5β-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

Slobodan M. Todorovic, Sriyani Pathirathna, Barbara C. Brimelow, Miljen M. Jagodic, Seong Hoon Ko, Xin Jiang, Kent R. Nilsson, Charles F. Zorumski, Douglas F. Covey, Vesna Jevtovic-Todorovic

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

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 5α-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 5β-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 5β-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 [(3β,5β,17β)-3- hydroxyandrostane-17-carbonitrile] that was also the most effective blocker of T currents. Compared with previously studied 5α-reduced steroids, these 5β-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.

Original languageEnglish
Pages (from-to)1223-1235
Number of pages13
JournalMolecular pharmacology
Volume66
Issue number5
DOIs
StatePublished - Nov 2004

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