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Presynaptic alpha2-GABAA receptors in primary afferent depolarization and spinal pain control

Spinal dorsal horn GABA(A) receptors are found both postsynaptically on central neurons and presynaptically on axons and/or terminals of primary sensory neurons, where they mediate primary afferent depolarization (PAD) and presynaptic inhibition. Both phenomena have been studied extensively on a cellular level, but their role in sensory processing in vivo has remained elusive, due to inherent difficulties to selectively interfere with presynaptic receptors. Here, we address the contribution of a major subpopulation of GABA(A) receptors (those containing the alpha2 subunit) to spinal pain control in mice lacking alpha2-GABA(A) receptors specifically in primary nociceptors (sns-alpha2(-/-) mice). sns-alpha2(-/-) mice exhibited GABA(A) receptor currents and dorsal root potentials of normal amplitude in vitro, and normal response thresholds to thermal and mechanical stimulation in vivo, and developed normal inflammatory and neuropathic pain sensitization. However, the positive allosteric GABA(A) receptor modulator diazepam (DZP) had almost completely lost its potentiating effect on PAD and presynaptic inhibition in vitro and a major part of its spinal antihyperalgesic action against inflammatory hyperalgesia in vivo. Our results thus show that part of the antihyperalgesic action of spinally applied DZP occurs through facilitated activation of GABA(A) receptors residing on primary nociceptors

Keywords : administration & dosage,Animals,Axons,biosynthesis,Diazepam,drug effects,drug therapy,Gene Expression Regulation,genetics,Hyperalgesia,Injections,Spinal,Membrane Potentials,metabolism,Mice,Mice,Knockout,Mice,Transgenic,Neuralgia,Neurons,Neurons,Afferent,Nociceptors,Pain,Patch-Clamp Techniques,pharmacology,physiology,physiopathology,Receptors,GABA-A,Receptors,Presynaptic,Spinal Nerve Roots,Switzerland,Universities,, Alpha2gabaa,Receptors,Primary,Afferent, lower back pain clinic london

Date of Publication : 2011 Jun 1

Authors : Witschi R;Punnakkal P;Paul J;Walczak JS;Cervero F;Fritschy JM;Kuner R;Keist R;Rudolph U;Zeilhofer HU;

Organisation : Institute of Pharmacology and Toxicology, University of Zurich, CH-8057 Zurich, Switzerland

Journal of Publication : J Neurosci

Pubmed Link : https://www.ncbi.nlm.nih.gov/pubmed/21632935

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