OPIOID MODULATION OF ANTINOCICEPTION OF CELECOXIB AND KETOROLAC AT PRE-CLINICAL PAIN

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat pain, fever, and inflammation. Among them are celecoxib and ketorolac, whose efficacy is dependent on the inhibition of COXs and seems to be modulated by additional mechanisms that would contribute to analgesic efficacy. On the other hand, the interaction of NSAIDs with other types of analgesics, especially with opioids, is often poorly identified. The objective of this work was to evaluate the effect of the opioid antagonists: naltrexone, naltrindole and nor-binaltorphimine on the efficacy of celecoxib and ketorolac in murine models of tonic and visceral pain induced by chemical stimuli, such as contortions induced by acetic acid and the formalin hind paw test. The antinociceptive potency of celecoxib and ketorolac was assessed using a dose-response curve from 0.1-10mg/kg, i.p. before and after pretreatment of mice with 1 mg/kg i.p. of the opioid antagonist's naltrexone, naltrindole, or norbinaltorphimine. Celecoxib was 1.58 to 4.85 times more potent than ketorolac. The effect of both NSAIDs was unequally modified by opioid antagonists. Thus, the efficacy of ketorolac increased in the writhing test and in the phase I formalin trial, while that of celecoxib only increased in the phase II formalin trial. The results demonstrate that ketorolac and celecoxib induce significant antinociception, whose efficacy was increased by specific opioid receptor antagonists, suggesting that the antinociception induced by ketorolac and celecoxib is dependent on opioid receptors.