The development and validation of a murine model for studying the role of histamine receptors in acute and chronic itch
Bell, Jonathan Keith
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Itch (pruritus) is an unpleasant sensation of the skin, which evokes the desire to scratch. The condition commonly presents in clinical practice, as a symptom of systemic disease and various skin disorders, such as atopic dermatitis. Itch has tended to be closely associated with pain, and older evidence suggests that the sensations involve the same sensory nerves, firing at different frequencies. Partly because of this, and the subjective cognitive nature of the condition, itch has been relatively ignored as a research area and there is a general lack of effective animal models for studying itch. This has restricted detailed studies into putative mediators of itch and their mechanism(s) of action.The present studies were undertaken to develop and validate acute and chronic models of itch in mice, based on the combined use of behavioural tests in awake mice and in vivo electrophysiological recordings from itch afferents in anaesthetized animals. The hypothesis was that scratching behaviour can be evoked in mice using intradem1al injections of pruritogenic drugs and that this can be measured automatically and objectively to provide a reliable indicator of itch. A further hypothesis was that electrophysiological recordings made in vivo from murine cutaneous sensory nerves can be used to distinguish between pruritogens and algogens.The model of itch that was developed is based on injection of histamine into the back of the mouse neck to evoke scratching of the area by the hind paws. Histamine is a pruritogen in both humans and mice, although the lack of effectiveness of traditional H 1-receptor antihistamines in treating all clinical itch disorders suggests other mediators are also responsible for pruritus. The studies demonstrated that scratching in mice can be induced using histamine and other pruritogens (e.g. trypsin and 5-HT) in a reproducible dose dependent manner. Scratching was established as a response to itch-provoking agents, but not to painful stimuli. A novel mechanism of histamine evoked scratching involving H4 receptors was discovered. Chronic itching 111 response to topical application of dinitrochlorobenzene was also established. A robust automated method for the detection and measurement of scratching in mice was developed, which considerably enhances accuracy and reduces the time taken, in comparison with manual observation of scratching.In vivo electrophysiological recordings showed that pruritogens evoke a pattern of response in cutaneous nerves distinct in nature from that evoked by algogenic stimuli. However, nerves responded to both stimuli, suggesting that in mice, there are probably no independent 'pruritoceptors', unlike the situation in man. In summary, scratching in mice can be recorded automatically and used as a reproducible quantitative measure of itch. This model can be used for further studies on putative mediators of itch to establish their mechanism of action. Knowledge from such studies should provide understanding of the sensation of itch in man, and should facilitate the development of novel therapies specific for pruritus.