| Summary: | We evaluated the effects of zonisamide on inflammatory and neuropathic pain using the mouse formalin test and streptozotocin (STZ)-induced diabetic mice with a reduced withdrawal threshold to mechanical stimuli, respectively. When administered systemically (subcutaneously, s.c.), intracerebroventricularly (i.c.v.) or intrathecally (i.t.) before formalin injection, zonisamide (3 and 10 mg/kg, s.c., 10 and 30 μg, i.c.v., or i.t.) significantly reduced licking/biting behavior during the second phase of the formalin test in a dose-dependent manner. However, zonisamide (30 μg, i.t.) did not affect the second phase of the formalin test when given after the first phase, suggesting that it can prevent the development of injury-induced hyperexcitability of the spinal dorsal horn triggered by the repetitive nociceptive input during the first phase. Moreover, zonisamide administered into the dorsal hindpaw ipsilateral but not contralateral to the formalin injection partly reduced the second phase. Thus it is likely that zonisamide generates analgesic effects in the formalin test via both central and peripheral mechanisms. In mice with STZ-induced diabetes, zonisamide (10 and 30 mg/kg, s.c. or 10 and 30 μg, i.t.) reversed the mechanical hyperexcitability. Our results suggest that zonisamide can be a useful therapeutic agent, presumably for both prevention and reversal of pathophysiologic pain. Keywords:: zonisamide, neuropathic pain, inflammatory pain, formalin, diabetes
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