Psychopharmacology

, Volume 231, Issue 17, pp 3503–3515 | Cite as

Inhibition of CaV3.2 T-type calcium channels in peripheral sensory neurons contributes to analgesic properties of epipregnanolone

  • Christine Ayoola
  • Sung Mi Hwang
  • Sung Jun Hong
  • Kirstin E. Rose
  • Christopher Boyd
  • Neda Bozic
  • Ji-Yong Park
  • Hari Prasad Osuru
  • Michael R. DiGruccio
  • Douglas F. Covey
  • Vesna Jevtovic-Todorovic
  • Slobodan M. Todorovic
Original Investigation

Abstract

Rationale

T-type calcium channels (T-channels) play an important role in controlling excitability of nociceptors. We have previously shown that a synthetic series of 5β-reduced steroids induce a voltage-dependent blockade of T-currents in rat dorsal root ganglia (DRG) cells in vitro and induce potent analgesia to thermal stimuli in rats in vivo (Mol Pharmacol 66:1223–1235, 2004).

Objectives

Here, we investigated the effects of the endogenous 5β-reduced neuroactive steroid molecule, epipregnanolone [(3β,5β)-3-hydroxypregnan-20-one], on peripheral nociception.

Methods

We used acutely dissociated DRG cells in vitro from adult rats as well as in vivo pain studies in mice and rats to investigate the effects of epipregnanolone on DRG T-channels.

Results

We found that epipregnanolone reversibly blocked DRG T-currents with a half-maximal inhibitory concentration (IC50) of 2 μM and stabilized the channel in the inactive state. However, sodium, potassium, and gamma-aminobutyric acid (GABA)-gated ionic currents were not sensitive to the blocking effects of epipregnanolone even at 10 μM. In ensuing in vivo studies, we found that intraplantar (i.pl.) injections of epipregnanolone directly into peripheral receptive fields reduced responses to nociceptive heat stimuli in rats in a dose-dependent fashion. Furthermore, i.pl. epipregnanolone injections effectively reduced responses to peripheral nociceptive thermal and mechanical stimuli in wild-type mice but had no effect on the responses of CaV3.2 knockout mice.

Conclusions

We conclude that the inhibition of peripheral CaV3.2 T-channels contributes to the potent analgesic effect of the endogenous steroid epipregnanolone.

Keywords

Low-voltage-activated Ca2+ Pain Dorsal root Hyperalgesia 

Abbreviations

DRG

Dorsal root ganglion

TEA-OH

Tetraethylammonium hydroxide

PWL

Paw withdrawal latency

PWR

Paw withdrawal responses

TMA-OH

Tetramethylammonium hydroxide

TTX

Tetrodotoxin

DMSO

Dimethylsulfoxide

EGTA

Ethylene glycol tetraacetic acid

3β5βCN

(3β,5β,17β)-3-Hydroxyandrostane-17-carbonitrile

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Christine Ayoola
    • 1
  • Sung Mi Hwang
    • 1
    • 3
  • Sung Jun Hong
    • 1
    • 4
  • Kirstin E. Rose
    • 1
  • Christopher Boyd
    • 1
  • Neda Bozic
    • 1
  • Ji-Yong Park
    • 7
  • Hari Prasad Osuru
    • 1
  • Michael R. DiGruccio
    • 1
    • 6
  • Douglas F. Covey
    • 2
  • Vesna Jevtovic-Todorovic
    • 1
    • 5
    • 6
  • Slobodan M. Todorovic
    • 1
    • 5
    • 6
  1. 1.Department of AnesthesiologyUniversity of Virginia Health SystemCharlottesvilleUSA
  2. 2.Department of Developmental Biology, School of MedicineWashington UniversitySt. LouisUSA
  3. 3.Department of Anesthesiology and Pain Medicine, Chuncheon Sacred Heart Hospital, College of MedicineHallym UniversitySeoulRepublic of Korea
  4. 4.Department of Anesthesiology and Pain Medicine, Kangdong Sacred Heart Hospital, College of MedicineHallym UniversitySeoulRepublic of Korea
  5. 5.Department of NeuroscienceUniversity of Virginia Health SystemCharlottesvilleUSA
  6. 6.Neuroscience Graduate ProgramUniversity of Virginia Health SystemCharlottesvilleUSA
  7. 7.Department of Anesthesiology and Pain Medicine, College of MedicineKorea UniversitySeoulRepublic of Korea

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