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BACKGROUND: Noxious cutaneous stimuli enhance spinal excitability. The behavioral correlate to this response is found in the rat formalin test, in which formalin injection into the hindpaw evokes signs of nociception (flinching and licking of the injected paw) with acute (phase 1) and delayed-hyperalgesic (phase 2) components. METHODS: The effect of intrathecal morphine (a mu agonist), U50488H (a kappa agonist), ST-91 (an alpha 2 agonist), L-PIA (an adenosine A1 agonist), and ketorolac (a nonsteroidal antiinflammatory drug, or NSAID), were examined in rats undergoing the formalin test. Spinal interactions between ketorolac and the mu, kappa, alpha 2, and adenosine A1 agonists were assessed using isobolographic analysis. RESULTS: Morphine and ST-91 caused a dose-dependent suppression of phase 1 and phase 2 of the formalin test, while U50488H and L-PIA had little effect on phase 1, but caused dose-dependent depression of phase 2. Intrathecal ketorolac inhibited the phase 2 response, but had limited effect on phase 1. The isobolographic analysis revealed a significant synergy (with fractional dose ratios of less than 1) between ketorolac and morphine or ST-91 for phase 1 and phase 2, but only an additive interaction was found between ketorolac and L-PIA or U50488H. CONCLUSIONS: These observations offer systematic support for the powerful interaction between NSAIDs and opioids and certain other analgesics in clinical pain states. These studies also demonstrate that spinal synergy is not a common property of all interactions. Thus, the NSAID synergy appears to occur with agents that exert a concurrent action both pre- and postsynaptic to the primary afferents.
Malmberg et al. (Sun,) studied this question.