Janus Molecule I: Dichotomous Effects of COMT in Neuropathic vs Nociceptive Pain Modalities
S. K. Segall, W. Maixner, I. Belfer, T. Wiltshire, Z. Seltzer and L. Diatchenko
Affiliation: Center for Neurosensory Disorders, University of North Carolina, Chapel Hill, NC, USA.
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 α1/2 and β2/3 receptors. While stimulation of α2
adrenergic receptors seems to uniformly produce analgesia, stimulation of α1 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.
Keywords: Adrenergic receptor signaling, COMT, intrathecal, nociception, neuropathic, pain, spinal cord, Catechol O Methyl Transferase, Haplotype, rs4680, Noxious stimuli, Epinephrin, Tempromandibular joint disorders
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