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


METHODS
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.


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
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.
Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, South Korea.
Seo-Yeon
SY
Yoon
Dae-Hyun
DH
Roh
Hyoung-Sig
HS
Seo
Suk-Yun
SY
Kang
Ho-Jae
HJ
Han
Alvin J
AJ
Beitz
Jang-Hern
JH
Lee
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage / Q000494:pharmacology*; D004347:Drug Interactions; D005029:Ethylenediamines / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009118:Muscimol / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects*; D011963:Receptors, GABA-A / Q000502:physiology*; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D000097605:Sigma-1 Receptor
D000700:Analgesics; D001640:Bicuculline; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D005029:Ethylenediamines; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D009118:Muscimol; D011963:Receptors, GABA-A; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C097963:N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin