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While histamine has historically dominated models of mast cell\u2010mediated itch, accumulating evidence indicates that non\u2010histaminergic pathways are central to chronic disease. In this review, we synthesize current understanding of mast cell\u2010neuron communication and propose a unifying framework in which these cells form functional neuroimmune units that sustain itch and pain through bidirectional signalling and feed\u2010forward amplification. Mast cells release proteases, cytokines, lipid mediators, and neurotrophins that activate and sensitize sensory neurons via receptors including PAR\u20102, IL\u201031RA, TrkA, and transient receptor potential channels. In parallel, neuron\u2010derived neuropeptides such as substance P and calcitonin gene\u2010related peptide drive mast cell activation, notably through MRGPRX2\u2010dependent mechanisms, reinforcing neurogenic inflammation. These interactions promote peripheral sensitization and structural remodelling of cutaneous innervation, providing a mechanistic basis for persistent symptoms across disorders such as atopic dermatitis, prurigo nodularis, urticaria, neuropathic itch, and chronic pruritus of unknown origin. Importantly, emerging therapies targeting key nodes of this axis \u2010 including IL\u20104R\u03b1, IL\u201031RA, KIT, and Bruton's tyrosine kinase\u2014offer clinical validation of this neuroimmune paradigm. We highlight critical gaps in translating these insights to human disease, including the need for spatially resolved biomarkers and real\u2010time functional mapping of neuroimmune interactions. Advancing this framework may enable precision\u2010targeted therapies for chronic itch and skin pain conditions that remain refractory to conventional treatment.<\/jats:p>","DOI":"10.1111\/exd.70320","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T07:34:39Z","timestamp":1787211279000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Histamine: Mast Cell\u2010Neuron Communication in Chronic Pruritic and Pain Disorders"],"prefix":"10.1111","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3983-6687","authenticated-orcid":false,"given":"Tomer","family":"Kagan","sequence":"first","affiliation":[{"name":"Department of Neuroscience and Brain Disorders, Gray Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv 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