Summary— The possible development of acute and chronic tolerance to 4, 5, 6, 7-tetrahydroisoxazole-(5, 4-C) pyridin-3-ol (THIP) and muscimol-induced analgesia was tested using the acetic acid induced writhing assay. Acute tolerance developed to their analgesic actions on repeated exposure at a 4-h interval which was sensitive to naloxone. Chronic tolerance gradually developed to these agents from the 4th day and was appreciable after 10 days of treatment. Injection of THIP or muscimol prior to morphine attenuated the acute tolerance developed to morphine analgesia. These findings reveal that acute and chronic tolerance developed to THIP and muscimol induced analgesia and are suggestive of a role for opioidergic system in the development of acute tolerance to their analgesic effect. However, these agents per se did not produce any dependence phenomena and failed to affect morphine dependence indicating that different mechanisms might be operating in the development of tolerance and dependence.