Analgesic, Respiratory and Endocrine Responses in Normal Man to THIP, a GABA‐Agonist

Abstract

In a controlled study, the effects of THIP (a synthetic gamma-aminobutyric-acid-agonist) on respiratory function (ventilatory response to CO2), first detection of stimulation (electrical stimulation of a tooth), pain threshold, magnitude of maximal tolerated pain stimulation, and plasma cortisol, prolactin and glucose were investigated in six normal men. Intramuscular injection of THIP in dosages of both 10 mg and 20 mg increased the magnitude of stimulus before first detection, and the pain threshold as well as the maximal tolerance of pain stimulation. THIP did not lead to changes in respiratory function, or in plasma cortisol, prolactin or glucose, suggesting an analgesic action independent of opiate receptors.

Effect of bucladesine, pentoxifylline, and H‐89 as cyclic adenosine monophosphate analog, phosphodiesterase, and protein kinase A inhibitor on acute pain

“…Protein kinase A also reduces the activation of γ‐aminobutyric acid (GABA)ergic function by phosphorylation of GABAA, an inhibitory neurotransmitter . Clinical trials showed that THIP, a GABA‐A agonist, imposed analgesic effect .…”

The analgesic effect of the GABA‐agonist THIP in patients with chronic pain of malignant origin. A phase‐1‐2 study.

“…THIP, (4,5,6,7 tetrahydroisoxazolo [5,4-c] pyridin-3ol) is a newly synthesized structural analogue to muscimol and a specific agonist of the GABA transmitter system which has shown sedative and analgesic properties in experimental systems (Hill et al, 1981. Studies in healthy human volunteers have shown that doses of 10 and 20 mg intramuscularly are easily tolerated without changes in respiratory function, plasma cortisol, prolactin or glucose (Lindeburg et al, 1983). Oral doses up to 120 mg day have been administered without adverse effects on vital signs (Korsgaard et al, 1982).…”

J.J. Bonica lecture[mdash ]2001: Role of spinal GABA in acute and persistent nociception

“…THIP produced analgesia in humans at doses of 10 to 20 mg in an open-label, single-blind trial of severe chronic cancer pain 56 and in a double-blind, placebo-controlled trial of experimental pain after tooth pulp stimulation in human volunteers. 57 However, between 30% and 80% of patients reported sedation and dizziness. The small therapeutic index be-tween the antinociceptive and sedative properties of THIP precluded further clinical development of this GABA A receptor agonist and no other such drugs have been brought forward since.…”