Itch: From mechanism to (novel) therapeutic approaches

Abstract

Itch is a common sensory experience that is prevalent in patients with inflammatory skin diseases, as well as in those with systemic and neuropathic conditions. In patients with these conditions, itch is often severe and significantly affects quality of life. Itch is encoded by 2 major neuronal pathways: histaminergic (in acute itch) and nonhistaminergic (in chronic itch). In the majority of cases, crosstalk existing between keratinocytes, the immune system, and nonhistaminergic sensory nerves is responsible for the pathophysiology of chronic itch. This review provides an overview of the current understanding of the molecular, neural, and immune mechanisms of itch: beginning in the skin, proceeding to the spinal cord, and eventually ascending to the brain, where itch is processed. A growing understanding of the mechanisms of chronic itch is expanding, as is our pipeline of more targeted topical and systemic therapies. Our therapeutic armamentarium for treating chronic itch has expanded in the last 5 years, with developments of topical and systemic treatments targeting the neural and immune systems.

Neuroimmune interactions in chronic itch of atopic dermatitis

“…12 Peripheral sensitization, defined by a decreased activation threshold of nociceptors on neurons, is induced by inflammatory mediators 54 and results in increased nerve fibre responsiveness and release of neurotransmitters such as glutamate and brain-derived neurotrophic factor. 12 Peripheral sensitization, defined by a decreased activation threshold of nociceptors on neurons, is induced by inflammatory mediators 54 and results in increased nerve fibre responsiveness and release of neurotransmitters such as glutamate and brain-derived neurotrophic factor.…”

“…[5][6][7][8][9][10][11] However, there is growing appreciation for the contribution of the nervous system in AD-associated itch. 12 Crosstalk between the nervous system, the cutaneous immune system and keratinocyte populations is central to the development and persistence of atopic itch. 13 While immunosuppressants and corticosteroids reduce inflammatory components of AD, as well as itch, most of these treatments fail to target the substantial neural component of itch pathophysiology and are associated with suboptimal risk-benefit profiles.…”

Characterization of a chloroquine‐induced canine model of pruritus and skin inflammation

“…Basic research has advanced our understanding of the mechanisms underlying pruritus. In healthy humans and mice, histamine‐dependent and histamine‐independent (nonhistaminergic) pathways have been identified to mediate acute and chronic itch sensations . Because histamine is not a potent acute itch inducer in dogs and first‐generation antihistamines have shown limited efficacy in control of canine pruritus, there is a need to investigate the nonhistaminergic itch pathways in dogs for the potential development of novel drugs to block itch pathways.…”

Dose‐dependent pruritogenic and inflammatory effects of intradermal injections of histamine, compound 48/80 and anti‐canine IgE in healthy dogs

“…Pruritus is defined as a sensation that provokes a desire to scratch. Atopic dermatitis, scabies, cutaneous T‐cell lymphoma, and bacterial and yeast infections cause pruritus as an important sign in humans and dogs . Therefore, it is reasonable to investigate in dogs the same substances and mediators of pruritus known to induce pruritus in healthy humans.…”

“…Atopic dermatitis, scabies, cutaneous T-cell lymphoma, and bacterial and yeast infections cause pruritus as an important sign in humans and dogs. 1,2 Therefore, it is reasonable to investigate in dogs the same substances and mediators of pruritus known to induce pruritus in healthy humans. Identifying canine models of pathological itching is essential for pharmacological evaluation of the antipruritic efficacy of more specific and potentially safer therapies to treat itch as a common and unpleasant sensation.…”