Attenuation of the effect of progesterone and 4'-chlordiazepam on stress-induced immune responses by bicuculline.

The present study investigates the effect of progesterone, a pregnane precursor of neurosteroids, and 4'-chlordiazepam (4'-CD), a specific ligand for mitochondrial diazepam binding inhibitor receptor (MDR) involved in neurosteroidogenesis, on restraint stress (RS)-induced modulation of humoral and cell-mediated immune responses. RS produced a significant reduction in anti-sheep red blood cells (SRBC) antibody titre, a measure of humoral immune response, and % leucocyte migration inhibition (LMI) and foot-pad thickness test, measures of cell-mediated immune responses. These effects of RS on immune responses were effectively blocked by pretreating the animals with progesterone (10 mg/kg, sc) or 4'-CD (0.5 mg/kg, sc) administered just before subjecting the animal to RS. The effect of both progesterone and 4'-CD on RS-induced immune modulation was significantly attenuated by bicuculline (2 mg/kg, ip) but not by flumazenil (10 mg/kg, ip). Unlike its effect on RS-induced immune responsiveness, progesterone (5, 10 mg/kg, sc) when administered to non-stressed animals produced a significant suppression of both humoral and cell-mediated immune responses which was not reversed by bicuculline. However, 4'-CD failed to modulate immune response in naive non-stressed animals. These results suggest that progesterone and 4'-CD affect stress-induced immune responses by modulating GABA-ergic mechanism. However, GABA-A receptor system does not appear to be involved in progesterone-induced immunosuppression in nonstressed animals.

Evaluation of the analgesic effect of neurosteroids and their possible mechanism of action.

The present study investigates the effect of progesterone (P), a pregnane precursor of neurosteroids and 4-chlordiazepam (4-CD), a high affinity ligand for mitochondrial diazepam binding inhibitor receptor (MDR) that stimulates neurosteroid synthesis, in both acute, (tail flick latency test, TFL) and chronic, (formalin-induced pain response, FT), models. Both P and 4-CD showed an analgesic response in these models. The effect of P and 4-CD was antagonized by bicuculline on TEL but not in FT. However, naloxone attenuated the antinociceptive response of P and 4-CD in TFL as well as FT. Further, P and 4-CD pretreatment potentiated the analgesic effect of morphine and nimodipine in both the models of pain sensitivity. Thus, neurosteroids produce an antinociceptive effect which may be mediated by modulation of GABAergic and/or opiodergic mechanisms as well as voltage gated calcium channels.