Substance P

Substance P is an 11-amino acid neuropeptide belonging to the tachykinin family, with the sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. It functions as both a neurotransmitter and neuromodulator in the central and peripheral nervous systems, playing a key role in pain signaling, neurogenic inflammation, and mood regulation. It was among the first neuropeptides discovered and has been studied for over 90 years.

Substance P acts primarily through the NK1 (neurokinin-1) receptor, a Gq-coupled GPCR, with lower affinity for NK2 and NK3. Binding to NK1R activates phospholipase C, raises intracellular calcium, and activates PKC, promoting neuronal excitation and synaptic facilitation. In primary afferent nociceptors, SP co-localizes with glutamate and CGRP, facilitating pain transmission to the dorsal horn. Peripheral SP release from afferent nerve endings triggers mast cell degranulation, vasodilation, plasma extravasation, and immune cell recruitment — the hallmarks of neurogenic inflammation.

NK1 receptor antagonists (aprepitant, netupitant) have been developed and are FDA-approved as antiemetics in chemotherapy-induced nausea/vomiting, validating the SP-NK1R axis as a therapeutic target. Research into NK1 antagonists for depression, PTSD, and chronic pain continues. Elevated SP levels are associated with fibromyalgia, IBS, and inflammatory arthritis. SP also plays a role in wound healing and angiogenesis, creating therapeutic interest beyond pain.