Catechol-O-methyltransferase (COMT) has recently been implicated in the modulation of persistent pain. We demonstrated that common human haplotypes of the COMT gene are associated with pain sensitivity and the risk for temporomandibular disorder (TMD), a chronic musculoskeletal pain condition (Diatchenko et al, Hum Mol Gen 2005). Haplotypes coding for low COMT activity are associated with high pain sensitivity and increased TMD incidence. Furthermore, reductions in COMT activity result in heightened pain sensitivity in animal models via actions at β-adrenergic receptors (Nackley et al, SfN 2004). The present study was conducted to elucidate the specific receptor mechanism/s whereby COMT modulates pain sensitivity. Separate groups of rats received intraperitoneal (i.p.) injections of the β1 antagonist betaxolol, the β2 antagonist ICI118,551, the β3 antagonist SR59230A, or vehicle 10 min prior to i.p. administration of the COMT inhibitor OR486 or vehicle. Administration of OR486 significantly increased the p...