ESTRADIOL BENZOATE POTENTIATES NEUROACTIVE STEROIDS EFFECTS ON PAIN SENSITIVITY

Progesterone (P), its metabolites, and other neuroactive steroids alte r pain thresholds consistent with their efficacies at modulating gamma -aminobutyric acid (GABA(A)) receptor complexes. We investigated wheth er estradiol benzoate (EB) potentiates low dosages of neuroactive ster oids' effects on pain. Subcutaneous EB (10 mu g) or sesame oil vehicle was administered to ovariectomized Long-Evans rats(n = 40) 48 h befor e intracerebroventricular (ICV) infusion of a neuroactive steroid (0.0 , 0.1, 0.3, or 0.5 mu g) in cyclodextrin vehicle. Neuroactive steroids (listed from greatest to least efficacious at GABA(A) receptor comple xes) were THP [5 alpha-pregnan-3 alpha-ol-20-one], THDOC [5 alpha-preg nan-3 alpha, 21-diol-20-one], DHP [5 alpha-pregnan-3,20-dione], P [4-p regnen-3,20-dione], and DHEAS [5-androsten-3 beta-ol-17-one sulfate]. Pain sensitivity was assessed using the radiant heat tail-flick method before and 20 and 60 min following infusion. Estradiol benzoate inter acted with the neuroactive steroids to alter tail-flick latencies. In particular, EB potentiated the antinociceptive effect of THP and DHP b y significantly increasing tail-flick latencies above those of non-EB- treated animals. A similar pattern of increased tail-flick latencies o ccurred in EB-primed animals that received THDOC. Estradiol benzoate l ess consistently altered the pain threshold of animals administered P, which is less effective at modulating GABAergic activity. Conversely, EB increased the nociceptive effect of the neurosteroid DHEAS, an all osteric antagonist of GABA(A) receptor complexes, by significantly dec reasing tail-flick latencies of EB- compared to vehicle-primed rats. T hus, EB priming potentiated neuroactive steroids' effects on pain thre shold.