Mechanical allodynia, a widespread pain symptom that still lacks effective therapy, is associated with the activation of a dorsally directed polysynaptic circuit within the spinal dorsal horn (SDH) or medullary dorsal horn (MDH), whereby tactile inputs into deep SDH/MDH can gain access to superficial SDH/MDH, eliciting pain. Inner lamina II (II_i) interneurons expressing the γ isoform of protein kinase C (PKCγ⁺) are key elements for allodynia circuits, but how they operate is still unclear. Combining behavioral,ex vivoelectrophysiological, and morphological approaches in an adult rat model of facial inflammatory pain (complete Freund's adjuvant, CFA), we show that the mechanical allodynia observed 1 h after CFA injection is associated with the following (1) sensitization (using ERK1/2 phosphorylation as a marker) and (2) reduced dendritic arborizations and enhanced spine density in exclusively PKCγ⁺interneurons, but (3) depolarized resting membrane potential (RMP) in all lamina II_iPKCγ⁺/PKCγ⁻interneurons. Blocking MDH 5HT_2Areceptors (5-HT_2AR) prevents facial mechanical allodynia and associated changes in the morphology of PKCγ⁺interneurons, but not depolarized RMP in lamina II_iinterneurons. Finally, activation of MDH 5-HT_2AR in naive animals is enough to reproduce the behavioral allodynia and morphological changes in PKCγ⁺interneurons, but not the electrophysiological changes in lamina II_iinterneurons, induced by facial inflammation. This suggests that inflammation-induced mechanical allodynia involves strong morphological reorganization of PKCγ⁺interneurons via 5-HT_2AR activation that contributes to open the gate for transmission of innocuous mechanical inputs to superficial SDH/MDH pain circuitry. Preventing 5-HT_2AR-induced structural plasticity in PKCγ⁺interneurons might represent new avenues for the specific treatment of inflammation-induced mechanical hypersensitivity.SIGNIFICANCE STATEMENTInflammatory or neuropathic pain syndromes are characterized by pain hypersensitivity such as mechanical allodynia (pain induced by innocuous mechanical stimuli). It is generally assumed that mechanisms underlying mechanical allodynia, because they are rapid, must operate at only the level of functional reorganization of spinal or medullary dorsal horn (MDH) circuits. We discovered that facial inflammation-induced mechanical allodynia is associated with rapid and strong structural remodeling of specifically interneurons expressing the γ isoform of protein kinase C (PKCγ) within MDH inner lamina II. Moreover, we elucidated a 5-HT_2Areceptor to PKCγ/ERK1/2 pathway leading to the behavioral allodynia and correlated morphological changes in PKCγ interneurons. Therefore, descending 5-HT sensitize PKCγ interneurons, a putative “gate” in allodynia circuits, via 5-HT_2Areceptor-induced structural reorganization.

Microglia control excitatory synapses, but their role in inhibitory neurotransmission has been less well characterized. Herein, we show that microglia control the strength of glycinergic but not GABAergic synapses via modulation of the diffusion dynamics and synaptic trapping of glycine (GlyR) but not GABAA receptors. We further demonstrate that microglia regulate the activity-dependent plasticity of glycinergic synapses by tuning the GlyR diffusion trap. This microglia–synapse cross talk requires production of prostaglandin E2 by microglia, leading to the activation of neuronal EP2 receptors and cyclic adenosine monophosphate–dependent protein kinase. Thus, we now provide a link between microglial activation and synaptic dysfunctions, which are common early features of many brain diseases.