Substance P (SP) is a member of the tachykinin family of peptides that binds preferentially to the neurokinin-1 receptor (NK-1R). The SP/NK-1R system is widely distributed in the whole body, including body fluids, and hence SP is ubiquitous throughout the human body. This system is involved in the molecular base of many pathophysiological actions: cancer, metastasis, pruritus, cough, inflammation, pain, rheumatoid arthritis, stress, depression, alcohol addiction, emesis, seizure, schizophrenia, bipolar disorder, asthma, irritable bowel syndrome, neuronal degeneration, migraine, cardiomyopathy, cholestasis, platelet aggregation, and bacteria/viral infection. This means that an in-depth knowledge of the SP/NK-1R system is the key for a better understanding/management of human diseases.

Because an upregulation occurs in the SP/NK-1R system of these diseases, NK-1R is a pivotal target for their treatment and hence the use of nonpeptide NK-1R antagonists (e.g., aprepitant, fosaprepitant) is a valuable therapeutic tool to treat these diseases. Non-peptide NK-1R antagonists, even administered at a high dose, are well tolerated, safe, and do not show serious side-effects. However, although the SP/NK-1R system is involved in many pathologies, to date, the use of only five NK-1R antagonists (aprepitant, fosaprepitant, rolapitant, netupitant, fosnetupitant) has been approved in humans. Preclinical studies have shown the beneficial effects of NK-1R antagonists in the treatment of diseases, but unfortunately, these beneficial effects were often not found in human clinical trials and hence its therapeutic potential is currently minimized. Many reasons have explained these findings; one of them is the dose administered of the NK-1R antagonist. Unfortunately, in many pathologies (e.g., cancer, viral infection) pharmacological therapy has not fully exploited the many possible therapies offered by nonpeptide NK-1R antagonists. For example, by increasing both the number of days on which nonpeptide NK-1R antagonists are administered and by increasing the dose of these antagonists. In addition, more preclinical/clinical studies are required to fully determine the safety/efficacy of some NK-1R antagonists (e.g., orvepitant, rolapitant, serlopitant) in diseases in which the SP/NK-1 receptor system is involved.

The aim of this Special Issue is to solicit original research articles, as well as review articles, highlighting basic, preclinical, and clinical research lines on the involvement of the SP/NK-1 receptor system in human pathology, and on the promising use of nonpeptide NK-1R antagonists in clinical practice. Moreover, this Special Issue hopes to explore the potential of NK-1R antagonists in different pathological conditions, and to increase the knowledge on the SP/NK-1R system. Submissions focusing on in-depth knowledge of the SP/NK-1R system to better understand how to handle human diseases are particularly encouraged.

Potential topics include but are not limited to the following:

• Respiratory diseases
• Inflammatory diseases
• Pathological basis of disease
• Cancer progression and metastasis
• Chemotherapy-induced nausea and vomiting
• Infection
• Postoperative therapy
• The genetic basis of disease
• Neurological and neuropathological conditions