Acute neurosteroids inhibit the spinal reflex potentiation via GABAergic neurotransmission

Abstract

Recently, we demonstrated a chronic neurosteroid-dependent inhibition of activity-dependent spinal reflex potentiation (SRP), but it remains unclear whether neurosteroids acutely modulate SRP induction. This study shows progesterone as well as two of its 3alpha,5alpha-derivatives, allopregnalonone and 3alpha,5alpha-tetrahydrodeoxycorticosterone (THDOC), to be capable of producing acute GABA(A) receptor (GABA(A)R)-dependent inhibition of SRP. When compared with test simulation (1 stimulation/30 s) of pelvic afferent nerves that evoked a baseline reflex activity in an external urethra sphincter electromyogram, repetitive stimulation (RS; 1 stimulation/1 s) induced SRP characterized by an increase in the evoked activity. Intrathecal progesterone (3-30 muM, 10 microl) at 10 min before stimulation onset dose dependently prevented RS induction. Intrathecal allopregnalonone (10 muM, 10 microl it) and THDOC (10 microM, 10 microl it) also prevented the SRP caused by RS. Pretreatment with the GABA(A)R antagonist bicuculline (10 microM, 10 microl it) at 1 min before progesterone/neurosteroid injection attenuated the inhibition of SRP caused by progesterone, allopregnanolone, and THDOC. Results suggest that progesterone and its neurosteroid metabolites may be crucial to the development of pelvic visceral neuropathic/postinflammatory pain and imply clinical use of neurosteroids, such as allopregnanolone and THDOC, for visceral pain treatment.