Sensitization to inflammatory pain is a pathological form of neuronal plasticity that is poorly understood and treated. Here we examine the role of the SH3 domain of postsynaptic density 95 (PSD95) by using mice that carry a single amino‐acid substitution in the polyproline‐binding site. Testing multiple forms of plasticity we found sensitization to inflammation was specifically attenuated. The inflammatory response required recruitment of phosphatidylinositol‐3‐kinase‐C2α to the SH3‐binding site of PSD95. In wild‐type mice, wortmannin or peptide competition attenuated the sensitization. These results show that different types of behavioural plasticity are mediated by specific domains of PSD95 and suggest novel therapeutic avenues for reducing inflammatory pain. Sensitization to inflammatory pain is a pathological form of neuronal plasticity that is poorly understood and treated. Here the authors report that the SH3 domain of the scaffold protein PSD‐95 binds a lipid signaling enzyme, PI3K‐C2a, that mediates inflammatory sensitization. The results show that different types of behavioural plasticity are mediated by specific domains of PSD‐95 and suggest that PI3K‐C2a is a potential drug target for inflammatory pain.