Intrathecal neurosteroids and a neurosteroid antagonist: effects on inflammation-evoked thermal hyperalgesia and tactile allodynia - PubMed (original) (raw)
Intrathecal neurosteroids and a neurosteroid antagonist: effects on inflammation-evoked thermal hyperalgesia and tactile allodynia
Elin Svensson et al. Neurosci Lett. 2013.
Abstract
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 (1-30 μg/10 μL 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 (30-60 μg in 20% cyclodextrin). Effective doses were not associated with suppressive effects on pinnae, blink or placing and stepping reflex. Effects of allopregnanolone (30 μg) on the normal and hyperalgesic paw were completely prevented by IT 17PA (30 μg). 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.
Keywords: Allodynia; Allopregnanolone; Alphaxalone; GABA(A); Intrathecal; Neurosteroids.
Published by Elsevier Ireland Ltd.
Figures
Fig 1
TOP: Effect of IT allopregnanolone or cyclodextrin (20%) vehicle on escape latency of ispilateral (A) and contralateral (B) hindpaw as a function of time after ipsilateral intraplantar carrageenan given at T=0. BOTTOM: Hyperalgesic index for ipsilateral (C) and contralateral (D) hindpaw shows that IT alloprenanolone resulted in dose dependent reversal of thermal hyperalgesia of inflamed paw and a significant increase above baseline (analgesia) in contralateral, un-inflamed paw. Positive scores indicate hyperalgesia; negative scores indicate analgesia. Each plot presents means±SEM, 5-9 animals. Comparisons: A,B: Two Way repeated measures ANOVA with Bonferroni post hoc comparison: *: p<0.05 vs baseline; C,D: Bars under each AUC graph link treatments that do not differ from each other (Bonferroni multiple comparisons, p<0.05)
Fig 2
TOP: Effect of IT alphaxalone or cyclodextrin (20%) vehicle on escape latency of ispilateral (A) and contralateral (B) hindpaw as a function of time after ipsilateral intraplantar carrageenan given at T=0. BOTTOM: Hyperalgesic index for ipsilateral (C) and contralateral (D) hindpaw shows that IT alloprenanolone resulted in dose dependent reversal of thermal hyperalgesia of the inflamed paw and a significant increase above baseline (analgesia) in contralateral, un-inflamed paw. Positive scores indicate hyperalgesia; negative scores indicate analgesia. Each plot presents means ± SEM, 5-9 animals. Comparisons: A,B: Two Way repeated measures ANOVA with Bonferroni post hoc comparison: *: p<0.05 vs baseline; C,D: Bars under each AUC graph link treatments that do not differ from each other (Bonferroni multiple comparisons, p<0.05)
Fig 3
TOP: Effect on escape latency of IT neurosteroid antagonist, (17PA)on escape latency in the ipsilateral -carrageenan injected-(A) and the contralateral (B) hindpaw when given alone or in the presence of allopregnanolone (30μg/10μL). IT 17PA (30 μg/10μL) was given 15 min (arrow 1) prior to IT allopregnanolone or vehicle (arrow 2). Carrageenan was injected into the ipsilateral hind paw at t=0 (arrow 3). BOTTOM: Hyperalgesic index for ipsilateral (C) and contralateral (D) hindpaw shows that IT 17PA had no effect upon the carrageenan evoked thermal hyperalgesia, but reversed effects of IT allopregnanolone. Each plot presents means ± SEM, 5-9 animals. Comparisons: A,B: Two Way repeated measures ANOVA with Bonferroni post hoc comparison: *: p<0.05 vs baseline; C,D: Bars under each AUC graph link treatments that do not differ from each other (Bonferroni multiple comparisons, p<0.05)
Fig 4
TOP: Effect on escape latency of IT neurosteroid antagonist, (17PA) on escape latency in the ipsilateral-carrageenan injected-(A) and contralateral (B) hindpaw when given in the presence of alphaxalone (60μg/10μL). IT 17PA (30 or 60μg/10μL) was given 15 min (arrow 1) prior to IT alphaxalone or vehicle (arrow 2). Carrageenan was injected into ipsilateral hind paw at t=0 (arrow 3). BOTTOM: Hyperalgesic index for ipsilateral (C) and contralateral (D) hindpaw shows that IT 17PA, 60, but not 30 μg/10μL resulted in reversal of the antinociceptive effects of IT alphaxalone. Each plot presents means±SEM, 5-9 animals. Comparisons: A,B: Two Way repeated measures ANOVA with Bonferroni post hoc comparison: *: p<0.05 vs baseline; C,D: Bars under each AUC graph link treatments that do not differ from each other (Bonferroni multiple comparisons, p<0.05)
References
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