An aberrant parasympathetic response: a new perspective linking chronic stress and itch

Abstract

Perceived stress has long been known to alter the dynamic equilibrium established between the nervous, endocrine and immune system and is widely recognised to trigger or enhance pruritus. However, the exact mechanism of how the major stress response systems, such as the hypothalamus-pituitary adrenal (HPA) axis and the autonomic nervous system induce or aggravate chronic itch, has not been elucidated. The limbic regions of the brain such as the prefrontal cortex and hippocampus are deeply involved in the regulation of the stress response and intersect with circuits that are responsible for memory and reward. According to the 'Polyvagal Theory', certain limbic structures that serve as a 'higher brain equivalent of the parasympathetic nervous system' play a foremost role in maintaining body homoeostasis by functioning as an active vagal brake. In addition, the limbic system has been postulated to regulate two distinct, yet related aspects of itch: (i) the sensorydiscriminative aspect; and (ii) the affective-cognitive aspect. Chronic stress-induced itch is hypothesised to be caused by stress-related changes in limbic structure with subsequent rewiring of both the peripheral and central pruriceptive circuits. Herein, we review data suggesting that a dysfunctional parasympathetic nervous system associated with chronic stress may play a critical role in the regulatory control of key candidate molecules, receptors and brain structures involved in chronic itch.Abbreviations: Ach, acetylcholine; ANS, autonomic nervous system; CNS, central nervous system; CRH, corticotropin-releasing hormone; DLPFC, dorsolateral prefrontal cortex; E, epinephrine; GRPs, gastrin releasing peptide and MrgprX1 G coupled proteins; HPA hypothalamus-pituitary adrenal axis; IL, interleukin; NAchRa7, The a7 subunit of the nicotinic acetylcholine receptor; NE, norepinephrine; NGF, nerve growth factor; PG, prostaglandins; PVN, paraventricular nucleus of the hypothalamus; SNS, sympathetic nervous system; SP, substance P; VIP, vasoactive intestinal peptide.

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“…and has been used as a theoretical perspective to generate research questions and explain findings by numerous different research teams (e.g., Ardizzi et al, 2013;Beauchaine, 2001;Beauchaine, Gatzke-Kopp, & Mead, 2007;Egizio et al, 2008;Hastings et al, 2008;Perry, Calkins, Nelson, Leerkes, & Marcovitch, 2012;Schwerdtfeger & Friedrich-Mai, 2009;Travis & Wallace, 1997;Weinberg, Klonsky, & Hajcak, 2009;Whitson & El-Sheikh, 2003). For example, the theory has been used as a core theoretical explanation to explain the biobehavioral shutting down that occurs following trauma (Bradshaw, Cook, & McDonald, 2011;Levine, 2010;Ogden, Minton, & Pain, 2006;Quintana, Guastella, Outhred, Hickie, & Kemp, 2012) and has also informed stress researchers of the important role the parasympathetic nervous system and its component vagal circuits play in neurophysiological mechanisms related to defensive strategies associated with reactivity, recovery, and resilience (Brown & Gerbarg, 2005;Evans et al, 2013;Kim & Yosipovitch, 2013;Kogan, Allen, & Weihs, 2012;McEwen, 2002;Wolff, Wadsworth, Wilhelm, & Mauss, 2012).…”

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“…Itch is a multidimensional perception encompassing sensory discriminative, affective, and emotional components. It is extensively processed by the brain network, including the primary and secondary sensory cortex, supramarginal gyrus, inferior parietal lobe, anterior and posterior cingulate cortex, precuneus and insula-claustrum complex [72]. Although itch and pain are distinct sensations, the same brain regions, such as the amygdala, hippocampus, and hypothalamus, can be activated by both sensations.…”

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“…The pathophysiology of itch is complex and not well-understood (for reviews, see [12;13]). There are many substances that evoke scratching behavior and also many receptors and neural pathways that are implicated.…”

“…The natriuretic polypeptide b (Nppb) has been found to be implicated in the GRP itch circuitry [15], though its exact role has not yet been fully elucidated [16]. In a recent publication, Kim and Yosipovitch [13] listed substances potentially involved in chronic stress-induced itch, which include, in addition to those mentioned above, nerve growth factor, acetylcholine, adrenocorticotropin hormone, corticotropin-releasing hormone, kinins, vasoactive intestinal peptide, and chemoattractants. Of this extensive (but not exhaustive) list, most have a role in pruritus signaling, whether it is directly on pruriceptors on nerve endings, or indirectly on nerve fiber sensitivity, activation of mast cells, or over-activation of the sympathetic nervous system.…”