Central neuromodulators

CGRP is widely distributed throughout the peripheral and central nervous systems and is found ia sensory neurons and ia the autonomic and enteric nervous systems. In many iastances CGRP is co-localized with other neuroregulators, eg, ACh ia motor neurons, substance P, somatostatin, vasoactive intestinal polypeptide (VIP), and galanin ia sensory neurons. It is also present ia the CNS, with ACh ia the parabigeminal nucleus and with cholecystokinin (CCK) ia the dorsal parabrachial area. CGRP functions as a neuromodulator or co-transmitter. 

As a neurotransmitter in the sensory nervous system, high levels of substance P are found in the dorsal horn of the spinal cord as well as in peripheral sensory nerve terminals. However, substance P also plays a significant role as a neuromodulator in the central, sympathetic, and enteric nervous system. NKA and NKB are also localized selectively in the CNS. 

Berry MD (2004) Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem 90 257—271... 

Nitric oxide (NO) A poisonous greenhouse gas that also serves as a neuromodulator in the central and peripheral nervous systems. 

The billions of individual neurones within the nervous system communicate with each other and with the target tissues via chemical neurotransmitters. There is a bewildering array of chemicals which act as neurotransmitters or neuromodulators in peripheral or central nervous systems. These compounds fall into four major groups and some examples are shown in Table 4.3. 

There is now evidence that the mammalian central nervous system contains several dozen neurotransmitters such as acetylcholine, noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), together with many more co-transmitters, which are mainly small peptides such as met-enkephalin and neuromodulators such as the prostaglandins. It is well established that any one nerve cell may be influenced by more than one of these transmitters at any time. If, for example, the inhibitory amino acids (GABA or glycine) activate a cell membrane then the activity of the membrane will be depressed, whereas if the excitatory amino acid glutamate activates the nerve membrane, activity will be increased. The final response of the nerve cell that receives all this information will thus depend on the balance between the various stimuli that impinge upon it. 

This confusion is complicated even further by receptor multiplicity. Consider, for example, the presence of opiate receptors in both the central nervous system and the ileum. Not only do they have different roles as participants in neuromodulation and peristaltic... 

Taurine (2-aminoethanesulfonic acid 4.235) is an inhibitory neurochemical that probably acts primarily as a neuromodulator rather than a neurotransmitter. It is formed from cysteine, and its accumulation can be prevented by the cardiac glycoside ouabain. Although receptor sites and specific actions cannot be elucidated without an antagonist, taurine has been implicated in epilepsy and, potentially, in heart disease. There are a large number of physiological effects attributed to taurine, among them cardiovascular (antiarrythmic), central (anticonvulsant, excitability modulation), muscle (membrane stabilizer), and reproductive (sperm motility factor) activity. Analogs of taurine, phthalimino-taurinamide (4.236) and its iV-alkyl derivatives, are less polar than taurine and are potent anticonvulsant molecules. 

In 1974, Liebeskind showed the existence of a central pain-suppressive system, and was able to produce analgesia by electrical stimulation of the periventricular gray matter within the brain. This electroanalgesia could be reversed by opiate antagonists, and showed a cross-tolerance with morphine-induced analgesia. These results indicated the existence of a neuronal system that uses an endogenous neuromodulator or neurotransmitter with opiate-like properties. 

A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS see Table 6-1. ACh, acetylcholine AC, absorptive cell CM, circular muscle layer EC, enterochromaffin cell EN, excitatory neuron EPAN, extrinsic primary afferent neuron 5HT, serotonin IN, inhibitory neuron IPAN, intrinsic primary afferent neuron LM, longitudinal muscle layer MP, myenteric plexus NE, norepinephrine NP, neuropeptides SC, secretory cell SMP, submucosal plexus. 

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 neurotransmission. When administered into the peripheral circulation, it causes vasodilation, hypotension, 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. 

The first observation was the more unexpected because we were under the mistaken impression that the locus coeruleus should turn on, not off, in REM. But once we realized that we had the role of norepinephrine backwards, it was not difficult to find other REM-off cells—not only in the locus coeruleus, but also in the raphe nuclei—and to see that both of the pontine aminergic neuromodulators supported waking just as any extension of Hess s principles would suggest. Even the central sympathetic system works toward ergotrophic ends. Eor sleep to occur, this system must first be deactivated to allow NREM sleep to develop, and then actively suppressed, to allow REM to develop. 

We don t know the basis of this loss of temperature control, but we do know that REM sleep is itself associated with failure of the central thermostat, and we know that REM sleep deprivation also causes a loss of temperature. A unifying hypothesis is that any condition that potentiates REM sleep physiology may also compromise the central regulation of body temperature. Relevant to this hypothesis is the fact that the two brain stem aminergic neuromodulators that are inactivated in REM sleep are active in responding to thermal stress. 

The central idea here is that the neuromodulators set the mode of the... 

VIP is widely distributed in the central and peripheral nervous systems where it functions as a neurotransmitter or neuromodulator. It is also present in several organs including the gastrointestinal tract, heart, lungs, kidneys, and thyroid gland. Many blood vessels are innervated by VIP neurons. VIP is present in the circulation but does not appear to function as a hormone. 

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