5-HT receptor-induced morphological reorganization of PKCγ-expressing interneurons gates inflammatory mechanical allodynia in rat.

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 (SD H) or medullary dorsal horn (MDH), whereby tactile inputs into deep SDH/MDH can gain access to superficial SDH/MDH, eliciting pain. Inner lamina II (IIi) interneurons expressing the gamma isoform of protein kinase C (PKC gamma(+)) are key elements for allodynia circuits, but how they operate is still unclear. Combining behavioral, ex vivo electrophysiological, 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 (I) sensitization (using ERK1/2 phosphorylation as a marker) and (2) reduced dendritic arborizations and enhanced spine density in exclusively PKC gamma(+) interneurons, but (3) depolarized resting membrane potential (RMP) in all lamina IIi PKC gamma(+)/PKC gamma(+) interneurons. Blocking MDH 5HT(2A) receptors (5-HT2A R) prevents facial mechanical allodynia and associated changes in the morphology of PKC gamma(+) interneurons, but not depolarized RMP in lamina IIi interneurons. Finally, activation of MDH 5-HT2A R in naive animals is enough to reproduce the behavioral allodynia and morphological changes in PKC gamma(+) interneurons, but not the electrophysiological changes in lamina IIi interneurons, induced by facial inflammation. This suggests that inflammation-induced mechanical allodynia involves strong morphological reorganization of PKC gamma(+) interneurons via 5-HT2A R activation that contributes to open the gate for transmission of innocuous mechanical inputs to superficial SDH/MDH pain circuitry. Preventing 5-HT2A R-induced structural plasticity in PKC gamma(+) interneurons might represent new avenues for the specific treatment of inflammation-induced mechanical hypersensitivity.