Sympathetic nervous system neurons

NET (SLC6A2) Noradre-naline, dopamine 1 CNS noradrenergic neurons (emanate from locus coeruleus and lateral tegmental area), sympathetic nervous system Clearance of interstitial neuro-transmitter, reuptake into neurons... 

Adrenal medulla. Derived from neural crest tissue, the adrenal medulla forms the inner portion of the adrenal gland. It is the site of production of the catecholamines, epinephrine and norepinephrine, which serve as a circulating counterpart to the sympathetic neurotransmitter, norepinephrine, released directly from sympathetic neurons to the tissues. As such, the adrenal medulla and its hormonal products play an important role in the activity of the sympathetic nervous system. This is fully discussed in Chapter 9, which deals with the autonomic nervous system. 

Known most famously for their part in the fight or flight response to a threat, challenge or anger, adrenaline (epinephrine) and dopamine from the adrenal medulla and noradrenaline (norepinephrine), mainly from neurones in the sympathetic nervous system are known collectively as catecholamines. Synthesis follows a relatively simple pathway starting with tyrosine (Figure 4.7). 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

Adrenaline is the main hormone released from the adrenal medulla. The glandular cells in this structure correspond to the second, postganglionic neuron of the sympathetic nervous system. Furthermore, adrenaline can be found in chromaffin cells in various tissues. For the better understanding of the function of noradrenaline it is important to realize that this substance, as a neuronal transmitter, affects only the innervated target structure, that is it acts mainly locally. Among these effects are the activation of the musculus dilatator to widen the pupillae in response to a reduced light intensity, an increase in heart rate as a response to a blood pressure drop due to a reduction of the peripheral resistance or constriction... 

The preganglionic neurons of the sympathetic nervous system have their cell bodies in the thoracic and lumbar regions of the spinal cord, termed the thoracolumbar division. The preganglionic neurons of the parasympathetic division have their cell bodies in the brainstem and in the sacral region of the spinal cord, termed the craniosacral division. The cranial part of the parasympathetic nervous system innervates structures in the head, neck, thorax, and abdomen (e.g., the stomach, part of the intestines, and pancreas). The cranial parasympathetic fibers leave the CNS in the oculomotor, facial, glos-... 

B. Smooth muscle relaxation is primarily under the influence of the sympathetic nervous system. This control is primarily through P2-receptors. Pi-Receptors are found chiefly in the heart and adipose tissue. tti-Receptors are at postjuctional sites on tissues innervated by adrenergic neurons. 2-Receptors are usually presynaptic, while Ps-adreno-ceptors appear to be primarily in adipose tissue. 

A unique property of bretylium as an antiarrhythmic agent is its positive inotropic action. This effect, related to its actions on the sympathetic nervous system, includes an initial release of neuronal stores of norepinephrine followed shortly by a prolonged period of inhibition of direct or reflex-associated neuronal norepinephrine release. The onset of bretylium-induced hypotension is delayed 1 to 2 hours because the initial catecholamine release maintains arterial pressure before this time. 

There is good evidence that the facilitation of peripheral sympathetic nervous system transmission prcxluced by the amphetamines also occurs in the CNS.The possibihty that amphetamines act indirectly (i.e., by releasing monoamines) at monoaminergic synapses in the brain and spinal cord seems likely. However, amphetamine has effects beyond displacement of catecholamines these include inhibition of neuronal amine uptake, direct stimulation of dopamine and serotonin receptors, antagonism of catecholamine action at certain subtypes of adrenoceptors, and inhibition of monoamine oxidase. Interestingly, none of these actions explains the therapeutic benefit of the amphetamines in hyperkinetic children. 

Both the parasympathetic and sympathetic nervous systems provide extrinsic gastrointestinal innervation. Parasympathetic stimulation increases muscle contraction of the gut, while sympathetic stimulation inhibits contractions. Stimulation of either a- or 13-adrenoceptors will result in inhibition of contractions. The intramural nervous system consists of a myenteric (Auerbach s) plexus between the circular and longitudinal muscle areas and a submucosal (Meissner s) plexus between the muscularis mucosa and the circular muscle layers. These two plexuses contain stimulatory cholinergic neurons. 

The chemical transmitters may be small molecules— notably acetylcholine, norepinephrine, epinephrine, serotonin, dopamine, or histamine. Acetylcholine and norpeinephrine are the dominant neurotransmitters in the parasympathetic and sympathetic nervous systems, respectively. Dopamine and serotonin are employed primarily in the central nervous system. Neurotransmitters may also be more complex peptides (small proteins) such as substance P, vasopressin, endorphins, and enkephalins. The latter agents are of particular importance to our considerations of opium since they represent the endogenous opiates—agents that exist within the body whose actions are mimicked by exogenous, or outside, agents such as morphine, heroin, codeine, and so on. These neurotransmitters serve to convey information between neurons across the synaptic cleft (the junction where two neurons meet) or at the neuroeffector junction (the site between neuron and an innervated organ such as muscle or secretory gland). 

Each neuron has specific synthetic machinery that enables it to both synthesize and eliminate a specific neurotransmitter. For example, neurons of the sympathetic nervous system employ norepinephrine and epinephrine as their transmitters. Other neurons, particularly in the central nervous system, employ dopamine as their transmitter. Dopamine is a particularly important transmitter for a variety of neuronal functions. Its loss is associated with Parkinson disease, and it is a critical agent in the mediation of pleasure and reward processes. Dopamine, due to its association with pleasurable sensations, is widely implicated in the actions of a number of drugs of abuse, including cocaine, opiates, and methamphetamines. 

NPY is one of the most abundant neuropeptides in both the central and peripheral nervous systems. In the sympathetic nervous system, NPY is frequently localized in noradrenergic neurons and apparently functions both as a vasoconstrictor and as a cotransmitter with norepinephrine. Peptide YY and pancreatic polypeptide are both gut endocrine peptides. 

Cocaine inhibits the presynaptic reuptake of the neurotransmitters norepinehrine, serotonin, and dopamine at synaptic junctions. This results in increased concentrations in the synaptic cleft. Since norepinephrine acts within the sympathetic nervous system, increased sympathetic stimulation is produced. Physiological effects of this stimulation include tachycardia, vasoconstriction, mydriasis, and hyperthermia.3 CNS stimulation results in increased alertness, diminished appetite, and increased energy. The euphoria or psychological stimulation produced by cocaine is thought to be related to the inhibition of serotonin and dopamine reuptake. Cocaine also acts as a local anesthetic due to its ability to block sodium channels in neuronal cells.3... 

As suggested in Chapter 6 Introduction to Autonomic Pharmacology, the Mi receptor subtype appears to be located on central nervous system neurons, sympathetic postganglionic cell bodies, and many presynaptic sites. M2 receptors are located in the myocardium, smooth muscle organs, and some neuronal sites. M3 receptors are most common on effector cell membranes, especially glandular and smooth muscle cells. 

Presynaptic neuropeptide Y receptors have been identified in the sympathetic, parasympathetic and enteric nervous system, on sensory neurones, and on many sites in the CNS they inhibit the release of 11 different transmitters (Table 3). Most presynaptic neuropeptide Y receptors are heteroreceptors, but some serve as autoreceptors, both in the sympathetic nervous system (pig spleen and kidney) and the brain (rat hypothalamus) (Table 3). Marked species differences occur. For example, Y2 receptors inhibit the sympathetically mediated tachycardia, the vagally mediated bradycardia, and the vagally mediated bronchoconstriction in the guinea pig but not in the rabbit (Serone et al. 1999 Abrahamsson 2000). Moreover, Y2 receptors inhibit noradrenaline release in the guinea pig carotid but not femoral artery, and conversely inhibit noradrenaline release in the rat femoral but not carotid artery (Potter and Tripovic 2006). 

The most well known of the naturally occurring phenethylamine derivatives (Table I) are the transmitters of the sympathetic nervous system, epinephrine, norepinephrine, and dopamine. All these compounds are 3,4-dioxygenated in the aromatic nucleus and are collectively known as the catecholamines. Norepinephrine is the transmitter of most sympathetic postganglionic fibers, dopamine is the predominant transmitter of the mammalian extrapyramidal system and of several mesocortical and mesolimbic neuronal pathways, and epinephrine is the major hormone of the adrenal medulla (363). The literature that has accumulated on the action of these compounds in higher animals is enormous. Metanephrine and normetanephrine are known from animals as deactivated metabolites of epinephrine and norepinephrine that result from the action of the enzyme catechol O-methyltransferase (364). 

Baroreflexes involving the sympathetic nervous system are responsible for the rapid moment-to-moment regulation of blood pressure. A fall in blood pressure causes pressure-sensitive neurons (baroreceptors in the aortic arch and carotid sinuses) to send fewer impulses to cardiovascular centers in the spinal cord. This prompts a reflex response of increased sympathetic and decreased parasympathetic output to the heart and vasculature, resulting in vasoconstriction and increased cardiac output. These changes result in a compensatory rise in blood pressure (Figure 19.3, and Figure 3.5, see p. 31). 

Usually excitatory, except for some parasympathetic nerve endings where it is inhibitory (such as the effect on the heart by the vagus nerve). Secreted by many neurons, including those in the motor area of the brain, basal ganglia, skeletal muscle motor neurons, all preganglionic autonomic nervous system neurons, all postganglionic parasympathetic neurons, and some postganglionic sympathetic neurons. 

---