The neuromodulatory interaction of sex steroids with the opioid system may involve in sex differences in pain sensitivity. Also, sex steroids undergo fluctuations during estrus cycle. On the other hand, adrenergic system can influence pain sensitivity. Thus, the aim of the present study was to investigate the effect of phenylephrine and prazocin on pain sensitivity during estrus cycle. For this purpose, 6 adult rats weighing 190-220 g were kept in a room with a controlled temperature (21-24 ?C) exposed to daily light from 6:00 a.m. to 6:00 p.m. Animals were divided into two control groups (intact and/or sham animals which received i.p. injection of saline) and one experimental group which received phenylephrine at doses of 3, 5, and 8 mg/kg and prazocin at doses of 1, 2, and 3 mg/kg via i.p. route. Then, tail flick test was performed before injection, and 15 and 30 minutes after injection. Data was presented as percentage of analgesic indices and were compared statistically using ANOVA test. It was shown that phenylephrine significantly (P<0.05) decreased pain sensitivity in all phases of estrus cycle. This analgesic effect was higher in diestrus and lower in proestrus rats. Prazocin significantly (P<0.05) increased pain sensitivity. This hyperalgesic effect was higher in diestrus and lower in proestrus rats. The presented data indicated that pain sensitivity after phenylephrine and prazocin administration was different during estrus cycle. It seems that fluctuations in ovarian hormones is responsible for these differences in pain sensitivity.