The relationship between endogenous gonadal steroid levels and persistent or chronic pain is poorly understood. These studies used an inflammation model to examine the role of the gonadal steroid, progesterone, in the development of persistent pain and hyperalgesia in lactating ovary-intact and ovariectomized rats. The results indicate that constant high plasma levels of progesterone attenuate inflammatory hyperalgesia by a mechanism involving inhibition of N-methyl-D-aspartate receptor activation at the spinal cord level. Since the pattern of high progesterone in lactating rats mimics the progesterone component of the luteal phase of the human menstrual cycle, these findings have significance in persistent or chronic pain conditions that are most prevalent in females.