PubMed · 13110680
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1953-10-30. [CORNECAIN].. https://pubmed.ncbi.nlm.nih.gov/13110680/
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The glycine receptors and neurosteroids in spinal cord are both implicated in nociceptive signal processing. However, the modulatory effects of neurosteroid pregnanolone (5beta-pregnan-3alpha-ol-20-one) on native glycine receptors remain unclear. In the present study, we examined the effects of pregnanolone and its three isomers on glycine receptors by using whole-cell patch-clamp technique. Our results showed that pregnanolone reversibly inhibited the amplitude of glycine-induced current mediated by native glycine receptors and recombinant alpha1-, alpha2-, alpha3- and alpha1beta-glycine receptors. In cultured spinal dorsal horn neurons of rats, pregnanolone inhibited the glycine-induced current in dose-dependent manner, with an antagonist concentration inducing half-maximal response of 1.0+/-0.3 microM. The inhibitory effect of pregnanolone on glycine-induced current was voltage-independent and pregnanolone shifted the concentration-response curve for glycine-induced current rightward in a parallel manner without altering the maximal value and Hill coefficient. The isomer of pregnanolone, allopregnanolone (5alpha-pregnan-3alpha-ol-20-one) slightly enhanced glycine-induced current, whereas iso-pregnanolone (5beta-pregnan-3beta-ol-20-one) and iso-allopregnanolone (5alpha-pregnan-3beta-ol-20-one) did not affect the glycine-induced current significantly in cultured spinal dorsal horn neurons. Thus, our results suggest that the inhibitory effect of pregnanolone on glycine-induced current is of a competitive type and depends on the stereo structure of pregnanolone. Furthermore, pregnanolone decreased the amplitude and frequency of the glycinergic miniature inhibitory postsynaptic currents. Through modulating the glycinergic inhibitory neurotransmission, pregnanolone may affect the nociceptive sensory processing under physiological and pathological conditions.
We previously demonstrated that after traumatic brain injury (TBI), acute progesterone withdrawal (AW) causes an increase in anxiety behaviors and cerebro-cellular inflammation compared to tapered progesterone withdrawal (TW). Our current study investigates the behavioral and cellular effects of AW two weeks after termination of treatments to determine the longer-term influence of withdrawal after injury. Adult, male Sprague-Dawley rats received either bilateral frontal cortex contusion (L) or sham (S) surgery. Rats were injected at 1 and 6 h post-injury, then every 24 h for six days. Vehicle (V)-treated rats were given 9 injections of 22.5% cyclodextrin, whereas AW rats received 9 injections of 16 mg/kg progesterone and TW rats received 7 injections of P at 16 mg/kg, followed by one at 8 mg/kg and one at 4 mg/kg. On day 8, sensory neglect and locomotor activity tests were initiated. Animals were killed 22 days post-TBI and the brains prepared for either molecular or histological analysis. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and heat shock protein 70 (HSP70) in TW vs. AW animals. P53 was increased in VL animals, whereas all progesterone-treated groups were equivalent to shams. TW animals had markedly decreased sensory neglect compared to AW animals and increased center time in locomotor activity assays. In addition, lesion reconstruction revealed a decreased lesion size for TWL over AWL over VL animals. Glial fibrillary acidic protein (GFAP) immunofluorescent staining followed this pattern as well. In conclusion, after TBI, AW affects select behaviors and molecular markers in the chronic recovery period.