In normal animals, peripheral nerve injury produces a persistent, neuropathic pain state in which pain is exaggerated and can be produced by nonpainful stimuli. Here, mice that lack protein kinase C gamma (PKCγ) displayed normal responses to acute pain stimuli, but they almost completely failed to develop a neuropathic pain syndrome after partial sciatic nerve section, and the neurochemical changes that occurred in the spinal cord after nerve injury were blunted. Also, PKCγ was shown to be restricted to a small subset of dorsal horn neurons, thus identifying a potential biochemical target for the prevention and therapy of persistent pain.