BACKGROUND: Protein kinase C (PKC) is a family of serine/threonine kinases that contains more than 10 isozymes. Evidence suggests that PKC may play important roles in pain modulation, but the isozyme-specific effects of PKC on different aspects of pain modulation are not fully understood. We hypothesize that different PKC isozymes play different roles in different aspects of pain modulation. METHODS: The nociceptive behaviors of mice with deletion of PKCα, β, γ, or δ in multiple pain models were compared with their respective wild-type littermates. Also, morphine analgesia and the development of morphine tolerance in mice with deletion of PKCγ were compared with their respective wild-type littermates. RESULTS: Thermal hyperalgesia induced by complete Freund's adjuvant injection was significantly attenuated by the deletion of PKCβ, γ, or δ, but not PKCα. Deletion of PKCγ significantly attenuated neuropathic mechanical allodynia induced by spared nerve injury, whereas deletion of PKCα enhanced this allodynia. Baseline thermal and mechanical sensitivity, nociceptive behaviors induced by formalin, mechanical allodynia induced by complete Freund's adjuvant injection, were not altered by deletion of PKCα, β, γ, or δ. Finally, morphine analgesia and the development of morphine tolerance were not altered in PKCγ-deficient mice. CONCLUSIONS: PKC has isozyme-specific effects in pain modulation.