Substance P and neurokinin 1 receptor are new targets for the treatment of chronic pruritus*

Abstract

Summary Background Chronic pruritus is a distressing symptom associated with various dermatological conditions and systemic diseases. Current treatment options are often inadequate, resulting in impaired quality of life for many patients. An understanding of the underlying mechanisms of itch across pruritic conditions is important for development of effective, targeted treatments for chronic pruritus. Objectives To provide an overview of the pathogenesis of chronic pruritus, focusing on the role of substance P (SP) and neurokinin 1 receptor (NK1R) in itch signalling, and to describe data supporting NK1R antagonism as a potential strategy for the treatment of chronic pruritus. Methods A PubMed search was conducted to determine what data were available that investigated the role of SP and NK1R in itch signalling. Results SP is a neuropeptide that is a mediator of itch signalling. One of the target receptors for SP is NK1R, which is expressed in the central nervous system and on multiple cell types involved in the initiation and transmission of itch. Studies demonstrating that SP and NK1R are overexpressed across multiple chronic itch‐inducing conditions and that NK1R antagonism disrupts itch signalling and reduces itch provide a rationale for targeting this pathway as a potential treatment of chronic pruritus across multiple diseases. Conclusions A large and growing body of evidence, including recent phase II clinical studies of NK1R antagonists, demonstrate that SP and NK1R play an important role in itch signalling. Additional studies are ongoing to further evaluate the use of NK1R antagonists for the treatment of chronic pruritus. What's already known about this topic? Chronic pruritus has a significant impact on quality of life. Current treatment options for chronic pruritus are inadequate. Substance P (SP) and neurokinin 1 receptor (NK1R) have been shown to play a role in itch signalling, and may be a rational target for addressing chronic pruritus. NK1R antagonists are being evaluated as potential treatment for chronic pruritus. What does this study add? This review provides a compilation of the most up‐to‐date data elucidating the role of SP and NK1R in itch signalling, which supports targeting this pathway as a potential treatment of chronic pruritus. NK1R antagonism disrupts itch signalling and reduces itch. A summary of the latest data on NK1R antagonists in the treatment of pruritus is provided.

Neurokinin-1 antagonist orvepitant for EGFRI-induced pruritus in patients with cancer: a randomised, placebo-controlled phase II trial

“…EGFRI-induced pruritus arises acutely within the first 2 weeks after initiation of the anticancer therapy5 and cutaneous accumulation, and activation of dermal mast cells16 17 62 may be the most important driver of the itch signalling in these patients. This acute course contrasts with that of chronic pruritus conditions (defined as being >6 weeks in duration),63 which are now linked to the sensitisation of itch signalling pathways similar to chronic pain, such that patients may report spontaneous itch (alloknesis) or an enhanced itch to normal itch-evoking stimuli (hyperknesis) 32 64 65. NK1 antagonists have shown great promise in randomised, placebo-controlled clinical studies as treatments for chronic pruritus conditions in general66 67 as well as specifically for prurigo nodularis,68 atopic dermatitis-associated pruritus69 and psoriasis-associated pruritus 70.…”

“…Scratching behaviour induced by intradermal injection of either SP or an NK1 agonist or topical administration of a hapten in animals can all be profoundly reduced by NK1 antagonist treatment, including both orvepitant and aprepitant 27–30. These data suggest that the NK1 receptor system is involved in itch signalling and therefore blockade of these pathways with NK1 receptor antagonists represents a potentially promising therapy for pruritic conditions, including EGFRI-induced pruritus 31 32…”

Mechanisms of Itch in Stasis Dermatitis: Significant Role of IL-31 from Macrophages

“…SP exerts its function mainly, but not exclusively, through its receptor NK1R (Azimi et al, 2017;Ständer and Yosipovitch, 2019). SP stimulates NK1R expressing cells, resulting in the release of additional itch mediators and evoking itch (Yosipovitch et al, 2018).…”

Emerging Therapeutic Options for Chronic Pruritus

“…SP binds to NK-1R, as well as the Mas-related G protein-coupled receptor (Mrgpr). NK-1R is more substantiated in eliciting pruritic response in humans as it induces vasodilatation, degranulation of mast cells, nerve growth factor (NGF) expression in keratinocytes and stimulates neurogenic inflammation [51]. In the study by Nattkemper et al [52], the authors utilized RNA sequencing and observed increased levels of both SP and NK-1R in lesional skin of patients with psoriasis and AD who experienced severe pruritus.…”