Pharmacotherapy of Itch-Antihistamines and Histamine Receptors as G Protein-Coupled Receptors

Abstract

Itching can decrease quality of life and exacerbate skin symptoms due to scratching. Itching not only contributes to disease progression but also triggers complications such as skin infections and eye symptoms. Therefore, controlling itching is very important in therapeutic management. In addition to the well-known histamine, IL-31, IL-4 and IL-13 have recently been reported as factors that induce itching. Itching may also be caused by factors other than these histamines. However, we do not know the extent to which these factors are involved in each disease. In addition, the degree of involvement is likely to vary among individuals. To date, antihistamines have been widely used to treat itching and are often effective, suggesting that histamine is more or less involved in itchy diseases. This review discusses the ligand-receptor perspective and describes the dynamics of G protein-coupled receptors, their role as biased agonists, their role as inverse agonists, proactive antihistamine therapy, and drug selection with consideration of impaired performance and anti-PAF effects.

Keywords: G protein-coupled receptors; anti-PAF effect; antihistamine; biased agonist; impaired performance; inverse agonist; itch; proactive antihistamine therapy.

Figure 1

Regulation of function and distribution of G-protein-coupled receptors.

Figure 2

Biased agonist.

Figure 3

Inverse agonist concept. (a) In the absence of histamine, inactive and active receptors are in dynamic equilibrium. (b) In the presence of histamine, histamine stabilizes active receptors and increases the percentage of active receptors. (c) In the presence of antihistamines, antihistamines stabilize inactive receptors and increase the proportion of inactive receptors.

Figure 4

H1 receptor occupancy and sedation of antihistamines in the brain.

Figure 5

Mechanisms by which mediators released from mast cells (A) and PAF induce allergic inflammation (B). (A) Circles mean first mediators derived from granules, such as histamine or tryptase. Squares mean second mediators newly synthesized from phospholipids, such as prostaglandins, leukotrienes, which derived from arachidonic acid, or PAFs. Triangles mean third mediators newly transcribed and translated, such as cytokines or chemokines.