THIP analgesia: cross tolerance with morphine.

THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c) pyridone-3-ol), a direct acting GABA receptor agonist, has been shown to have antinociceptive properties. To determine whether tolerance develops to the analgesic response, mice received multiple injections of THIP for up to 21 days after which analgesia was tested using both tail immersion and hot-plate methods. Both tests indicated a significant reduction in the antinociceptive response to THIP, as well as other GABA agonists, beginning between days 3 and 5 of chronic administration. Moreover, these animals demonstrated a decreased analgesic response to morphine, and morphine tolerant animals were also less responsive to THIP. These data indicate that opiates and GABA agonists induce analgesia by acting through separate but related pathways in the central nervous system.