Adrenergic and Cholinergic Control in the Biology of Epidermis: Physiological and Clinical Significance

Abstract

The presence of an autocrine adrenergic and cholinergic intra/intercellular signal transduction network in the human epidermis contributes significantly to homeostatic and compensatory responses regulating vital functions in keratinocytes and melanocytes. The ligands produced control autocrine and paracrine loops to initiate responses through cognate receptors expressed within the same or adjacent cells. The epidermal adrenergic signal controls calcium homeostasis, cell growth, differentiation, motility, and pigmentation via the beta2 and alpha1 adrenoceptors. The cholinergic system is highly complex comprising both nicotinic and muscarinic receptors with multiple subtypes and this system plays an important role in keratinocyte cell cycle progression, differentiation, directional migration, adhesion, and apoptotic secretion. Moreover, lymphocytes also express adrenergic and cholinergic receptors. Both types of signal transduction receptors are coupled to classical intracellular second messenger pathways, including cAMP-, cGMP-, and calcium-mediated downstream responses. To date, it has been recognized that several dermatoses such as psoriasis, atopic dermatitis, Mal de Meleda, vitiligo, palmoplantar pustulosis, and pemphigus may be mediated, in part, by the non-neuronal adrenergic/cholinergic systems. A detailed understanding of the physiology and pathophysiology of the adrenergic/cholinergic network in the skin could offer the development of specific drugs for novel treatment modalities.

Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naïve CD4 T cells toward the Th1, Th2 and Th17 lineages

“…28 The immunoregulatory effects of ACh may differ depending on the repertoire of cholinergic receptors expressed by a T cell, because different ACh receptor types couple distinct signaling pathway leading to unique changes in cell state and function (reviewed in ref. 21). In the past, the changes in the pattern of expression of mouse nAChR subunits during T-cell development and differentiation were suggested by Figure 3 The nicotinic effects on cytokine production by CD4 þ CD62L þ T cells.…”

“…Furthermore, the repertoire of ACh receptors expressed in non-neuronal cells changes during cell development, leading to reciprocal changes in the cellular functions controlled by autocrine/paracrine ACh (reviewed in ref. 21).…”

Increased Expression of Cutaneous α1-Adrenoceptors After Chronic Constriction Injury in Rats

“…it might not only sensitize nociceptive afferents but could also promote the growth of re-innervating cutaneous sympathetic nerve fibers into the upper dermis after CCI; these fibers grow in close proximity to nociceptors and are a possible source of the norepinephrine needed to activate α 1 -ARs 51 . Keratinocytes and melanocytes also have the capacity to synthesize catecholamines 13 . Thus, one could speculate that autocrine stimulation of α 1 -or β 2 -ARs 23 on these epidermal cells triggers a cascade of inflammatory mediators that augment neuropathic pain.…”

Inflammation contributes to axon reflex vasodilatation evoked by iontophoresis of an alpha-1 adrenoceptor agonist

“…Whether the adrenergic axon reflex is induced by direct activation of neural  1 -adrenoceptors or by stimulation of  1 -adrenoceptors on other cutaneous cells (e.g., melanocytes or immune cells) (Kavelaars, 2002;Maestroni, 2006;Grando et al, 2006) requires further investigation. Adrenergic mediation of axon reflexes could contribute to aberrant sensory-sympathetic coupling in inflammatory diseases of the kidney and lower urinary tract (Kopp et al, 2007;Trevisani et al, 2007), and could exacerbate pain and inflammation after peripheral nerve and tissue injury (Birklein and Schmelz, 2008;Gibbs et al, 2008).…”

“…In general, pain ratings were low and some of the participants described the sensations experienced during the iontophoreses as a sharp feeling or an itch rather than pain. Nevertheless, phenylephrine increases sensitivity to heat-pain in mildly burnt skin (Drummond, 2009a); conversely, depletion of cutaneous adrenergic stores inhibits electrically-evoked pain in mildly burnt skin (Drummond, 2008).Similarly, the nociceptive effects of noradrenaline are greater in skin sensitized by capsaicin than in untreated skin (Drummond, 1998) (Kavelaars, 2002; Maestroni, 2006;Grando et al, 2006) requires further investigation. Adrenergic mediation of axon reflexes could contribute to aberrant sensory-sympathetic coupling in inflammatory diseases of the kidney and lower urinary tract (Kopp et al, 2007;Trevisani et al, 2007), and could exacerbate pain and inflammation after peripheral nerve and tissue injury (Birklein and Schmelz, 2008;Gibbs et al, 2008) …”