Like many other neuropeptides, NT serves a dual function as a neurotransmitter or neuromodulator in the central nervous system and as a local hormone in the periphery. When administered centrally, NT exerts potent effects including hypothermia, antinociception, and modulation of dopamine and glutamate neurotransmission. When administered into the peripheral circulation, it causes vasodilation, hypotension, tachycardia, increased vascular permeability, increased secretion of several anterior pituitary hormones, hyperglycemia, inhibition of gastric acid and pepsin secretion, and inhibition of gastric motility. It also exerts effects on the immune system.
In the central nervous system, there are close associations between NT and dopamine systems, and NT may be involved in clinical disorders involving dopamine pathways such as schizophrenia, Parkinson’s disease, and drug abuse. Consistent with this, it has been shown that central administration of NT produces effects in rodents similar to those produced by antipsychotic drugs.
The effects of NT are mediated by three subtypes of NT receptors, designated NTR1, NTR2, and NTR3, also known as NTS1, NTS2, and NTS3. NTR1 and NTR2 receptors belong to the Gq protein-coupled superfamily. NTR1 has a higher affinity for NT than NTR2 and is the major mediator of the diverse effects of NT. The NTR3 receptor is a single-transmembrane protein that is structurally unrelated to NTR1 or NTR2. It belongs to a family of sorting proteins and is therefore known as NTR3/sortilin.
The potential use of NT as an antipsychotic agent has been hampered by its rapid degradation in the circulation and inability to cross the blood-brain barrier. However, a series of analogs of NT(8-13) that exert antipsychotic-like activity in animal studies has been developed. These agonists include NT69L, which binds with high affinity to NTR1 and NTR2; and NT79, which preferentially binds to NTR2. Another agonist, PD149163, has improved metabolic stability.
In addition to their possible role as antipsychotic drugs, these agonists may be useful in the treatment of pain, psychostimulant abuse, and Parkinson’s disease. Potential adverse effects include hypothermia and hypotension. Development of tolerance to some of the effects of the agonists may occur.
NT receptors can be blocked with the nonpeptide antagonists SR142948A and meclinertant (SR48692). SR142948A is a potent antagonist of the hypothermia and analgesia produced by centrally administered NT. It also blocks the cardiovascular effects of systemic NT.
Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides, which also includes calcitonin, adrenomedullin, and amylin. CGRP consists of 37 amino acids. In humans, CGRP exists in two forms termed α-CGRP and β-CGRP, which are derived from separate genes and differ by three amino acids but exhibit similar biological activity. Like calcitonin, CGRP is present in large quantities in the C cells of the thyroid gland. It is also distributed widely in the central and peripheral nervous systems, cardiovascular and respiratory systems, and gastrointestinal tract. In the cardiovascular system, CGRP-containing neuronal fibers are more abundant around arteries than around veins and in atria than in ventricles. CGRP fibers are associated with most smooth muscles of the gastrointestinal tract. CGRP is found with substance P (see above) in some of these regions and with acetylcholine in others.