Biological and Pharmacological Aspects of the NK1-Receptor

Abstract

The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis.

Mechanisms of Pain in Sickle Cell Disease

“…SP acts via NK-1 receptors and NK-1 receptor antagonists have been efective in diferent pain pathologies in animal models, but have failed to show eicacy in clinical trials [111]. "prepitant, an FD"-approved NK-1 receptor antagonist for chemotherapy-induced nausea and vomiting, has been assessed for the efects on electrical hyperalgesia models of human volunteers, but did not show any eicacy [112].…”

“…small study in a cohort of 17 patients using a nasal spray form of the mast cell stabilizer, cromolyn, in combination with hydroxyurea indicated that these patients experienced reduced pain when compared to placebo or to the use of cromolyn or hydroxyurea alone [110]. Thus, FD"-approved mast cell stabilizers available for reducing airway inlammation can be potentially efective as adjuvants for sickle pain.SP acts via NK-1 receptors and NK-1 receptor antagonists have been efective in diferent pain pathologies in animal models, but have failed to show eicacy in clinical trials [111]. "prepitant, an FD"-approved NK-1 receptor antagonist for chemotherapy-induced nausea and vomiting, has been assessed for the efects on electrical hyperalgesia models of human volunteers, but did not show any eicacy [112].…”

Efficacy and safety of fosaprepitant in the prevention of nausea and vomiting following highly emetogenic chemotherapy in Chinese people: A randomized, double-blind, phase III study

“…The neurokinin‐1 receptor (NK‐1R) is closely involved in CINV, and substance P induces vomiting by binding to NK‐1R in the central nervous system. This anatomical localization has led to the successful clinical development of antagonists against NK‐1R in the treatment of CINV (Garcia‐Recio & Gascón, 2015). …”

Additional Antidepressant Pharmacotherapies According to a Neural Network

“…Substance P exerts a neuromodulating effect in the central and peripheral nervous systems and is associated with depression, stress, anxiety, and emesis. The NK1 receptor antagonist aprepitant is prescribed for high or moderate emesis [24].…”