Anxiolytic effects of hippocampal neurosteroids in normal and neuropathic rats with spared nerve injury.

ABSTRACT

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of GABAA receptors, which play a vital role in modulating hippocampal functions. Chronic pain is accompanied by increased neurosteroid production in the spinal cord and thalamus. We hypothesize that hippocampal neurosteroids participate in pain or pain-associated emotions, which we tested with high-performance liquid chromatography/tandem mass spectrometry and pharmacological behavioral tests. We observed increased levels of hippocampal neurosteroids (pregnenolone, progesterone, deoxycorticosterone, and allopregnanolone) in rats with chronic neuropathic pain (28 days after spared nerve injury). Meanwhile, the expression of the translocator protein, the upstream steroidogenesis rate-limiting enzyme, increased in the ventral but not dorsal hippocampus of neuropathic rats. In both naïve and neuropathic rats, in vivo stereotaxic microinjection of PK 11195, the translocator protein inhibitor, into the ventral hippocampus exacerbated anxiety-like behaviors. These results indicate anxiolytic effects of hippocampal neurosteroids in both normal and neuropathic rats. Neurosteroids could be considered as agents for treatment of general and pain-related anxiety disorders.