Neuropeptides

Neuropeptides vs common neurotransmitters

Neuropeptides exhibit a distinctive biosynthesis and mechanism of action that distinguishes them from common neurotransmitters. A fundamental difference lies in the fact that neuropeptide biosynthesis occurs in the neural body, not the neural axon. This is crucial due to their protein nature, necessitating processing in the Golgi reticulum. Specifically, all neuropeptides stem from larger, inactive precursors that are generally at least 90 amino acid residues. Initially, these pro-propeptides break down into smaller peptides, which are subsequently packed into vesicles and transported through the neural body. Pro-propeptides are expressed in different tissues but the enzymatic breakdown differs so the final product that occurs is tissue-specific. For instance, proenkephalin is processed in the medulla of suprarenal gland to a set of opiate peptides of 15 to 35 residues, while proenkephalin in the brain is cleaved primarily to the pentapeptides metenkephalin and leuenkephalin. Neuropeptides are packaged into large dense core vesicles (LDCVs) and usually all the parts of the pro-peptides are in the same vesicle. Nonetheless, there are examples that the peptides are then separated into distinct types of vesicles, which are sent to different parts of the cell.

Another characteristic of neuropeptides is that their receptors respond to significantly lower concentrations compared to classical neurotransmitters. The release of neuropeptides typically demands a more intense stimulus, leading to a greater influx of Ca2+ into the presynaptic terminal than what is necessary for the release of conventional neurotransmitters. This heightened stimulus requirement is presumably due to the increased distance that Ca2+ must diffuse to reach the vesicles.

Substance P

Substance P is a conserved peptide derived from the tachykinins family and is found in the central nervous system (CNS), the peripheral nervous system (PNS) and immune cells. In mammals, there are three tachykinins neuropeptides; substance P, neurokinin A, and neurokinin B. All tachykinins are derived from alternate splicing of tachykinin genes. Substance P interacts with neurokinin family G protein–coupled receptors, specifically NK1R, NK2R, and NK3R. Neurokinin receptors are present on the surface of diverse cell types, spanning blood vessels, lymphatic endothelial cells, immune cells, fibroblasts and neurons.

Substance P plays diverse physiological and pathological roles, primarily in nociception and neurogenic inflammation, mediated by the NK1R. However, expression of this receptor on various non-neuronal cells suggests additional functions, including extracellular matrix integrity, angiogenesis, vasodilation, and bone metabolism, as well as effects on smooth muscle cells, skin fibroblasts, and synoviocytes.

The best studied actions of substance P are the following:

• In the spinal cord, substance P is abundant in terminals of primary afferent nerves in the posterior horn, posterior ganglion cells, and posterior roots. Its release in the spinal cord, especially in the substantia gelatinosa, occurs in response to various noxious stimuli.
• In the PNS, NK1R are present in posterior root ganglia, intrinsic gut neurons, and unmyelinated axons in glabrous skin. Substance P, along with other tachykinins, contributes to neurogenic inflammation, causing vasodilation, plasma protein extravasation, leukocyte adhesion and various tissue-specific responses.
• Substance P is a potent vasodilator, inducing hypotensive responses via NK1R activation and nitric oxide release. In cerebral arteries, substance P release results in relaxation, potentially playing a role in migraine pathophysiology.
• In asthma and bronchitis, substance P contributes to bronchoconstriction and bronchodilation, secretion from glands, and mediator release from airway epithelium.
• In the gut, substance P is present in both extrinsic and intrinsic enteric neurons, regulating motility and fluid secretion.
• Substance P in the renal pelvis and ureter stimulates motility and is associated with NK1R expression. Additionally, substance P affects motility and plasma extravasation in the genitourinary tract.

Neuropeptide Y

Neuropeptide Y is recognized as one of the most abundant neuropeptides in the brain and is a vital member of the biologically active neuropeptide Y family, which also includes peptide YY and pancreatic polypeptide. Its crucial roles encompass various physiological functions, including food intake, energy homeostasis, circadian rhythm, and cognition, while also being implicated in stress responses with anxiolytic properties.

The biologically active form of neuropeptide Y is derived from a 97-amino acid precursor, pre-pro-neuropeptide Y, through a series of posttranslational enzymatic events. Neuropeptide Y receptors belong to the G protein-coupled receptor family, mediating physiological effects through the inhibition of adenylyl cyclase.

Cerebral neuropeptide Y synthesis primarily occurs in key regions, including the hypothalamic arcuate nucleus, cerulean nucleus, nucleus of solitary tract and septohippocampal nucleus. Additionally, neuropeptide Y is found in various brain regions, forming an important fiber tract between the arcuate nucleus and the paraventricular nucleus of the hypothalamus, facilitating crosstalk between neuropeptide Y and corticotropin-releasing hormone systems.

Seven Y receptors have been described in vertebrates, with neuropeptide Y displaying a strong affinity for Y1, Y2, and Y5 receptors, while pancreatic polypeptide acts as the preferential agonist at the Y4 receptor. Neuropeptide Y emerges as a potent orexigenic peptide, playing a pivotal role in controlling food intake and body weight within the hypothalamus. Its release precedes feeding onset, contributing to a shift toward positive energy balance by increasing food intake and reducing energy expenditure, primarily through thermogenesis reduction in brown adipose tissue and facilitating fat deposition in white adipose tissue. The increased expression of neuropeptide Y in poor metabolic conditions underscores its involvement in the regulation of energy balance. The discovery of hormones governing adiposity signals supports a feedback mechanism between peripheral fat stores and neuronal centers controlling food intake.

In stress adaptation, neuropeptide Y interacts with major biological pathways, including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. Neuropeptide Y counteracts the actions of corticotropin-releasing hormone (CRH), displaying anxiolytic effects. The limbic system, particularly the amygdala and hippocampus, plays a crucial role in mediating these anxiolytic effects. Stress-induced alterations in neuropeptide Y expression are influenced by stress type, duration, time point of measurement, and brain region examined. The anxiolytic activity of neuropeptide Y is primarily mediated by the Y1 receptor.

Opioids

Endogenous opioid peptides are small molecules naturally produced in the CNS and various glands, including the pituitary and suprarenal glands. These peptides share similarities with classic alkaloid opiates such as morphine and heroin. Functioning as both hormones and neuromodulators, endogenous opioid peptides play crucial roles in physiological processes. Hormonal opioid peptides are released into circulation, influencing distant target tissues, while neuromodulatory peptides act within the CNS, modulating neurotransmitter actions.

Enkephalins, dynorphins, and β-endorphin are generated through the proteolytic cleavage of large protein precursors, namely preproenkephalin, preprodynorphin, and proopiomelanocortin, respectively.

Opioid receptors, classified into mu, delta, and kappa categories, belong to the G protein-coupled receptor superfamily and exhibit distinct functions and binding characteristics. The interaction between opioid peptides and receptors initiates biochemical events, leading to various effects, including analgesia and euphoria.

Opioid receptors are widely expressed throughout the peripheral and CNS, primarily in the cortex, the limbic system, and the brainstem. While binding sites for all three receptors overlap in most structures, certain regions express one receptor type more prominently. For example, mu receptors dominate in the amygdala, thalamus, midbrain and some brainstem nuclei, kappa receptors prevail in the basal anterior forebrain, and delta receptors are abundant in the olfactory tract and cortices.

Recent studies highlight the essential role of mu receptors in mediating natural rewards, influencing motivation and food-anticipatory behavior. Delta receptors exhibit contrasting behavioral phenotypes, affecting anxiety levels, depressive-like behavior, ethanol self-administration, and impulsivity. Kappa receptors, known for their aversive effects, modulate hedonic homeostasis and may have hallucinogenic properties. Pharmacological and knockout studies suggest that kappa receptors oppose mu receptors in regulating reward processes and play a role in addictive behaviors under stressful conditions.