Targeted treatment of pruritus: a look into the future

Abstract

Recent advances in pruritus research have elucidated mediators and neuronal pathways involved in itch transmission, and this fast emerging knowledge may possibly be translated into new therapies in the near future. In the skin and peripheral nerves, potential mediator and receptor therapeutic targets include the H4 histamine receptor, protease-activated receptor 2, serine proteases, cathepsin S, peripheral mu- and kappa-opioid receptors, interleukin-31, transient receptor potential vanilloid 1 and 3, fatty acid amide hydrolase, nerve growth factor and its receptor, acetylcholine, and the Mas-related G protein-coupled receptors. In the spinal cord, gastrin-related peptide and its receptor, as well as substance P and its receptor neurokinin receptor-1 serve as potential therapeutic targets. In the brain, reduction of itch perception and modulation of emotions may possibly be achieved through drugs acting on the anterior cingulate cortex. Clinically, management of pruritus should be instituted early and should address the skin pathology, peripheral neuropathy, central sensitization, and the cognito-affective aspects of the disease.

Fig. 1

Current understanding of the pathological mechanisms of itch and the potential targets for itch therapeutics in the periphery, spinal cord, and brain. Histamine-induced itch is transmitted via histamine-sensitive and mechanical-insensitive C-fibres and protease-induced itch is transmitted via PAR-2 and mechanical positive C-fibres. Free nerve endings reach the stratum granulosum. Neurogenic inflammation is mediated by the axonal reflex, releasing neuropeptides (substance P in particular) which cause vasodilation and further inflammatory changes. PAR, proteinase-activated receptor; Mech., Mechanical; Hist., Histamine; GRP, gastrin-releasing peptide; GRPR, gastrin-releasing peptide receptor; Mrgpr, Mas-related G-protein-coupled receptor; NKR-1, neurokinin receptor-1.