Intrathecal injection of the neurosteroid, DHEAS, produces mechanical allodynia in mice: involvement of spinal sigma-1 and GABA receptors.

Abstract

BACKGROUND AND PURPOSE:

The neurosteroid, dehydroepiandrosterone sulphate (DHEAS) and its non-sulphated form, DHEA, are considered as crucial endogenous modulators of a number of important physiological events. Evidence suggests that DHEAS and DHEA modulate central nervous system-related functions by activating sigma-1 receptors and/or allosterically inhibiting gamma-aminobutyric acid receptor type A (GABA(A)) receptors. As both the sigma-1 receptor and the GABA(A) receptor play important roles in spinal pain transmission, the present study was designed to examine whether intrathecally injected DHEAS or DHEA affect nociceptive signalling at the spinal cord level.

EXPERIMENTAL APPROACH:

We first determined whether intrathecal (i.t.) DHEA or DHEAS injection was able to affect nociceptive thresholds to peripheral mechanical stimulation and subsequently examined whether this effect was mediated by sigma-1 or the GABA(A) receptors.

KEY RESULTS:

The i.t. DHEAS injection dose-dependently decreased the nociceptive threshold to mechanical stimulation, thus producing mechanical allodynia. Moreover, this DHEAS-induced mechanical allodynia was significantly reduced by administration of the sigma-1 receptor antagonist, BD-1047 or the GABA(A) receptor agonist, muscimol. Conversely, i.t. DHEA had no effect on mechanical sensitivity. However, when i.t. DHEA was combined with the GABA(A) receptor antagonist bicuculline, DHEA dose-dependently produced mechanical allodynia similar to that of DHEAS. This effect was blocked by BD-1047 and by muscimol.

CONCLUSIONS AND IMPLICATIONS:

These findings indicate that i.t. injection of DHEAS produces mechanical allodynia and that the development of this mechanical allodynia is mediated by sigma-1 and GABA(A) receptors. The findings of this study raise several interesting questions for further investigations into the mechanisms underlying neurosteroid modulation of spinal pain transmission.

• Authors: Seo-Yeon Yoon, Dae-Hyun Roh, Hyoung-Sig Seo, Suk-Yun Kang, Ho-Jae Han, Alvin J Beitz, Jang-Hern Lee
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 157 Issue 4 Pg. 666-73 (Jun 2009) ISSN: 1476-5381 [Electronic] England
• PMID: 19422393 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics
• Ethylenediamines
• GABA Agonists
• GABA-A Receptor Agonists
• GABA-A Receptor Antagonists
• Receptors, GABA-A
• Receptors, sigma
• sigma-1 receptor
• N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin
• Muscimol
• Dehydroepiandrosterone
• Dehydroepiandrosterone Sulfate
• Bicuculline

Topics

• Analgesics (pharmacology)
• Animals
• Bicuculline (pharmacology)
• Dehydroepiandrosterone (administration & dosage, pharmacology)
• Dehydroepiandrosterone Sulfate (administration & dosage, pharmacology)
• Drug Interactions
• Ethylenediamines (pharmacology)
• GABA Agonists (pharmacology)
• GABA-A Receptor Agonists
• GABA-A Receptor Antagonists
• Injections, Spinal
• Male
• Mice
• Mice, Inbred ICR
• Muscimol (pharmacology)
• Pain Threshold (drug effects)
• Receptors, GABA-A (physiology)
• Receptors, sigma (antagonists & inhibitors, physiology)
• Spinal Cord (drug effects, physiology)