Long-Lasting Spinal Oxytocin Analgesia Is Ensured by the Stimulation of Allopregnanolone Synthesis Which Potentiates GABAA Receptor-Mediated Synaptic Inhibition

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 lambda-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.