A body of evidence links decreased expression and activity of catechol-o-methyltransferase (COMT), an enzyme that metabolizes catecholamines, with idiopathic pain conditions including temporomandibular joint disorder and fibromyalgia. Parallel with clinical studies, COMT inhibition in rodents results in increased pain, but the mechanisms required for the onset and maintenance of pain remained unknown. The purpose of this dissertation was to determine the downstream mechanisms required for COMT-dependent pain as well as to understand how environmental triggers can lead to decreased COMT expression. Our lab previously identified that β2- and β3ARs are required for the onset of COMT-dependent pain, but the molecules downstream of β2- and β3AR activation remained unknown. Here we examined the mechanisms required for the onset and maintenance of COMT-dependent pain. During the onset of pain, we found that previously identified β2- and β3ARs, together with circulating pro-inflammatory molecules were required for the onset of pain. Furthermore, release of these pro-inflammatory molecules was βAR-dependent. We then sought to understand if βARs and pro-inflammatory cytokines were required during the maintenance phase of COMT-dependent pain. We find that while βARs are important during the onset phase, blockade of βARs following the onset phase was not able to reverse COMT-dependent pain. Similarly, we did not observe differences in circulating pro-inflammatory molecules. Rather, the maintenance of COMT-dependent pain resulted in increased levels of activated mitogen activated protein kinases (MAPKs) including p38 and extracellular regulated protein-kinase 1/2. Intrathecal inhibition of these molecules on day 14, after the onset of COMT-dependent pain, was able to reverse COMT-dependent pain, indicating that these molecules contribute to the maintenance of COMT-dependent pain. Finally, we sought to understand if environmental triggers could decrease COMT expression. We found that the inflammatory pathway nuclear factor-κB (NF-κB) is involved in prolonged inflammatory pain and decreased COMT expression in the brain. Taken together, these data point to COMT and downstream effectors play a central role in driving the onset and maintenance of pain.