| Many peptides act as neurotransmitters
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| It is an open question whether all of the peptides that have been described are really true neurotransmitters. Nevertheless, more than 50 small peptides have now been shown to influence neural function. All known peptide receptors are metabotropic and coupled to G-proteins (see Chapter 38), and so act comparatively slowly. There are no specific uptake pathways or degradative enzymes, and the main route of disposal is simple diffusion followed by cleavage by a number of peptidases in the extracellular fluid. This allows a peptide to affect a number of neurons before it is finally degraded.
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| Vasoactive intestinal peptide (VIP) is one of many peptides that affect the function of the intestine through the enteric nervous system. It was originally described as a gut hormone that affected blood flow and fluid secretion, but it is now known to be an important enteric neuropeptide, inhibiting smooth muscle contraction. It also causes vasodilatation in several secretory glands, and potentiates stimulation by ACh.
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| Many neuropeptides belong to multigene families
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The opioid peptides (receptors) provide a good example of a multigene family. They are the endogenous ligands for opiate analgesics such as morphine and codeine. The control of pain is complex, and opioid peptides and receptors are found both in the spinal cord and in the brain itself. There are at least three genes that code for these peptides, and each contains the sequences for several active molecules:
- pro-opiomelanocortin contains β-endorphin, which binds to opiate μ-receptors, and also adrenocorticotropic hormone (ACTH) and the melanocyte-stimulating hormones (MSH), which are pituitary hormones (see Chapter 37);
- proenkephalin A contains the sequences for Met- and Leu-enkephalins, which bind to δ-receptors and are involved in pain regulation at local levels in the brain and spinal cord;
- prodynorphin contains sequences for dynorphin and several other peptides, which bind to the κ class of receptors.
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| Opiates also affect pleasure pathways in the brain, which explains their euphoriant effects, and they also have side effects, such as respiratory depression, that limit their use. In excess, they cause contraction of the muscles of the eye, resulting in 'pinpoint' pupils. It has been shown that endorphins are released after strenuous exercise, giving the so-called 'jogger's high'. It is hoped that increased knowledge of the specific opioid receptors and neural opioid pathways will allow the development of analgesics with fewer side effects and less likelihood of abuse.
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| Substance P is another example of a member of a multigene family, known as the tachykinin family. It is present in afferent fibers of sensory nerves and transmits signals in response to pain. It is also involved in so-called neurogenic inflammation stimulated by nerve impulses, and is an important neurotransmitter in the intestine.
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| Neuropeptides can act as neuromodulators
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| Some peptides do act as true neurotransmitters, but they have many other actions in addition. They often alter the action of other transmitters, acting as neuromodulators but having no action of their own. For instance, VIP enhances the effect of ACh on salivary gland secretion in cat submandibular glands (glands located under the jawbone) by causing vasodilatation and potentiating the cholinergic component. NPY causes inhibition of the release of norepinephrine at autonomic nerve terminals, acting at presynaptic autoreceptors, and potentiates the action of norepinephrine in certain arteries while having only weak actions itself. Opioid peptides also are capable of modulating neurotransmitter release.
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