Neuroactive steroids as targets for development of novel pain therapies

It is well established that the neuroactive steroids can modulate neuronal activity in the peripheral and central nervous system causing a variety of behavioral and neuroendocrine changes in humans and animals. It is largely believed that their effects on neurosensory processing and neuronal excitability are primarily mediated by effects on various ligand-gated ion channels, with much attention focused on the modulation of γ-aminobutyric acid (GABAA) receptors. However, some important behavioral effects of neuroactive steroids may be mediated by the family of voltage-gated calcium channels. Recent evidence strongly suggests that modulation of peripheral T-type calcium channels influences somatic and visceral nociceptive inputs and that inhibition of T currents results in significant anti-nociception in a variety of animal pain models. Therefore, T channels in peripheral nociceptors may be important, although previously unappreciated, targets for anti-nociceptive therapeutic agents including neuroactive steroids. Currently available pain therapies remain limited with inadequate efficacy and numerous side effects. Hence, the development of novel neuroactive steroids that are selective and potent blockers of neuronal T-type Ca²⁺ channels may greatly aid in revealing roles for these channels in sensory pathways (nociception in particular) and in the development of novel analgesics that might be safer and more effective for pain therapy. In the present review, we summarize the putative role of peripheral T-type calcium channels in nociception and our recent in vivo and in vitro structure-activity studies focusing primarily on 5β-reduced neuroactive steroids that are potent peripheral analgesics and potent blockers of neuronal T-type calcium channels.