The
enzyme catechol-O-methyltransferase (COMT) has been shown to play a critical role in pain perception by regulating levels of
epinephrine (Epi) and
norepinephrine (NE). Although the key contribution of
catecholamines to the perception of
pain has been recognized for a long time, there is a clear dichotomy of observations. More than a century of research has demonstrated that increasing
adrenergic transmission in the spinal cord decreases
pain sensitivity in animals. Equally abundant evidence demonstrates the opposite effect of
adrenergic signaling in the peripheral nervous system, where
adrenergic signaling increases
pain sensitivity. Viewing
pain processing within spinal and peripheral compartments and determining the directionality of
adrenergic signaling helps clarify the seemingly contradictory findings of the
pain modulatory properties of
adrenergic receptor agonists and antagonists presented in other reviews. Available evidence suggests that
adrenergic signaling contributes to
pain phenotypes through α(1/2) and β(2/3) receptors. While stimulation of α(2)
adrenergic receptors seems to uniformly produce
analgesia, stimulation of α(1) or β receptors produces either
analgesic or hyperalgesic effects. Establishing the directionality of
adrenergic receptor modulation of
pain processing, and related COMT activity in different
pain models are needed to bring meaning to recent human molecular genetic findings. This will enable the translation of current findings into meaningful clinical applications such as diagnostic markers and novel therapeutic targets for complex human
pain conditions.