3.3.5 Neuropeptides
Knowledge of Neuropeptides
Neuropeptides are amino acids that have been formed into short chains. Neurons produce and release these chemical messengers. Neuropeptides bind to G-protein coupled receptors to regulate tissue and neural activity (muscles, heart, and gut).
Released by dense core vesicles in the synaptic terminal following depolarization of the cell. When contrasted against neurotransmitters, then neuropeptides are much more sensitive. They are measured in the nanomolar-micromolar range while neurotransmitters are in the micromolar-millimolar range.
| Neuropeptide: | Location secreted: | Function: |
| Corticotrophin-releasing hormone | Hypothalamus | Suppresses appetite. Increases anxiety. Improves memory and selective attention. |
| Cholecystokinin | Small intestine (mostly duodenum and jejunum) via enteroendocrine cells called I-cells. | Fundamental in the process of triggering bile and enzymes to break down food. |
| Ghrelin | Stomach | Stimulates appetite and growth hormone release. |
| Leptin | Adipose tissue | Suppresses food intake/satiety. |
| GLP-1 | Pancreatic alpha cells. | Stimulate insulin secretion. Inhibit glucagon secretion. Limits post-prandial glucose increases. |
| Encephalins/endorphins | Central nervous system and adrenal medulla. | Encephalins are tiny peptides that can function in the brain as neurotransmitters. Encephalins block afferent pain fibres and reduce substance P release in the dorsal horn of the spinal cord. |
| Orexin | Hypothalamus | Regulates wakefulness, appetite, reward, and thermogenesis. |
| Substance P | Neurons | Neuropeptide/neurotransmitter modulating pain perception |
| Neurotransmitter: | Coexisting neuropeptides: |
| Acetylcholine | Substance P |
| Adrenaline | Neuropeptide Y Neurotensin |
| Dopamine | Cholecystokinin Neurotensin Glucagon-like peptide-1 |
| GABA | Somatostatin Cholecystokinin Neuropeptide Y |
| Noradrenaline | Neuropeptide Y Enkephalin Galanin |
| Serotonin | Substance P Enkephalin Thyrotropin-releasing hormone |
Corticotrophin-releasing hormone:
Corticotropin-releasing hormone (CRH) is a neuropeptide hormone that emphasizes regulating sympathetic, behavioural functions, and neuroendocrine functions. It contains 41 amino acids and is secreted through the hypothalamus. CRH regulates the behavioural functions and neuroendocrine in response to threats or stress. When the hypothalamus releases the corticotrophin-releasing hormone that triggers the release of adrenocorticotrophic hormone (ACTH). ACTH binds with the adrenal cortex, it triggers the release of the stress hormone known as cortisol. This entire system plays an important part in the fight or flight response (Walia, 2021).
Increased CRH production has been associated with depression and Alzheimer’s disease (Raadsheer, 1995).
Cholecystokinin:
Cholecystokinin (CCK) is produced in the small intestine and plays an important role in digestion. When protein and fats transit into the small intestine, CCK activates the pancreas and gallbladder to function. This process works so finely, it delivers enzymes and bile to the duodenum that helps in food absorption (Walia, R., H., Ahuja, 2021).
CCK is found throughout the central nervous system, specifically in the limbic system. Elevated CCK increases levels of anxiety and can reliably induce a panic attack. Positron emission tomography imaging showing CCK-4-induced panic attacks demonstrates changes in the anterior cingulate gyrus, amygdala and cerebellar vermis (Bowers, 2012).
Ghrelin:
Ghrelin is a neuropeptide hormone released by enteroendocrine cells of the stomach. It is often referred to as the ‘hunger hormone’ since it increases your drive to eat, or reduces your satiety. Ghrelin levels in the blood are greatest before meals when people are hungry, and they return to normal after meals. Ghrelin may aid in meal preparation by enhancing stomach motility and boosting gastric acid output (Okonkwo, 2021).
Obese people have lower ghrelin levels in their plasma than thinner people (Müller, 2015).
In anorexia nervosa the ghrelin levels are higher compared to normal-weight controls (Tolle, 2003).
Leptin:
Leptin is a neuropeptide hormone synthesized predominantly by adipose cells but also by enterocytes in the small intestine. Leptin acts upon receptors in the lateral hypothalamus which inhibit hunger, and in the medial hypothalamus stimulate satiety. This inhibition of hunger consequently reduces fat storage in adipocytes and regulates homeostatic energy levels.
Glucagon-like peptide-1:
Glucagon-like peptide-1 (GLP-1) is a neuropeptide hormone produced and secreted by intestinal enteroendocrine cells and certain neurons in the brainstem.
The main function of GLP-1 is the promotion of insulin secretion in a glucose-dependent manner. GLP-1 binds to GLP-1 receptors on pancreatic beta cells. Following this GLP-1 also replaces its used stores by promoting insulin gene transcription and biosynthesis (Baggio, 2007).
Enkephalins and Endorphins:
Enkephalins are pentapeptides involved in nociception is the process through which the sensory nerve system encodes noxious sensations. It is concerned with the sequence of events and processes necessary for an organism to receive a painful input, convert it to a molecular signal, detect and define the signal, and initiate an appropriate defensive reaction (Miller, 1979). Enkephalins are found in the cells of the adrenal medulla.
Endorphins are often referred to as opioid neuropeptides and act as chemical signals that either block the perception of pain or increase feelings of well-being. They are synthesised and stored in the pituitary gland (Steffano, 2011). There a three endogenous opioid neuropeptide classes: alpha-endorphin, beta-endorphin and gamma-endorphin. All three endorphin classes are fragments of the precursor protein proopiomelanocortin.
The endocannabinoid system:
The endocannabinoid system (ECS) is a neuromodulatory system in the central nervous system. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes involved in endocannabinoid synthesis and breakdown. CB1 cannabinoid receptors are the most numerous, although cannabinoids also engage CB2 cannabinoid receptors, transient receptor potential (TRP) channels, and peroxisome proliferator-activated receptors (PPARs). Exogenous cannabinoids, including tetrahydrocannabinol, exert biological effects by interacting with cannabinoid receptors. The best-studied endogenous cannabinoids are 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide).
The endogenous cannabinoids are endogenous lipids that consequently engage cannabinoid receptors.
Anandamide is broken down in the central nervous system by the enzyme fatty acid amino hydrolase. 2-AG is broken down by a much more complex pathway.
Cannabis has a tightly bound relationship with the ECS. Epidemiology notes a relationship between increased cannabis use and heightened risk for schizophrenia in susceptible individuals (Lu, 2015).
Orexins:
Orexin is a neuropeptide that regulates appetite, wakefulness, thermogenesis and arousal. The vast majority of orexin is produced by neurons in the lateral hypothalamus and perifornical area.
Lack of orexin can cause type 1 narcolepsy, in which a person loses their muscle tone. Narcolepsy occurs due to the destruction of the cells that synthesise orexin. This destruction is thought to occur by the immune system mistakenly attacking the cells/neurons in the hypothalamus or the receptors that allow it to function (Krieger, D.T., 1982).
Substance P:
Substance P (where ‘P’ stands for preparation or powder) is a neuropeptide that interacts with the receptor neurokinin type 1. Released from neurons, substance P is a primary peptide in responding to noxious stimuli or pain (O’Connor, 2014).
References:
(1) Baggio LL, Drucker DJ (May 2007). “Biology of incretins: GLP-1 and GIP”. Gastroenterology. 132 (6): 2131–57.
(2) Bowers ME, Choi DC, Ressler KJ (December 2012). “Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y”. Physiology & Behavior. 107 (5): 699–710.
(3) Krieger, D.T., 1982. Endorphins and enkephalins. Disease-a-Month, 28(10), pp.3-53.
(4) Lu, H.-C. and Mackie, K. (2016). An Introduction to the Endogenous Cannabinoid System. Biological Psychiatry, [online] 79(7), pp.516–525. doi:10.1016/j.biopsych.2015.07.028.
(5) Miller, R.J. and Cuatrecasas, P. (1979). Enkephalins and Endorphins. [online] ScienceDirect. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0083672908609875 [Accessed 5 Jan. 2023].
(6) Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. (June 2015). “Ghrelin”. Molecular Metabolism. 4 (6): 437–60.
(7) O’Connor TM, O’Connell J, O’Brien DI, Goode T, Bredin CP, Shanahan F (Nov 2004). “The role of substance P in inflammatory disease”. Journal of Cellular Physiology. 201 (2): 167–80.
(8) Raadsheer FC, van Heerikhuize JJ, Lucassen PJ, Hoogendijk WJ, Tilders FJ, Swaab DF (September 1995). “Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer’s disease and depression”. The American Journal of Psychiatry. 152 (9): 1372–1376.
(9) Stefano GB, Ptáček R, Kuželová H, Kream RM (1515). “Endogenous morphine: up-to-date review 2011”. Folia Biologica. 58 (2): 49–56.
(10) Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, et al. (January 2003). “Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women”. The Journal of Clinical Endocrinology and Metabolism. 88 (1): 109–16.
(11) Walia, R., Gupta, R., Bhansali, A., Pivonello, R., Kumar, R., Singh, H., Ahuja, C., Chhabra, R., Singh, A., Dhandapani, S. and Sahoo, S., 2021. Molecular imaging targeting corticotropin-releasing hormone receptor for corticotropinoma: a changing paradigm. The Journal of Clinical Endocrinology & Metabolism, 106(4), pp.1816-1826.