A Brief Overview of Neuropeptides

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More than 100 neuropeptides have been identified, many of which are known to be hormones but also function as neurotransmitters. Hormones are produced by the endocrine system and neurotransmitters by the nervous system. Hormones send signals through the circulatory system (blood flow) while neurotransmitters through the synaptic cleave. The hormone works far from where it is released but the neurotransmitter is directly juxtaposed with its target cells. Since the hormone's job is to reach a distant "target cell," the signal transmission is much slower, which can take minutes to days, than that of the neurotransmitters that send messages between nerve cells. Usually, these neuropeptides are released in conjunction with small-molecule neurotransmitters. Propeptides are larger than their active peptide products and can produce more than one neuropeptide. Some neuropeptides are involved in regulating mood and certain peptides, such as Substance P and opioid peptides, are involved in pain perception. There are other peptides like melanocyte-stimulating hormones, adrenocorticotropin, and β-endorphin, that regulate the complex stress response. Neuropeptide transmitters can be classified into five broad categories:

1. Brain/gut peptides

Substance P is an example of a brain/gut neuropeptide. The research for neuropeptides began over 60 years ago with the accidental discovery of Substance P, a potent antihypertensive agent. Substance P is a peptide found in the human hippocampus, neocortex, and gastrointestinal tract thus, it is classified as a brain/gut peptide. Substance P is also a sensory neurotransmitter in the spinal cord, which releases opioid peptides that can be inhibited by spinal interneurons, thereby inhibiting pain. The gene encoding Substance P also encodes many other neuroactive peptides, including neurokinin A, neuropeptide K, and neuropeptide γ.

Fig 1. The structure of Substance P

The endogenous receptor of Substance P is the NK1-receptor (NK1R). It belongs to the GPCR family of receptors called Tachykinin peptides. Substance P and NK1 receptors are widely distributed in the brain and are located in specific brain regions that regulate mood. They are closely associated with serotonin and norepinephrine-containing neurons that are targets of currently used antidepressant drugs. Substance P is associated with the release of NO and is therefore a potent vasodilator with significant efficacy in lowering blood pressure. In addition, Substance P also plays a role in a range of indications, including anti-inflammatory, pain, mood, anxiety, learning, and control of vomiting.

2. Opioid peptides

Opioid peptides can bind to opioid receptors in the brain, leading to the design of many opioid drugs based on these peptide models. Opioid peptides can be produced by the body itself, such as endorphin, and have different functions. The endogenous ligands of opioid receptors contain more than 20 opioid peptides, which are divided into three categories: endorphins (e.g., β-endorphins, γ-endorphins), enkephalin, and dynorphin.

Fig 2. The structure of β-endorphins and γ-endorphins (the red part is the overlap area)

Fig 3. The structure of Met-enkephalin and Leu-enkephalin

Fig 4. The structure of Dynorphin A and Dynorphin B (the red part is the overlap area)

Opioid peptides are widely distributed throughout the brain and are commonly co-located with other small molecule neurotransmitters such as GABA and serotonin. In general, these peptides tend to be inhibitors. The brain opioid peptide system matters in motivation, emotion, attachment behavior, response to stress and pain, control of food intake, and so forth. They act as analgesics when injected intravenously and have connection with the mechanism by which acupuncture induces analgesia. Opioids are also involved in complex behaviors, such as sexual attraction and aggressive/submissive behavior. They have been linked to psychiatric disorders as well, such as schizophrenia and autism, although the evidence for this is disputed. Repeated administration of opioids can lead to tolerance and addiction. Therefore, a better understanding of these neurotransmitters and their roles is critical to developing strategies to deal with this social and medical matter.

3. Pituitary peptides

Pituitary peptides include the following types:

• Adrenocorticotropic hormone (ACTH)
• Thyroid-stimulating hormone (TSH)
• Luteinising hormone (LH)
• Follicle-stimulating hormone (FSH)
• Prolactin (PRL)
• Growth hormone (GH)
• Melanocyte-stimulating hormone (MSH)

4. Hypothalamic neuropeptides

The hypothalamus is the source of neural progenitor cells, which produce different specialized and differentiated cell populations during brain development. Newly formed neurons in the hypothalamus can synthesize and release various neuropeptides, mediating both short - and long-term effects on brain development. And it may also be involved in regulating metabolism, energy balance, body weight, and social behavior. Neuropeptides released by neurons in the hypothalamus play a major role in regulating feeding, acting on the hypothalamus, and other appetite regulatory centers throughout the brain.

Hypothalamic neuropeptides or hypothalamic-releasing hormones typically include oxytocin and vasopressin. Oxytocin and arginine vasopressin (AVP) are neuropeptides synthesized in the hypothalamus and secreted from the posterior pituitary gland, thus placing them in the category of hypothalamic neuropeptides. Both oxytocin and vasopressin significantly affect social processes in mammals. There is growing concern about these molecules and their receptors, which offer potential treatments for social disorders such as neurodevelopmental disorders, including autism spectrum disorders. Many behavioral genetics studies have shown a clear association between these peptides and an individual's ability to socialize.

Fig 5. Structure of Oxytocin and Vasopressin

At the earliest stages of its discovery, oxytocin was thought to play an important role in stimulating uterine contractions and speeding up the production process, as well as in postpartum milk production. In addition to being a neuropeptide, oxytocin also has peripheral effects as a hormone released into the bloodstream. Research has examined oxytocin's role in a variety of behaviors, including orgasm, social approval, partnership, anxiety, in-group bias, situational lack of honesty, autism, and maternal behavior. Oxytocin is also thought to play an important role in social learning. There are indications that oxytocin may help reduce noise in the brain's auditory system, increase the perception of social cues, and support more targeted social behavior. It can also enhance the reward response.

Oxytocin produces antidepressant-like effects in animal models of depression and the lack of oxytocin may be related to the pathophysiology of human depression. Carbetocin is a close analog of oxytocin and oxytocin receptor agonist and shows an antidepressant effect in animals. Therefore, oxytocin or its analogs have the potential to develop antidepressants.

References

1. Gerard, N. P. et al. Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones. Biochemistry. 1991, 30, 10640–10646.
2. Matsuzaki, M. et al. Oxytocin: a therapeutic target for mental disorders. The Journal of Physiological Sciences. 2012, 62, 441–444.
3. Matsushita, H. et al. Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation. Neuroscience. 2012, 200, 13–18