Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has been implicated in the modulation of persistent pain. Studies show that reduced COMT activity results in increased pain sensitivity and proinflammatory cytokine production in animal models¹, and that human genetic variants coding for low COMT activity are associated with heightened pain sensitivity^2-3. As increased pain sensitivity is a characteristic of inflammation, we hypothesize that the regulation of COMT under inflammatory conditions may contribute to the development of pain. Substantial evidence points to a role for nuclear factor kB (NF-kB) in the modulation of inflammatory pain. Recent work in our lab demonstrates that TNFa down-regulates endogenous COMT expression in PC-12 cells through a NF-kB-dependent mechanism. Thus, inflammatory pain could be mediated through the NF-kB-dependent down-regulation of COMT. The purpose of the present work was to evaluate the role of NF-kB in regulating pain sensitivity and COMT expression in the complete Freund's adjuvant (CFA) model of inflammation. Separate groups of rats received intraperitoneal administration of the NF-kB inhibitor PDTC or MG132 or vehicle one hour prior to intraplantar administration of CFA or saline. Behavioral responses to mechanical and thermal stimuli were then assessed during acute, subacute and chronic phases of CFA-induced inflammation. Administration of either PDTC or MG132 significantly decreased CFA-induced mechanical allodynia and thermal hyperalgesia. The effects of NF-kB inhibition on COMT expression were also assessed. Elucidating the signaling mechanisms that underlie inflammatory pain conditions will promote the development of novel therapies with minimal side-effects. (¹Nackley, Pain, 2006; ²Nackley, Science, 2006; ³Diatchenko, Hum Mol Gen, 2006) Supported by the NIH/NICHHD K12 HD052191 to A.N., NIH/NIDCR R01 DE016558 to L.D., and NIH/NINDS P01 NS045685 to W.M.