Janus molecule I: dichotomous effects of COMT in neuropathic vs nociceptive pain modalities

Abstract

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.

Fig. 1. Model of relationship between COMT activity alleles and pain sensitivity in different pain modalities

a: COMT enzyme is depicted as “pacman” and Epi and NE as small black dots. High COMT activity in human or mouse alleles or in rat strains is assumed to result in less adrenergic signaling. b: Axis between neuropathic pain and nociceptive types of pain is tilted by catecholamine signaling. c: Two models of catecholamine metabolism, with the spinal cord colored to denote increasing or decreasing pain sensitivity. High COMT activity is hypothesized to be a risk factor for neuropathic pain and low COMT activity is hypothesized to be a risk factor for nociceptive pain.

Fig. 2. Summary of Adrenergic Receptors in Neuropathic and Nociceptive types of Pain

Arrows pointing upwards indicate increased nociception, X indicates no change. Agmat = agmatine; Atenol = atenolol; Bamb = bambuterol; Betaxo = betaxolol; BRL44 = BRL44408; Clen = clenbuterol; Dex = dexmedetomidine; Fadol = fadolmidine; Feno = fenotero; Form = formoterol; Isopre = isoprenaline; Medet = medetomidine; Meta = metaproterenol; Meth = methoxamine; Oxym = oxymetazoline; Phenox = phenoxybenzamine; Phento = phentolamine; Phenyl = phenylephrine; Procat = procaterol; Propran = propranolol; Radol = radolmidine; Rito = ritodrine; RS422 = RS42206; Salb = salbutamol; Salm = salmetoral; Terb = terbutaline; Tizan = tizanidine; Uinox = uinoxaline; WB-41= WB-4101.