Estradiol replacement in ovariectomized rats is antihyperalgesic in the formalin test.

UNLABELLED: A subcutaneous implant of 17beta-estradiol or progesterone provides steady-state serum hormone levels from 7 to 24 days after implantation and allows the evaluation of the effects of the replacement with these hormones on phase 1 and phase 2 formalin-induced behaviors in ovariectomized (OVX) rats. Graded doses of 17beta-estradiol (5% to 40%) reduce formalin-induced behavior by 35% to 49% during phase 2 but not during phase 1, as measured with an automated formalin apparatus. The maximal response is seen with 20% 17beta-estradiol. The antihyperalgesic effect of 20% 17beta-estradiol is significant at 8 days after implantation and persists at 21 days. In contrast, graded doses of progesterone have no effect on either phase of formalin. The estrogen receptor antagonist tamoxifen completely prevents the antihyperalgesic effect of the 20% 17beta-estradiol implant. Formalin-induced behaviors during phase 2 are significantly less in proestrus females and OVX rats given 20% 17beta-estradiol compared with OVX control rats. Also, the formalin-induced increase in serum corticosterone is attenuated in OVX control rats compared with proestrus females and OVX rats given 20% 17beta-estradiol. These results indicate that estrogen replacement in OVX rats restores the maximal corticosterone response to tonic pain and, by an estrogen receptor-mediated process, inhibits tonic pain. PERSPECTIVE: Hormone replacement (HR) therapy remains a widely used modality. We used a pharmacokinetically based rat HR model that results in continuous physiological levels of 17beta-estradiol to demonstrate the analgesic (antihyperalgesic) effects of estrogen replacement in an inflammatory pain model (formalin). These results suggest a potentially important consequence of HR therapy.

Pharmacokinetics and effects of 17beta-estradiol and progesterone implants in ovariectomized rats.

UNLABELLED: For the pharmacokinetic evaluation of Silastic capsules, ovariectomized (OVX) rats were implanted subcutaneously with this dosage form containing 17beta-estradiol (5, 10, 15, or 20% in cholesterol, where 5% 17beta-estradiol equals 0.4 mg) or progesterone (20, 40, 110, or 220 mg of crystalline progesterone). The time-course of serum 17beta-estradiol and progesterone released from these capsules in the OVX rat is characterized by an initial increase in serum hormone levels followed by a decline and then an apparent steady-state that persists from 7 to 24 days postimplant. Both hormones have large clearance values (total clearance is 97.7 L/day for 17beta-estradiol and 20.9 L/day for progesterone). For 17beta-estradiol and progesterone only, 11% of the dose was released from the implant after 24 days. Thus, the Silastic membrane represents the rate controlling barrier for these hormones. The relationship between graded doses of 17beta-estradiol or progesterone and serum concentration was linear. Neither tail flick latencies measured at 48, 52.5, and 55 degrees C nor the antinociceptive potency of morphine (ED(50) values) were altered by continuous administration to steady-state of graded doses of 17beta-estradiol or progesterone. We demonstrate how a dose-dependent analysis of some of the behavioral effects of 17beta-estradiol or progesterone can be conducted at steady-state serum hormone concentrations. PERSPECTIVE: We describe a method to obtain sustained serum levels of estrogen or progesterone and the consequences of these sustained hormone levels on acute thermal nociception and the antinociceptive response to morphine. This rat model of hormone replacement may provide insights into the role of these hormones in pathological pain states.