Preclinical and human surrogate models of itch

Abstract

Pruritus, or simply itch, is a debilitating symptom that significantly decreases the quality of life in a wide range of clinical conditions. While histamine remains the most studied mediator of itch in humans, treatment options for chronic itch, in particular antihistamine-resistant itch, are limited. Relevant preclinical and human surrogate models of non-histaminergic itch are needed to accelerate the development of novel antipruritics and diagnostic tools. Advances in basic itch research have facilitated the development of diverse models of itch and associated dysaesthesiae. While experimental itch in humans is induced over a short period of time and usually assessed psychophysically, the study of itch reactions in animals allows for both short-term and long-term studies but relies heavily on behavioural assessments. This review provides a background and a presentation of the established models of itch currently applied in animals and humans with emphasis on translatability. K E Y W O R D Sanimal, histaminergic itch, non-histaminergic itch, pruritus, surrogate models, translational ineffective. Itch and pain are related but distinct sensations, and while pain has been extensively studied, the understanding of itch transmission is lacking behind. 6 There is evidence for different peripheral and central mechanisms underlying histaminergic and non-histaminergic itch, 3,7 and elucidation of the pathways and mechanisms mediating itch, especially chronic itch, is essential to the development of novel antipruritic drugs. In this regard, both preclinical and human surrogate models serve as important tools to expand the current knowledge. 3,8This review presents an overview of the currently available preclinical and human surrogate models of itch. | APPLICABILITY OF TRANSLATIONAL MODELSIdeal translational models of pruritus should induce itch through pathways associated with those involved in human pruritic diseases while closely mimicking one or several symptomatological aspects of these diseases.For example, itch in urticaria is well linked to mast cell degranulation and can be mimicked experimentally with histamine administration in both animal and human surrogate models. 9-13 The validity is confirmed by comparable efficacy of antihistamines between the animal models, the human surrogate models and the urticarial patient population. 10-13Translational models of itch can also provide a platform for screening compounds for antipruritic activity in a preclinical setting, evaluation of antipruritic drug candidates in phase Ib, and to mechanistically profile and select patients for phase II-III clinical trials.

Neuroimmune interactions in chronic itch of atopic dermatitis

“…4,15,16 In the peripheral nervous system, the first event is binding of pruritogens to a subset of primary afferent C-fibre somatosensory neurons (pruritoceptors) that innervate skin. 4,15,16 In the peripheral nervous system, the first event is binding of pruritogens to a subset of primary afferent C-fibre somatosensory neurons (pruritoceptors) that innervate skin.…”

“…[17][18][19] The brain processes the itch signal, and motor activity (scratching) is induced. A few notable examples of pruritogen receptor-pruritogen pairs relevant to AD are as follows: (i) proteinase-associated receptor 2 (PAR2), which binds a pro-peptide released by mast cell proteases or house dust mite extract proteases 4,25 ; and (ii) several members of the Mas-related G protein-coupled receptor (Mrgprx) family, in particular Mrgprx2, which can be activated by the neuropeptide substance P. 16,[26][27][28] Many non-histaminergic pruritoceptors require the calcium ion channels TRPA1 and TRPV1 for itch signalling to the spinal cord. One system for functionally classifying groups of pruritoceptors is by sensitivity to histamine, a common pruritogen.…”

Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage

“…For a better understanding and interpretation of the sensory qualities of itch in different clinical conditions, knowledge about sensory profiles in different experimental models of itch is indispensable. Different models of experimentally induced itch are being increasingly used in recent years to investigate pathomechanisms and to test novel therapies of itch …”

Characterization of the chloroquine‐induced mouse model of pruritus using an automated behavioural system

“…These models are simple and short in terms of execution, but the assessment of pruritus is tedious and time‐consuming, and results may vary depending on the observer. Several attempts have been made to automatize the procedure, but most of the current scientific publications are still using the manual approach . Additionally, measurement of scratching alone does not allow for a correct interpretation of the efficacy results.…”

“…However, to date, its use has been limited and no extensive validation with pharmacological tools is available. One potential explanation is that scratching, used as a surrogate endpoint of itch severity, is generally quantified manually by analysis of video recordings of animals . Such a procedure is tedious, time‐consuming and has very low throughput.…”