Chronic pain is sustained by a maladaptive form of neuronal plasticity occurring in all stations of the pain neuraxis, including cortical regions of the pain matrix. We report that chronic inflammatory pain induced by unilateral injection of Complete Freund’s Adjuvant (CFA) in the hindpaw of male mice was associated with a progressive build-up of perineuronal nets (PNNs) in the contralateral somatosensory cortex (SSCtx), medial prefrontal cortex (mPFCtx), and reticular thalamic nucleus. In the SSCtx, the density of PNNs labeled by Wisteria Fluribunda Agglutinin (WFA) was increased at both 3 and 7 days following CFA injection, but only after 7 days in the mPFCtx. The number of parvalbumin (PV)-positive interneurons enwrapped by WFA+/PNNs was also increased in all three brain regions of mice injected with CFA. Remarkably, PNN degradation induced by intracortical infusion of chondroitinase-ABC significantly reduced mechanical and thermal pain, and also reversed the increased frequency of inhibitory postsynapt...