Intrathecal Neurosteroids and a Neurosteroid Antagonist: Effects on Inflammation-evoked Thermal Hyperalgesia and Tactile Allodynia

Overview

Journal Neurosci Lett

Specialty Neurology

Date 2013 May 28

PMID 23707652

Citations 11

Authors

Elin Svensson

Josefin Persson

Bethany Fitzsimmons

Tony L Yaksh

Affiliations

Soon will be listed here.

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.

Citing Articles

Neurosteroids and their potential as a safer class of general anesthetics.

Tateiwa H, Evers A J Anesth. 2024; 38(2):261-274.

PMID: 38252143 PMC: 10954990. DOI: 10.1007/s00540-023-03291-4.

Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation.

Hornung R, Benton W, Tongkhuya S, Uphouse L, Kramer P, Averitt D Front Integr Neurosci. 2020; 14:26.

PMID: 32457584 PMC: 7225267. DOI: 10.3389/fnint.2020.00026.

Realising the therapeutic potential of neuroactive steroid modulators of the GABA receptor.

Belelli D, Hogenkamp D, Gee K, Lambert J Neurobiol Stress. 2020; 12:100207.

PMID: 32435660 PMC: 7231973. DOI: 10.1016/j.ynstr.2019.100207.

Intrathecal drug delivery in the era of nanomedicine.

Fowler M, Cotter J, Knight B, Sevick-Muraca E, Sandberg D, Sirianni R Adv Drug Deliv Rev. 2020; 165-166:77-95.

PMID: 32142739 PMC: 8182643. DOI: 10.1016/j.addr.2020.02.006.

Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans: A Randomized Clinical Trial.

Naylor J, Kilts J, Shampine L, Parke G, Wagner H, Szabo S JAMA Netw Open. 2020; 3(3):e200287.

PMID: 32119096 PMC: 7052727. DOI: 10.1001/jamanetworkopen.2020.0287.

References

Cottrell G, Lambert J, Peters J . Modulation of GABAA receptor activity by alphaxalone. Br J Pharmacol. 1987; 90(3):491-500. PMC: 1917172. DOI: 10.1111/j.1476-5381.1987.tb11198.x. View

Chery N, De Koninck Y . Junctional versus extrajunctional glycine and GABA(A) receptor-mediated IPSCs in identified lamina I neurons of the adult rat spinal cord. J Neurosci. 1999; 19(17):7342-55. PMC: 6782499. View

Ostrom R, Liu X . Detergent and detergent-free methods to define lipid rafts and caveolae. Methods Mol Biol. 2007; 400:459-68. DOI: 10.1007/978-1-59745-519-0_30. View

Malkmus S, Yaksh T . Intrathecal catheterization and drug delivery in the rat. Methods Mol Med. 2004; 99:109-21. DOI: 10.1385/1-59259-770-X:011. View

Chang J, Peng H, Wu H, Lu H, Pan S, Chen M . Acute neurosteroids inhibit the spinal reflex potentiation via GABAergic neurotransmission. Am J Physiol Renal Physiol. 2010; 299(1):F43-8. DOI: 10.1152/ajprenal.00632.2009. View

Weir C, Ling A, Belelli D, Wildsmith J, Peters J, Lambert J . The interaction of anaesthetic steroids with recombinant glycine and GABAA receptors. Br J Anaesth. 2004; 92(5):704-11. DOI: 10.1093/bja/aeh125. View

Peng H, Chen G, Lee S, Lai C, Chiu C, Cheng C . Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABA(A) receptor subtypes. Pain. 2009; 143(1-2):12-20. DOI: 10.1016/j.pain.2008.12.023. View

Horikawa Y, Patel H, Tsutsumi Y, Jennings M, Kidd M, Hagiwara Y . Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury. J Mol Cell Cardiol. 2007; 44(1):123-30. PMC: 2701396. DOI: 10.1016/j.yjmcc.2007.10.003. View

Goodchild C, Guo Z, Nadeson R . Antinociceptive properties of neurosteroids I. Spinally-mediated antinociceptive effects of water-soluble aminosteroids. Pain. 2000; 88(1):23-29. DOI: 10.1016/S0304-3959(00)00301-8. View

10.

Reddy D . Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010; 186:113-37. PMC: 3139029. DOI: 10.1016/B978-0-444-53630-3.00008-7. View

11.

Shu H, Zeng C, Wang C, Covey D, Zorumski C, Mennerick S . Cyclodextrins sequester neuroactive steroids and differentiate mechanisms that rate limit steroid actions. Br J Pharmacol. 2006; 150(2):164-75. PMC: 2042897. DOI: 10.1038/sj.bjp.0706973. View

12.

Bohlhalter S, Weinmann O, Mohler H, Fritschy J . Laminar compartmentalization of GABAA-receptor subtypes in the spinal cord: an immunohistochemical study. J Neurosci. 1996; 16(1):283-97. PMC: 6578721. View

13.

Mitchell E, Gentet L, Dempster J, Belelli D . GABAA and glycine receptor-mediated transmission in rat lamina II neurones: relevance to the analgesic actions of neuroactive steroids. J Physiol. 2007; 583(Pt 3):1021-40. PMC: 2277187. DOI: 10.1113/jphysiol.2007.134445. View

14.

Winfree C, Coombs D, DeLeo J, Colburn R . Analgesic effects of intrathecally-administered 3 alpha-hydroxy-5 alpha-pregnan-20-one in a rat mechanical visceral pain model. Life Sci. 1992; 50(14):1007-12. DOI: 10.1016/0024-3205(92)90095-7. View

15.

Witschi R, Punnakkal P, Paul J, Walczak J, Cervero F, Fritschy J . Presynaptic alpha2-GABAA receptors in primary afferent depolarization and spinal pain control. J Neurosci. 2011; 31(22):8134-42. PMC: 3567284. DOI: 10.1523/JNEUROSCI.6328-10.2011. View

16.

Yaksh T, Jang J, Nishiuchi Y, Braun K, Ro S, Goodman M . The utility of 2-hydroxypropyl-beta-cyclodextrin as a vehicle for the intracerebral and intrathecal administration of drugs. Life Sci. 1991; 48(7):623-33. DOI: 10.1016/0024-3205(91)90537-l. View

17.

Akk G, Covey D, Evers A, Steinbach J, Zorumski C, Mennerick S . Mechanisms of neurosteroid interactions with GABA(A) receptors. Pharmacol Ther. 2007; 116(1):35-57. PMC: 2047817. DOI: 10.1016/j.pharmthera.2007.03.004. View

18.

Poisbeau P, Patte-Mensah C, Keller A, Barrot M, Breton J, Luis-Delgado O . Inflammatory pain upregulates spinal inhibition via endogenous neurosteroid production. J Neurosci. 2005; 25(50):11768-76. PMC: 6726017. DOI: 10.1523/JNEUROSCI.3841-05.2005. View

19.

Kelley S, Alan J, OBuckley T, Mennerick S, Krishnan K, Covey D . Antagonism of neurosteroid modulation of native gamma-aminobutyric acid receptors by (3alpha,5alpha)-17-phenylandrost-16-en-3-ol. Eur J Pharmacol. 2007; 572(2-3):94-101. PMC: 2098702. DOI: 10.1016/j.ejphar.2007.06.028. View

20.

Yaksh T, Rudy T . Chronic catheterization of the spinal subarachnoid space. Physiol Behav. 1976; 17(6):1031-6. DOI: 10.1016/0031-9384(76)90029-9. View