Evolving evidence in the neural sensitization of prurigo nodularis

Prurigo nodularis is a chronic inflammatory skin disorder characterized by relentlessly pruritic, hyperkeratotic nodules. Recent studies have provided compelling evidence for the pivotal role of dysregulated interactions between the nervous and immune systems in its pathogenesis. This article reviews the latest findings on the neurogenic mechanisms contributing to prurigo nodularis, particularly how these processes lead to the sensation of increased itch intensity. Peripheral sensitization is primarily driven by abnormal innervation of histamine-independent, small unmyelinated C fibers, epidermal hypoplasia, and dermal hyperinnervation. This sensitization is further amplified by the cyclic release of neuropeptides such as Substance P, calcitonin gene-related peptide, and nerve growth factor. Although the mechanisms underlying central sensitization in prurigo nodularis remain less understood, it likely involves enhanced itch signaling in the dorsal spinal cord or a lowered threshold for itch perception. Additionally, parallels between pruritus and pain-such as allodynia and alloknesis, as well as hyperalgesia and hyperknesis-along with the association of prurigo nodularis with various comorbid systemic conditions, offer valuable insights into the disorder's pathology. A deeper understanding of the complex neural sensitization mechanisms in prurigo nodularis may lead to the identification of novel therapeutic targets, ultimately alleviating the burden of this debilitating condition.