Neurokinins are a group of small protein-like molecules, known as neuropeptides, that act as chemical messengers in the body. They are found extensively throughout both the central nervous system and the peripheral nervous system. These peptides belong to a larger family of signaling molecules called tachykinins, named for their ability to rapidly induce the contraction of smooth muscle tissue. The widespread distribution of neurokinins suggests a broad range of biological functions, influencing processes from sensory perception to emotional regulation.
The Neurokinin Family and Their Receptors
The three primary neurokinins found in mammals are Substance P (SP), Neurokinin A (NKA), and Neurokinin B (NKB). These peptides share a similar chemical structure, including a conserved sequence of amino acids at their C-terminal end, which is necessary for their biological activity. They are all derived from precursor proteins that are “cut” into their smaller, active peptide forms through a process called alternative splicing of specific genes.
These three neurokinins exert their effects by binding to three corresponding receptor types, all of which are G protein-coupled receptors (GPCRs) found on the surface of various cells. The receptors are designated as Neurokinin-1 (NK1), Neurokinin-2 (NK2), and Neurokinin-3 (NK3). While each neurokinin can interact with all three receptors to some degree, they exhibit preferential binding affinity.
Substance P shows the strongest preference for the NK1 receptor, which is the most widely distributed of the three receptor types. Neurokinin A primarily targets the NK2 receptor, and Neurokinin B has the highest affinity for the NK3 receptor. This receptor selectivity dictates where and how each neurokinin signal is transmitted, allowing for distinct physiological outcomes. The activation of these receptors initiates a cascade of intracellular events, which relays the signal within the cell.
Primary Roles in Pain and Inflammation
Substance P, acting mainly through the NK1 receptor, is a powerful mediator of peripheral pain transmission. This neuropeptide is stored and released by the peripheral terminals of primary sensory neurons, which are the nerve fibers that respond to painful stimuli like heat, pressure, or chemical irritants. Upon detecting a strong noxious signal, Substance P is released into the spinal cord to transmit the pain signal to the brain, and also locally at the site of the injury.
The local release of Substance P is a primary driver of a protective mechanism known as neurogenic inflammation. By binding to NK1 receptors on nearby blood vessels, Substance P causes vasodilation. This effect increases blood flow to the injured area, leading to the redness and warmth associated with inflammation.
Vasodilation is immediately followed by plasma extravasation, where the walls of the post-capillary venules become more permeable. This increased permeability allows fluid, plasma proteins, and immune cells to leak out of the bloodstream and accumulate in the surrounding tissue, causing localized swelling and edema. Substance P also promotes the recruitment and activation of various immune cells. Beyond pain and inflammation, Substance P and Neurokinin A also play a role in smooth muscle contraction, such as in the gastrointestinal tract and airways, contributing to normal gut motility and bronchoconstriction.
Central Nervous System Functions
Neurokinins perform actions within the brain, separate from their peripheral roles in pain and inflammation. The Substance P/NK1 receptor system is implicated in the regulation of mood, stress, and anxiety. High levels of NK1 receptor availability in brain regions like the amygdala, which is central to fear and emotional processing, have been positively correlated with anxious personality traits in humans.
The NK1 receptor system acts as a neuromodulator that contributes to the brain’s ability to cope with stress and emotional arousal. Research suggests that activation of the NK1 receptor in the central nervous system is associated with increased stress and anxiety-related behaviors in animal models. Conversely, blocking this receptor system can have anxiolytic effects, suggesting that an overactive Substance P/NK1 pathway may contribute to conditions like generalized anxiety disorder and major depressive disorder.
Neurokinin B, through its preferred NK3 receptor, has been a focus of research for its role in central regulatory functions, particularly in the hypothalamus. The NK3 system is involved in controlling the release of reproductive hormones and is also being investigated for its connection to psychiatric conditions. Dysregulation of the NK3 system has been linked to the pathology of schizophrenia, making it a target for developing new psychiatric medications.
Therapeutic Applications
The physiological roles of neurokinins have led to the development of drugs that target their receptors, primarily antagonists. The most successful application of this approach has been in treating chemotherapy-induced nausea and vomiting (CINV). Drugs like aprepitant and fosaprepitant are selective NK1 receptor antagonists that prevent Substance P from binding to its receptor in the brain’s vomiting center.
By competitively blocking the NK1 receptor, these medications effectively prevent the transmission of the emetic signal, offering significant relief for patients undergoing highly emetogenic chemotherapy. Aprepitant is administered in combination with other antiemetics, such as 5-HT3 receptor antagonists and corticosteroids, and is available in both oral and intravenous formulations. The success of NK1 antagonists in this area has established them as a standard component of CINV prophylaxis protocols.
NK1 receptor antagonists have also been investigated for their antidepressant and anxiolytic properties, based on the central role of the Substance P/NK1 system in mood regulation. While some initial clinical trials for major depressive disorder showed mixed results, the potential remains an area of ongoing research. Furthermore, scientists are exploring NK3 receptor antagonists for different therapeutic uses, including the treatment of hormonal disorders related to reproductive function and for managing symptoms associated with schizophrenia.