Neurokinins are a family of small protein-like molecules, or neuropeptides, that serve as signaling molecules throughout the body. These compounds play an important role in communication within the nervous system and various other bodily systems. Understanding neurokinins helps explain how our bodies manage physiological processes, from sensation to internal organ function.
Understanding Neurokinins
Neurokinins function as both neurotransmitters, sending signals between nerve cells, and neuromodulators, adjusting signal strength. The three most well-known types in humans are Substance P (SP), Neurokinin A (NKA), and Neurokinin B (NKB). These peptides are part of a larger family called tachykinins, recognized for their ability to rapidly stimulate intestinal muscle contraction.
Each neurokinin interacts with specific receptors on cells to exert its effects. Substance P binds to the Neurokinin 1 (NK1) receptor, Neurokinin A binds to the Neurokinin 2 (NK2) receptor, and Neurokinin B binds to the Neurokinin 3 (NK3) receptor. These neurokinin receptors are found on diverse cell types, including neurons, immune cells, and cells lining blood vessels and lymphatic vessels.
Their Diverse Roles in the Body
Neurokinins are involved in a wide range of physiological processes. Their actions contribute to how we perceive pain, manage inflammation, regulate digestion, and influence mood.
Pain Transmission
Substance P plays an important role in the transmission of pain signals. When a painful stimulus occurs, Substance P is released from primary sensory neurons in the periphery. This neuropeptide relays pain signals to the central nervous system, activating second-order neurons in the dorsal horn of the spinal cord. The activation of the NK1 receptor by Substance P in these spinal neurons contributes to the sensation and persistence of pain.
Inflammation and Immune Responses
Neurokinins contribute to inflammatory processes and immune responses. Substance P can enhance inflammatory responses by interacting with its NK1 receptor, leading to the activation of nuclear factor-kappa-b (NF-κB) and increased production of pro-inflammatory cytokines like IL-1, IL-6, and TNF-α. This interaction can lead to vasodilation, where blood vessels widen, and increased immune cell activity, such as granulocyte infiltration in the skin. These actions highlight neurokinins’ role as messengers between the nervous and immune systems, influencing tissue repair and disease resistance.
Gastrointestinal Function
Neurokinins are active in the gastrointestinal tract, influencing its motility and secretion. While NK1 and NK3 receptors may not play major roles in normal digestive functions, they are implicated in defensive or pathological processes within the gut. NK3 receptors are involved in disruptions of intestinal motility and visceral sensations, potentially increasing the sensitivity of nerve fibers in the enteric nervous system. Research suggests the presence of NK1, NK2, and NK3 receptors in the gastrointestinal tract, where they can modulate gut movement.
Central Nervous System Activities
Within the central nervous system, neurokinins contribute to mood regulation, stress responses, anxiety, and nausea and vomiting. The Substance P/NK1 receptor system is implicated in emotional processing, with studies suggesting that NK1 receptor antagonists can reduce anxiety symptoms and negative affect. Substance P and its NK1 receptor are present in brain regions associated with emotion and are found in close proximity to neurons targeted by antidepressant drugs.
Neurokinin Pathways and Therapeutic Approaches
Understanding the specific roles of neurokinins and their receptors has created new possibilities for medical treatments. By targeting these neurokinin pathways, scientists can develop interventions to manage various health conditions, either by blocking or activating their receptors. This research has already yielded practical medical solutions and continues to be an active area of investigation.
Anti-emetic Drugs
A key example of targeting neurokinin pathways is the development of anti-emetic drugs for preventing chemotherapy-induced nausea and vomiting (CINV). Chemotherapy can trigger the release of Substance P, which binds to NK1 receptors in the brain’s vomiting centers, such as the area postrema and nucleus tractus solitarius, leading to nausea and vomiting. Drugs like aprepitant, fosaprepitant, netupitant, and rolapitant work by blocking these NK1 receptors, preventing Substance P from activating them and thereby inhibiting the emetic signal. These NK1 receptor antagonists are often used in combination with other anti-emetic agents to provide more comprehensive control of CINV, especially for highly and moderately emetogenic chemotherapy regimens.
Pain Management Research
Neurokinin modulators are also being explored for their potential in pain management, especially for chronic pain conditions. Substance P is an important endogenous modulator of nociception in both the peripheral and central nervous systems, making its receptor a promising target. While early clinical trials for NK1 receptor antagonists as standalone pain relievers have shown a lack of consistent efficacy, research continues into combination therapies. For example, combining NK1 receptor antagonists with opioid fragments is being investigated to develop more effective analgesic drugs with potentially fewer side effects.
Other Potential Areas
Beyond nausea and pain, neurokinin pathways are under investigation for their roles in other conditions. Research is ongoing into their involvement in disorders like migraine and irritable bowel syndrome (IBS). The NK1 receptor, present in both the central nervous system and the gastrointestinal tract, is a target of interest for relieving symptoms in these conditions. Neurokinin antagonists are also being studied for their potential in psychiatric disorders and substance abuse, highlighting diverse therapeutic possibilities.