Prostaglandin E ₂ (PGE ₂ ) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR α3) by PGE ₂ -induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR α3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR α3 not only lack the inhibition of glycinergic neurotransmission by PGE ₂ seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE ₂ injection or peripheral inflammation. Thus, GlyR α3 may provide a previously unrecognized molecular target in pain therapy.

The spinal dorsal horn is the first level of the CNS in which nociceptive input from sensory afferents is integrated and transmitted. Although inhibitory control in this region has a crucial impact on pain transmission, the respective contribution of GABA and glycine to this inhibition remains elusive. We have previously documented co-release of GABA and glycine at the same inhibitory synapse in spinal laminas I–II of adult rats [older than postnatal day 30 (P30)]. However, despite this co-release, individual miniature inhibitory postsynaptic currents (mIPSCs) were mediated by either glycine receptors (GlyR) or GABA_A receptors (GABA_AR), yet never by the two together. In contrast, recent studies of ventral horn immature inhibitory synapses (≤P21) reported individual mIPSCs that were mediated by both GABA_ARs and GlyRs. This raises the question of whether mixed mIPSCs are present in immature lamina I–II neurons yet are lost through a maturation-dependent synaptic specialization. To test this, we recorded mIPSCs using patch-clamp techniques in lamina I–II neurons in spinal slices taken at different stages of development. We found that, in neurons younger than P23, both GlyR-only and GABA_AR-only mIPSCs could be recorded, in addition to mixed GABA_AR–GlyR mIPSCs. With maturation however, both lamina I–II neurons gradually discontinued exhibiting mixed mIPSCs, although with differing patterns of specialization. Yet, at all developmental stages, benzodiazepine administration could unmask mixed mIPSCs. Together, these findings indicate that, although GABA and glycine are continually co-released throughout development, junctional codetection ceases by adulthood. This indicates an age-dependent postsynaptic tuning of inhibitory synapses that occurs in a region-specific manner.

Background: Recent evidence suggests that oxytocin (OT), secreted in the superficial spinal cord dorsal horn by descending axons of paraventricular hypothalamic nucleus (PVN) neurons, produces antinociception and analgesia. The spinal mechanism of OT is, however, still unclear and requires further investigation. We have used patch clamp recording of lamina II neurons in spinal cord slices and immunocytochemistry in order to identify PVN-activated neurons in the superficial layers of the spinal cord and attempted to determine how this neuronal population may lead to OT-mediated antinociception. Results: We show that OT released during PVN stimulation specifically activates a subpopulation of lamina II glutamatergic interneurons which are localized in the most superficial layers of the dorsal horn of the spinal cord (lamina I-II). This OT-specific stimulation of glutamatergic neurons allows the recruitment of all GABAergic interneurons in lamina II which produces a generalized elevation of local inhibition, a phenomenon which might explain the reduction of incoming Aδ and C primary afferent-mediated sensory messages. Conclusion: Our results obtained in lamina II of the spinal cord provide the first clear evidence of a specific local neuronal network that is activated by OT release to induce antinociception. This OT-specific pathway might represent a novel and interesting therapeutic target for the management of neuropathic and inflammatory pain.