Intrathecal neurosteroids and a neurosteroid antagonist: Effects on inflammation-evoked thermal hyperalgesia and tactile allodynia

•Spinal allopregnanolone and alphaxalone increase thermal threshold in normal and inflamed paw.•Effects of allopregnanolone were prevented by neurosteroid antagonist 17PA.•Reversal of an equi-analgesic dose of alphaxalone occurred only at higher antagonist dosing.•Spinal neurosteroid binding site(s)...

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Bibliographic Details
Published in:Neuroscience letters 2013-08, Vol.548, p.27-32
Main Authors: Svensson, Elin, Persson, Josefin, Fitzsimmons, Bethany, Yaksh, Tony L.
Format: Article
Language:English
Subjects:
Allodynia
Allopregnanolone
Alphaxalone
Androstenols - administration & dosage
Animals
Dose-Response Relationship, Drug
GABAA
Hot Temperature
Hyperalgesia - drug therapy
Hyperalgesia - etiology
Hyperalgesia - physiopathology
Inflammation - complications
Inflammation - drug therapy
Inflammation - physiopathology
Injections, Spinal
Intrathecal
Male
Neurosteroids
Neurotransmitter Agents - administration & dosage
Neurotransmitter Agents - antagonists & inhibitors
Pain Threshold - drug effects
Rats
Rats, Sprague-Dawley
Touch
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Summary:•Spinal allopregnanolone and alphaxalone increase thermal threshold in normal and inflamed paw.•Effects of allopregnanolone were prevented by neurosteroid antagonist 17PA.•Reversal of an equi-analgesic dose of alphaxalone occurred only at higher antagonist dosing.•Spinal neurosteroid binding site(s) acted upon by 17PA regulates spinal pain processing Neurosteroids regulate neuronal excitability though binding sites associated with the ionotropic γ-aminobutyric acid (GABAA) receptor. We sought to characterize the spinal analgesic actions in rats of two 5α-reduced neurosteroids, allopregnanolone and alphaxalone, on nociceptive processing and to determine whether a putative neurosteroid antagonist attenuates this effect: (3α,5α)-17-phenylandrost-16-en-3-ol (17PA). Intrathecal (IT) injection of allopregnanolone (1–30μg/10μL in 20% cyclodextrin) delivered through lumbar catheters produced a dose-dependent analgesia in rats as measured by thermal thresholds in the ipsilateral (inflamed by intraplantar carrageenan) and in the contralateral (un-inflamed paws). Similar observations were made with alphaxalone (30–60μg in 20% cyclodextrin). Effective doses were not associated with suppressive effects on pinnae, blink or placing and stepping reflex. Effects of allopregnanolone (30μg) on the normal and hyperalgesic paw were completely prevented by IT 17PA (30μg). Reversal by IT 17PA of an equi-analgesic dose of alphaxalone occurred only at higher antagonist dosing. These results suggest that a spinal neurosteroid-binding site with which 17PA interacts may regulate spinal nociceptive processing in normal and inflamed tissue.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2013.05.027