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5-Reduced Neuroactive Steroids Are Novel Voltage-Dependent Blockers of T-Type Ca²⁺ Channels in Rat Sensory Neurons in Vitro and Potent Peripheral Analgesics in Vivo

Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, Virginia (S.M.T., S.P., B.C.B., M.M.J., S.-H. K., V. J.-T.); and Departments of Molecular Biology and Pharmacology (X.J., K.R.N., D.F.C.) and Psychiatry (C.F.Z.), Washington University School of Medicine, St. Louis, Missouri

T-type Ca²⁺ channels are believed to play an important role in pain perception, and anesthetic steroids such as alphaxalone and allopregnanolone, which have a 5-configuration at the steroid A, B ring fusion, are known to inhibit T-type Ca²⁺ channels and cause analgesia in a thermal nociceptive model ( Soc Neurosci Abstr 29:657.9, 2003). To define further the structure-activity relationships for steroid analgesia, we synthesized and examined a series of 5-reduced steroids for their ability to induce thermal antinociception in rats when injected locally into the peripheral receptive fields of the nociceptors and studied their effects on T-type Ca²⁺ channel function in vitro. We found that most of the steroids completely blocked T-type Ca²⁺ currents in vitro with IC₅₀ values at a holding potential of -90 mV ranging from 2.8 to 40 µM. T current blockade exhibited mild voltage-dependence, suggesting that 5-reduced neuroactive steroids stabilize inactive states of the channel. For the most potent steroids, we found that other voltage-gated currents were not significantly affected at concentrations that produce nearly maximal blockade of T currents. All tested compounds induced dose-dependent analgesia in thermal nociceptive testing; the most potent effect (ED₅₀, 30 ng/100 µl) obtained with a compound [(3,5,17)-3-hydroxyandrostane-17-carbonitrile] that was also the most effective blocker of T currents. Compared with previously studied 5-reduced steroids, these 5-reduced steroids are more efficacious blockers of neuronal T-type Ca²⁺ channels and are potentially useful as new experimental reagents for understanding the role of neuronal T-type Ca²⁺ channels in peripheral pain pathways.

Address correspondence to: Vesna Jevtovic-Todorovic, Department of Anesthesiology, University of Virginia Health System, P.O. Box 800710, Charlottesville, VA 22908-0710. E-mail: vj3w{at}virginia.edu

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