et al, 1983;Kendall et al, 1982;Vaught et al, 19851, although not all investigators agree with these results [Hynes et al, 19841. Much evidence illustrates the important role of several opioid-and non-opioid-containing cell groups in the rostra1 brain stem in the perception of nociceptive stimuli and mediation of analgesia [see Basbaum and Fields, 1984;Gebhart, 1982;Watkins and Mayer, 19821.…”