ANALGESIC EFFECTS OF THE NEUROSTEROID 3-ALPHA-ANDROSTANEDIOL

The efficacy of 5 alpha-androstane-3 alpha,17 beta-diol 3 alpha-Andros tanediol; 3 alpha-Diol) and 4-pregnen-3,20-dione (progesterone; P) in promoting analgesia was investigated. Ovariectomized rats received dai ly injections of 3 alpha-Diol (0.6, 3.0, 6.0 and 7.5 mg/kg) or vehicle and twice daily injections of estradiol-17 beta (E(2): 1 mu g) for 2 days. Progesterone (0.5, 1.0, 2.0 and 4.0 mg/kg) or its vehicle was gi ven on the third day and nociceptive testing using the radiant heat ta ilflick method was carried out 4 h later. In Expt. 1, P and 3 alpha-Di ol both produced analgesia and had biphasic dose-response effects when administered singly. 3 alpha-Diol (3.0 mg/kg) elevated tailflick late ncies in E(2)-primed animals above those following vehicle, 6.0 or 7.5 mg/kg 3 alpha-Diol; 6.0 and 7.5 mg/kg produced elevations that were g reater than vehicle but less than 3.0 mg/kg. Progesterone (0.5 and 1.0 mg/kg) also elevated tailflick latencies above vehicle controls, whil e 2.0 and 4.0 mg/kg produced intermediate effects. In Expt. 2, 3 alpha -Diol (3 alpha-Diol:BSA) and P (P:BSA) conjugated to bovine serum albu min (BSA) were applied to the medial basal hypothalamus (MBH) and preo ptic area (POA) to ascertain whether the steroids' analgesic actions w ere mediated by membrane actions in these sites. Free P and P:BSA both increased tailflick latencies when applied to the MBH, while 3 alpha- Diol and 3(alpha-Diol:BSA elevated latencies when applied to the POA, suggesting the steroids' effects occur in part at the neuronal membran e. In Expt. 3, free P or P:BSA applied to the MBH did not increase tai lflick latencies if systemic P was given concurrently. Similarly, free 3 alpha-Diol and 3 alpha-Diol:BSA implants into the POA failed to inc rease tailflick latencies if s.c. 3 alpha-Diol was co-administered. Th ese data indicate that P and 3 alpha-Diol at moderate doses have analg esic effects in part via membrane actions within the MBH and POA, resp ectively.