Calcitonin gene-related peptide (CGRP) is a vasodilatory peptide, and it is primarily synthesized in dorsal root ganglia (DRG). Plasma CGRP levels increase during pregnancy and with steroid hormones, and nerve growth factor (NGF) stimulates calcitonin/CGRP promoter and CGRP synthesis in DRG. We previously showed that CGRP levels in DRG were stimulated with steroid hormone treatments in vivo but not in vitro. Thus, the stimulation of CGRP by these hormones may be indirect through the upregulation of NGF effects. We hypothesized that the female sex steroid hormones upregulate NGF receptors, trkA and p75NTR, in DRG. We examined the effects of 17β-estradiol (E2) and progesterone (P4) on NGF receptors in DRG obtained from ovariectomized (ovx) rats. Groups of 4 ovx rats were injected s.c. with 5 μg E2, 4 mg P4, or 5 μg E2 4 mg P4 in 0.2 ml sesame oil or injected with oil only and were killed at 6, 24, and 48 h. In addition, ovx rats were also injected s.c. with varying doses (0.2, 1.0, 5.0, 25 μg) of E2 (0.5, 1.5, 4, 10 mg) P4, and (5 μg) E2 (0.5, 1.5, 4.0, 10 mg) P4 in 0.2 ml sesame oil, or vehicle, and killed at 6 (for E2) or 24 (for P4 and E2 P4) h. Furthermore, groups of ovx rats were also killed at 12 and 24 h; 3 and 7 days; 2, 4, and 6 wk after ovariectomy. The DRGs were collected from all groups and then processed for Western immunoblotting to examine both trkA and p75NTR levels. Estradiol increased trkA at 6 h but not p75NTR. Progesterone caused upregulation of trkA and p75NTR at 6 and 24 h. 17β-Estradiol P4 increased trkA at 6 and 24 h and p75NTR at all time points examined. One microgram of E2 increased trkA but did not affect p75NTR levels. Progesterone at 4 and 10 mg upregulated trkA but only 10 mg P4 increased p75NTR. Five micrograms of E2 coinjected with P4 at 1.5 and 4 mg increased trkA, while p75NTR receptor was upregulated when coinjected with P4 at 1.5 to 10 mg. The ovariectomy caused a decrease in trkA receptors compared to proestrus rats, and these decreases were significant by 6 wk, but surprisingly p75NTR increased at 2 wk after ovariectomy. 17β-Estradiol increased trkA but not p75NTR receptors in DRG, whereas P4 caused increases in both trkA and p75NTR in DRG. In addition, the combination of these steroid hormones had more effect on both receptors than either hormone alone. Thus, we concluded that high levels of female steroid hormones such as those due to pregnancy or hormonal replacement therapy could increase NGF receptor expression in DRG that carry more NGF to elevate the CGRP synthesis in these groups. We suggested that the regulation of NGF receptors by ovarian steroids may underlie steroidal regulation of other factors such as CGRP.
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