PROGESTERONE METABOLITES, EFFECTIVE AT THE GABA(A) RECEPTOR COMPLEX, ATTENUATE PAIN SENSITIVITY IN RATS

To investigate whether progesterone metabolites' antinociceptive effec ts correlate with their previously established binding efficacies at t he GABA receptor complex (GBR), seven progestin metabolites were admin istered to ovariectomized Long-Evans rats s.c. (Expt. 1), via i.c.v. i mplantation (Expt. 2) and then i.c.v. infusion (Expt. 3). Progestins, listed from most to least efficacious at the GBR, were THP 5 alpha-pr egnan-3 alpha-ol-20-one, THDOC 5 alpha-pregnan-3 alpha,21-diol-20-on e, P 4-pregnen-3,20-di-one, DHP 5 alpha-pregnan-3,20-dione,17-OH- P 17-hydroxyprogesterone, DHEAS 5-androsten-3 beta-ol-17-one sulfat e and PS 5-pregnen-3 beta-ol-20-one sulfate. Pain sensitivity was m easured via the radiant heat tailflick method 0, 5, 20, 40, 60, 80, 10 0 and 120 min after weekly progestin administration. Peripheral admini stration of 0.0, 0.1, 0.4, 1.6, 3.2 or 6.4 mg/kg of potent to moderate agonists of the GBR (THP, THDOC, P and DHP) tended to elevate tailfli ck latencies above baseline, whereas administration of the non-5 alpha -reduced metabolite (17-OH-P) and GBR antagonists (DHEAS and PS) did n ot. Intracerebroventricular implantation and infusion (0.0, 0.5, 1.0, 2.0 mu g/rat) of THP, THDOC, P and DHP all significantly increased tai lflick latencies above baseline and vehicle control, consistent with t heir GBR efficacies. Central 17-OH-P, DHEAS and PS did not elevate tai lflick latencies. These rapid differences were unlikely confounded by stress given that corticosterone levels were not elevated (Expt. 4). A s pain sensitivity was attenuated rapidly (0-5 min post-i.c.v.) and co nsistent with GBR efficacies, this suggests that progestins' modulatio n of pain may occur via GBR action.