Substance P is widely distributed in the central and peripheral nervous systems and in the cardiovascular system. It is also present in the gastrointestinal tract, where it may play a role as a transmitter in the enteric nervous system and as a local hormone (see Chapter 6).
Substance P is the most important member of the tachykinin family. It exerts a variety of central actions that implicate the peptide in behavior, anxiety, depression, nausea, and emesis. It is present in peripheral afferent pain fibers and participates in nociception. It is a potent arteriolar vasodilator, producing marked hypotension in humans and several animal species. The vasodilation is mediated by release of nitric oxide from the endothelium. Substance P causes contraction of venous, intestinal, and bronchial smooth muscle. It stimulates secretion by the salivary glands and causes diuresis and natriuresis by the kidneys.
The actions of substance P and neurokinins A and B are mediated by three Gq protein-coupled tachykinin receptors designated NK1, NK2, and NK3. Substance P is the preferred ligand for the NK1 receptor. This receptor is widespread throughout the body and is the predominant tachykinin receptor in the human brain. However, neurokinins A and B also possess considerable affinity for this receptor. In humans, most of the central and peripheral effects of substance P are mediated by NK1 receptors. All three receptor subtypes are coupled to inositol trisphosphate synthesis and calcium mobilization.
Several nonpeptide NK1 receptor antagonists have been developed. These compounds are highly selective and orally active, and enter the brain. Recent clinical trials have shown that these antagonists may be useful in treating depression and other disorders and in preventing chemotherapy-induced emesis. The first of these to be approved for the prevention of chemotherapy-induced and postoperative nausea and vomiting is aprepitant (see Chapter 62). Fosaprepitant is a prodrug that is converted to aprepitant after intravenous administration and may be a useful parenteral alternative to oral aprepitant.
The substance P-NK1 system has also been implicated in cancer. Substance P and NK1 receptors are present in a variety of tumor cells, and NK1 receptor antagonists exert an antitumor action. Thus, drugs such as aprepitant may have potential as anticancer agents.
Neurotensin (NT) is a tridecapeptide that was first isolated from the central nervous system but subsequently was found to be present in the gastrointestinal tract. It is also present in the circulation and in several organs including the heart, lungs, liver, pancreas, and spleen.
NT is synthesized as part of a larger precursor that also contains neuromedin N, a six-amino-acid NT-like peptide. In the brain, processing of the precursor leads primarily to the formation of NT and neuromedin N; these are released together from nerve endings. In the gut, processing leads mainly to the formation of NT and a larger peptide that contains the neuromedin N sequence at the carboxyl terminal. Both peptides are secreted into the circulation after ingestion of food. Most of the activity of NT is mediated by the last six amino acids, NT(8-13).