The neurotransmitter hypothesis of urticaria

Abstract

The role of the CNS in the pathophysiology of urticaria has, historically, been almost totally neglected. The concept of the urticarias as “neurovascular disorders” is not a new one, and was first proposed at the turn of the century. Recent advances in the understanding of the physiology of histamine (particularly in the CNS) permit an extension of the old “neurovascular hypothesis”. In this paper, evidence is presented to support the propositions that (i) disordered histamine metabolism and/or release is common to all forms of urticaria, and (ii) that such peripheral upsets alter the hypothalamic functions of the histaminergic, serotoninergic and other amine neurotransmitter systems. Such hypothalamic upsets may disorder peripheral vascular function, thus amplifying or perpetuating the initial antigenic insult. Thus, stress (by acting via the hypothalamic-vascular axis) may be part of the initiating event. Further, since the central histaminergic system is an ascending one, certain behavioural associations of urticaria (such as anxiety and depression) may have a physiological basis. While the physical urticarias (cold, cholinergic and solar types) have been shown to be useful models of mast-cell histamine release, behavioural sequelae of such release should be assessed: recently, cholinergic urticaria was shown to result in alterations in lung-function, so other systemic effects are likely. Mastocytosis and urticaria pigmentosa (as extreme examples of conditions with excess plasma histamine release) have been associated with gross changes in CNS function. While this paper argues the case for an intimate, two-way interplay between CNS and peripheral histamine in urticaria, it is suggested that the study of “food urticaria” might provide valuable insights into the effects of other mediators (such as prostaglandins) on CNS functioning; the effects of absorbed peptide fragments on CNS functioning provide yet another interactive pathway between the brain and peripheral vasculature. Thus, it is suggested here that the CNS plays an important role in the pathogenesis of the urticarias, and that future research should not be restricted to the skin or the mastcell.