Abstract
ABSTRACTVoltage-activated calcium channels play an important role in excitability of sensory nociceptive neurons in acute and chronic pain models. We have previously shown that low-voltage-activated calcium channels, or T-type channels (T-channels), increase excitability of sensory neurons after surgical incision in rats. We have also found that endogenous 5β-reduced neuroactive steroid epipregnanolone [(3β,5β)-3-hydroxypregnan-20-one] blocked isolated T-currents in dorsal root ganglion (DRG) cells in vitro, and reduced nociceptive behavior in vivo, after local intraplantar application into the foot pads of heathy rats and mice. Here, we investigated if epipregnanolone exerts an antinociceptive effect after intrathecal (i.t.) application in healthy rats, as well as an antihyperalgesic effect in a postsurgical pain model. We also studied if this endogenous neurosteroid blocks currents originating from high voltage-activated (HVA) calcium channels in rat sensory neurons. In in vivo studies, we found that epipregnanolone alleviated thermal and mechanical nociception in healthy rats after i.t. administration without affecting their sensory-motor abilities. Furthermore, epipregnanolone effectively reduced mechanical hyperalgesia after i.t application in rats after surgery. In subsequent in vitro studies, we found that epipregnanolone blocked isolated HVA currents in nociceptive sensory neurons with an IC50 of 3.3 μM in a G-protein-dependent fashion. We conclude that neurosteroids that have combined inhibitory effects on T-type and HVA calcium currents may be suitable for development of novel pain therapies during the perioperative period.
Highlights
Despite the fact that numerous life-saving surgical procedures are performed on a daily basis, treatment of pain arising after surgery continues to be an underestimated problem in patients
Given the importance of multiple subtypes of voltage-gated calcium channels (VGCCs) in pain transmission, this study examined the effects of epipregnanolone on isolated HVA calcium currents in nociceptive sensory neurons in the dorsal root ganglion (DRG)
These results are consistent with a notion that HVA current reduction occurring after epipregnanolone application is most likely G-protein dependent. This is the first study investigating the analgesic potential of an endogenous neurosteroid in an acute somatic postsurgical pain model
Summary
Despite the fact that numerous life-saving surgical procedures are performed on a daily basis, treatment of pain arising after surgery continues to be an underestimated problem in patients. On the basis of the membrane potential at which they become activated, VGCCs are subdivided into two major classes: high-voltage-activated (HVA) or sustained currents; and low-voltage-activated (LVA) or transient (T-type) currents [5]. These channels are products of different genes that encode α1 subunits, which form the pores of the VGCCs. The genes can be grouped into families based on α1 subunits: CaV1 (former α1S, α1C, α1D, α1F) encoding L-type channels; CaV2.1 (α1A) encoding P/ Q-type channels; CaV2.2 (α1B) encoding N-type channels; and CaV2.3 (α1E) encoding R-type channels, which activate at more negative potentials than other HVA channels
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