NK1

The neurokinin-1 receptor (NK1) is a G protein-coupled receptor that binds substance P with high affinity. It is a member of the tachykinin receptor family and is encoded by the TACR1 gene. NK1 is expressed in both the central and peripheral nervous systems, with notable populations in the dorsal horn of the spinal cord and brain regions including the area postrema, nucleus tractus solitarius, and limbic structures.

Activation of NK1 predominantly couples to Gq/11 proteins, activating phospholipase C and leading to the production of inositol trisphosphate and diacylglycerol, which increases intracellular calcium. This signaling modulates neurotransmitter release and neuronal excitability, contributing to pain transmission, emesis, mood regulation, and inflammatory responses. Receptor activity can be limited by desensitization and internalization after sustained stimulation.

Substance P is the principal endogenous ligand, though other tachykinins can interact with NK1 with lower affinity. NK1 signaling participates in nociception, migraine, chemotherapy- and postoperative-induced nausea, anxiety, and depressive-like behavior in some models, and has been linked to inflammatory processes and certain cancers.

Therapeutically, NK1 receptor antagonists block NK1 signaling and are used to prevent chemotherapy-induced nausea and vomiting and post-operative nausea. Approved agents include aprepitant, fosaprepitant, rolapitant, and netupitant (often in combination with the 5-HT3 antagonist palonosetron). Drugs are typically administered orally or intravenously and can interact with CYP3A4 substrates. Common side effects are generally mild, such as fatigue, dizziness, or hiccups. Ongoing research investigates broader uses in pain, migraine, mood disorders, and inflammatory diseases.