HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 583/3/1021    most recent jphysiol.2007.134445v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mitchell, E. A. Articles by Belelli, D. Search for Related Content PubMed PubMed Citation Articles by Mitchell, E. A. Articles by Belelli, D. Related Collections Neuroscience

¹ Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK
² Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G1 1XW, UK

Analgesic neurosteroids such as 5-pregnan-3-ol-20-one (53) are potent selective endogenous modulators of the GABA_A receptor (GABA_AR) while certain synthetic derivatives (i.e. minaxolone) additionally enhance the function of recombinant glycine receptors (GlyR). Inhibitory transmission within the superficial dorsal horn has been implicated in mediating the analgesic actions of neurosteroids. However, the relative contribution played by synaptic and extrasynaptic receptors is unknown. In this study, we have compared the actions of 53 and minaxolone upon inhibitory transmission mediated by both GABA_A and strychnine-sensitive GlyRs in lamina II neurones of juvenile (P15–21) rats. At the near physiological temperature of 35°C and at a holding potential of –60 mV we recorded three kinetically distinct populations of miniature IPSCs (mIPSCs): GlyR-mediated, GABA_AR-mediated and mixed GABA_AR-GlyR mIPSCs, arising from the corelease of both inhibitory neurotransmitters. In addition, sequential application of strychnine and bicuculline revealed a small (5.2 ± 1.0 pA) GlyR- but not a GABA_AR-mediated tonic conductance. 53 (1–10 µM) prolonged GABA_AR and mixed mIPSCs in a concentration-dependent manner but was without effect upon GlyR mIPSCs. In contrast, minaxolone (1–10 µM) prolonged the decay of GlyR mIPSCs and, additionally, was 10-fold more potent than 53 upon GABA_AR mIPSCs. However, 53 and minaxolone (1 µM) evoked a similar bicuculline-sensitive inhibitory conductance, indicating that the extrasynaptic GABA_ARs do not discriminate between these two steroids. Furthermore, 92% of the effect of 1 µM 53 upon GABAergic inhibition could be accounted for by its action upon the extrasynaptic conductance. These findings are relevant to modulation of inhibitory circuits within spinally mediated pain pathways and suggest that extrasynaptic GABA_ARs may represent a relevant molecular target for the analgesic actions of neurosteroids.

(Received 13 April 2007; accepted after revision 23 July 2007; first published online 26 July 2007)
Corresponding author D. Belelli: Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. Email: d.belelli{at}dundee.ac.uk

This article has been cited by other articles:

				R. A. Ingram, M. Fitzgerald, and M. L. Baccei Developmental Changes in the Fidelity and Short-Term Plasticity of GABAergic Synapses in the Neonatal Rat Dorsal Horn J Neurophysiol, June 1, 2008; 99(6): 3144 - 3150. [Abstract] [Full Text] [PDF]