title: Long-lasting spinal oxytocin analgesia is ensured by the stimulation of allopregnanolone synthesis which potentiates GABA(A) receptor-mediated synaptic inhibition.
abstract: Hypothalamospinal control of spinal pain processing by oxytocin (OT) has received a lot of attention in recent years because of its potency to reduce pain symptoms in inflammatory and neuropathic conditions. However, cellular and molecular mechanisms underlying OT spinal antinociception are still poorly understood. In this study, we used biochemical, electrophysiological, and behavioral approaches to demonstrate that OT levels are elevated in the spinal cord of rats exhibiting pain symptoms, 24 h after the induction of inflammation with an intraplantar injection of λ-carrageenan. Using a selective OT receptor antagonist, we demonstrate that this elevated OT content is responsible for a tonic analgesia exerted on both mechanical and thermal modalities. This phenomenon appeared to be mediated by an OT receptor-mediated stimulation of neurosteroidogenesis, which leads to an increase in GABA(A) receptor-mediated synaptic inhibition in lamina II spinal cord neurons. We also provide evidence that this novel mechanism of OT-mediated spinal antinociception may be controlled by extracellular signal-related protein kinases, ERK1/2, after OT receptor activation. The oxytocinergic inhibitory control of spinal pain processing is emerging as an interesting target for future therapies since it recruits several molecular mechanisms, which are likely to exert a long-lasting analgesia through nongenomic and possibly genomic effects.
authors.affiliation: Centre National de la Recherche Scientifique and University of Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, F-67084 Strasbourg, France.
authors.forename: Pierre-Eric
authors.initials: PE
authors.lastname: Juif
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Breton
authors.forename: Mathieu
authors.initials: M
authors.lastname: Rajalu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Charlet
authors.forename: Yannick
authors.initials: Y
authors.lastname: Goumon
authors.forename: Pierrick
authors.initials: P
authors.lastname: Poisbeau
mesh_terms: D000698:Analgesia; D000818:Animals; D002351:Carrageenan; D006727:Hormone Antagonists / Q000494:pharmacology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008297:Male; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010121:Oxytocin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000378:metabolism*; D011280:Pregnanolone / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D018045:Receptors, Oxytocin / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D006727:Hormone Antagonists; D011963:Receptors, GABA-A; D018045:Receptors, Oxytocin; C033683:oxytocin, tri-Gly-; D010121:Oxytocin; D002351:Carrageenan; D011280:Pregnanolone