Pretreatment with intraperitoneal (IP) indomethacin was used to determine whether indomethacin preferentially affected the development of edema and hyperalgesia to thermal and mechanical stimuli produced by injection of zymosan in the ispsilateral hindpaw of the rat. Indomethacin also was delivered intrathecally (IT) either 30 minutes before or 4 hours after intraplantar zymosan to determine whether spinal prostaglandin production was important for the induction and/or maintenance of hyperalgesia. Zymosan alone produced a robust edema, a monophasic mechanical hyperalgesia, and a biphasic thermal hyperalgesia in the ipsilateral hindpaw. Systemic administration of indomethacin reduced zymosan-induced edema and increased thermal and mechanical response thresholds in the zymosan-injected paw. Systemic indomethacin did not affect thermal withdrawal response thresholds in the uninjected contralateral hindpaw of zymosan-treated rats, but significantly increased mechanical withdrawal thresholds of the uninjected contralateral paw of zymosan-treated rats. IT administration of indomethacin before the induction of hyperalgesia attenuated the development of zymosan-induced mechanical hyperalgesia, but did not affect the development of either zymosan-induced edema or thermal hyperalgesia. Once hyperalgesia was established, IT indomethacin also attenuated the mechanical hyperalgesia whereas it had no effect on thermal hyperalgesia or edema. These data suggest that peripheral, but not spinal prostaglandins contribute to the edema and development of thermal hyperalgesia produced by zymosan. In contrast, spinal prostaglandins contribute to the development and maintenance of mechanical hyperalgesia.