Nervous system
Two major subdivisions: |
1. Central nervous system |
(CNS; the brain and spinal cord) |
2. Peripheral nervous system |
(PNS; neuronal tissues outside the CNS). |
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Anatomically divided into the: |
1. Autonomic |
2. Somatic |
Autonomic nerves can also influence cancer development and progression.
ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM
Two major portions: |
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1. Sympathetic (thoracolumbar) division |
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2. Parasympathetic (traditionally “craniosacral"). |
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a. The sympathetic preganglionic fibers leave CNS through the thoracic, lumbar, and sacral spinal nerves.
b. The parasympathetic preganglionic fibers leave the CNS through the cranial nerves (3rd, 7th, 9th, and 10th).
for Sympathetic
PARAVERTEBRAL |
PREVERTEBRAL |
Most thoracic and lumbar sympathetic preganglionic fibers are SHORT and terminate in ganglia located in here. |
Most of the remaining sympathetic preganglionic fibers are somewhat LONGER and terminate |
*Short |
*Longer |
For PARASYMPATHETIC:
-Preganglionic parasympathetic fibers terminate in parasympathetic ganglia located outside the organs innervated:
1.Ciliary
2. Pterygopalatine
3. Submandibular
4. Otic ganglia.
ANS vs SNS
Autonomic nervous system (ANS) |
Somatic nervous system (SNS) |
It is concerned with control and integration of visceral functions necessary for life such as cardiac output, blood flow distribution, and digestion. |
Motor portion of the somatic subdivision is largely concerned with movement, respiration, and posture. |
Largely independent (autonomous) in that its activities are not under direct conscious control. |
Both have important afferent (sensory) inputs that provide information regarding the internal and external environments and modify motor output through reflex arcs of varying complexity. |
Vagus nerve, also influences immune function and some CNS functions such as seizure discharge.
Major difference CNS vs ANS
Presence of a GANGLION in ANS |
Differentiating divisions of ANS
a. Sympathetic Nervous System |
b. Parasympathetic Nervous System |
c. Enteric Nervous System |
-Prepares body for intense "FIGHT OR FLIGHT" response. |
-Relaxes body and inhibits or slows many high energy functions |
-Large and highly organized collection of neurons located in walls of GI system. |
FIGHT OR FLIGHT (F/F |
REST OR DIGEST |
THIRD DIVISION OF ANS |
- |
- |
Control motor activity of colon |
ENS includes:
1. MYENTERIC PLEXUS or the Plexus of Auerbach
2. SUBMUCOUS PLEXUS or the Plexus of Meissner
ENS neuronal networks
1. Myenteric plexus (the plexus of Auerbach) |
2. Submucous plexus (the plexus of Meissner). |
Neurotransmitters
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Location |
NT |
Preganglionic |
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Ach |
Postganglionic |
a. Parasympathetic |
Ach |
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b. Sympathetic |
NE & few locations Ach |
Receptors
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Type |
Parasympathetic |
N |
Excitatory |
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M |
Excitatory or Inhibitory |
Sympathetic |
Alpha |
Excitatory |
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Beta |
Excitatory or Inhibitory |
Figure 6–1
Parasympathetic |
Cardiac and smooth muscle, gland cells, nerve terminals |
Ach/M |
Sympathetic |
Sweat glands |
Ach, M |
Sympathetic |
Cardiac and smooth muscle, gland cells, nerve terminals |
NE, α, β |
Sympathetic |
Renal vascular smooth muscle |
NE, D/α, D1 |
Somatic |
Skeletal muscle |
Ach, N |
TABLE 6–1
Substance |
Functions |
Acetylcholine (ACh) |
The primary transmitter at ANS ganglia, at the somatic neuromuscular junction, and at parasympathetic postganglionic nerve endings. A primary excitatory transmitter to smooth muscle and secretory cells in the ENS. Probably also the major neuron-to-neuron (“ganglionic”) transmitter in the ENS. |
Adenosine triphosphate (ATP) |
Acts as a transmitter or cotransmitter at many ANS-effector synapses. |
Calcitonin gene-related peptide (CGRP) |
Found with substance P in cardiovascular sensory nerve fibers. Present in some secretomotor ENS neurons and interneurons. A cardiac stimulant. |
Cholecystokinin (CCK) |
May act as a cotransmitter in some excitatory neuromuscular ENS neurons. |
Dopamine |
A modulatory transmitter in some ganglia and the ENS. Possibly a postganglionic sympathetic transmitter in renal blood vessels. |
Enkephalin and related opioid peptides |
Present in some secretomotor and interneurons in the ENS. Appear to inhibit ACh release and thereby inhibit peristalsis. May stimulate secretion. |
Galanin |
Present in secretomotor neurons; may play a role in appetite-satiety mechanisms. |
GABA (γ-aminobutyric acid) |
May have presynaptic effects on excitatory ENS nerve terminals. Has some relaxant effect on the gut. Probably not a major transmitter in the ENS. |
Gastrin-releasing peptide (GRP) |
Extremely potent excitatory transmitter to gastrin cells. Also known as mammalian bombesin. |
Neuropeptide Y (NPY) |
Found in many noradrenergic neurons. Present in some secretomotor neurons in the ENS and may inhibit secretion of water and electrolytes by the gut. Causes long-lasting vasoconstriction. It is also a cotransmitter in some parasympathetic postganglionic neurons. |
Nitric oxide (NO) |
A cotransmitter at inhibitory ENS and other neuromuscular junctions; may be especially important at sphincters. Cholinergic nerves innervating blood vessels appear to activate the synthesis of NO by vascular endothelium. NO is not stored, it is synthesized on demand by nitric oxide synthase, NOS; see Chapter 19. |
Norepinephrine (NE) |
The primary transmitter at most sympathetic postganglionic nerve endings. |
Serotonin (5-HT) |
An important transmitter or cotransmitter at excitatory neuron-to-neuron junctions in the ENS. |
Substance P, related tachykinins |
Substance P is an important sensory neurotransmitter in the ENS and elsewhere. Tachykinins appear to be excitatory cotransmitters with ACh at ENS neuromuscular junctions. Found with CGRP in cardiovascular sensory neurons. Substance P is a vasodilator (probably via release of nitric oxide) |
Vasoactive intestinal peptide (VIP) |
Excitatory secretomotor transmitter in the ENS; may also be an inhibitory ENS neuromuscular cotransmitter. A probable cotransmitter in many cholinergic neurons. A vasodilator (found in many perivascular neurons) and cardiac stimulant. |
CHOLINERGIC TRANSMISSION
STEP 1: Synthesized by Choline Acetyltransferase (ChAT) |
-Acetyl-CoA synthesized in mitochondria |
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Choline transported into the neuron |
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Blocked by hemicholinium (blocks uptake of choline) |
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STEP 2: Ach transported into SMALL CLEAR VESICLES |
Transporter can be blocked by vesamicol (prevents storage or depletes transmitter storage) |
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STEP 3: Release of transmitter is Calcium-dependent |
-triggered by action potentials |
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-ACh release blocked by botulinum toxin |
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STEP 4: ACh binds to receptors |
(cholinoceptors) |
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STEP 5: Catabolized by acetylcholinesterase (AChE) |
-breaks ACh into choline and acetate |
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terminate action of transmitter |
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half-life of ACh is very short |
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AChE in other tissues (eg. RBC) |
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Butyrylcholinesterase (pseudo-) |
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ChAT and AChE used during synthesis and degradation of ACh.
5 KEY FEATURES OF NEUROTRANSMITTER FUNCTION
1. Synthesis |
2. Storage |
3. Release |
4. Termination Of Action Of The Transmitter |
5. Receptor Effects |
Acetylcholine Synthesis
1. ACh made from choline + acetyl CoA |
2. In synaptic cleft, ACh is rapidly broken down by enzyme Acetylcholinesterase |
3. Choline is transported back into axon terminal and used to make more ACh. |
STEPS in ADRENERGIC TRANSMISSION
STEP 1 |
Synthesis of catecholamines (Dopamine, NE) |
STEP 2 |
Uptake into storage vesicle |
STEP 3 |
Release of NT |
STEP 4 |
Binding to receptor |
STEP 5/6 |
Degradation of NE |
Termination of NORADRENERGIC TRANSMISSION
1. Simple diffusion away from receptor site (with eventual metabolism in plasma or liver |
2. Reuptake into the nerve terminals by NET or into perisynaptic glia or other cells |
BIOSYNTHESIS OF CATECHOLAMINES
1. Tyrosine convert to DOPA by Tyrosine hydroxylase |
can be inhibited by metyrosine (a tyrosine analog) |
2. DOPA convert to Dopamine by Dopa decarboxylase |
- |
3. Dopamine convert to NE by Dopamine-β-hydroxylase |
In most sympathetic postganglionic neurons, NE is the final product) |
4. NE convert to Epinephrine by Phenylethanolamine-N-methyltransferase |
Methylated form |
~ |
Additional
a. Tyrosine metabolized by L-Amino acid decarboxylase to form TYRAMINE (the product of metabolism of tyrosine).
b. Tyramine metabolized by Dopamine-β-hydroxylase to Octopamine
c. Octopamine metabolized by hydroxylase (from the liver) to form NE
WAYS OF STOPPING NEUROTRANSMITTER
1. DIFFUSION |
- |
2. DEGRADATION |
metabolic enzyme process (eg. AChE metabolize ACh) |
3. REUPTAKE |
into the noradrenergic neuron/ adrenergic neuron |
NT CHEMISTRY OF THE ANS
CHOLINERGIC FIBERS |
NORADRENERGIC (ADRENERGIC) FIBERS |
releasing Ach (Acetylcholine) |
release Norepinephrine (NE)/ Noradrenaline |
AUTONOMIC RECEPTOR (NT, R)
PARASYMPATHETIC |
SYMPATHETIC |
NT: ACh (Cholinoceptors) |
NT: NE (Adrenoceptors) |
R=N/M |
R= α,β, D |
Nicotinic receptors= NN/NM |
α= 1/2 |
Muscarinic receptors= M1 to M5 |
β= 1-3 |
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D= (D1-D5) |
AUTONOMIC RECEPTOR
Alkaloids |
Muscarine and Nicotine |
The sensory fibers in the nonadrenergic, noncholinergic systems are probably better termed “sensory-efferent” or “sensorylocal effector” fibers because, when activated by a sensory input, they are capable of releasing transmitter peptides from the sensory ending itself*, from local axon branches, and from collaterals that terminate in the autonomic ganglia.
These peptides are potent agonists in many autonomic effector tissues.
METABOLISM OF CATECHOLAMINES by COMT & MAO
Catecholamines |
COMT/MAO |
Product 1 |
COMT/MAO |
Product 2 |
EPINEPHRINE |
=MAO |
Dihydroxymandelic acid |
COMT |
3-Methoxy-4-hydroxymandelic acid (VMA) |
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=COMT |
Metanephrine |
MAO |
3-Methoxy-4-hydroxymandelic acid (VMA) |
NE |
=MAO |
Dihydroxymandelic acid |
COMT |
3-Methoxy-4-hydroxymandelic acid (VMA) |
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=COMT |
Normetanephrine |
MAO |
3-Methoxy-4-hydroxymandelic acid (VMA) |
DOPAMINE |
=MAO |
Dihydroxyphenylacetic acid |
COMT |
Homovanillic acid |
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=COMT |
3-Methoxytyramine |
MAO |
Homovanillic acid |
Read
Read Katzung CH. 6 (P.99) TABLE 6-2 Major autonomic receptor types |
FUNCTIONAL ORGANIZATION OF AUTONOMIC ACTIVITY
A. Integration of Cardiovascular Function
Mean arterial pressure |
the primary controlled variable in cardiovascular function |
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-changes in any variable contributing to mean arterial pressure (eg, a drug-induced increase in peripheral vascular resistance) evoke powerful homeostatic secondary responses |
Homeostatic response |
may be sufficient to reduce the change in mean arterial pressure and to reverse the drug’s effects on heart rate. |
Example: Slow infusion of NE
Increased baroreceptor activity causes the decreased central sympathetic outflow and increased vagal outflow.
Net effect of ordinary pressor doses of norepinephrine in a normal subject is to produce a marked increase in peripheral vascular resistance.
An increase in mean arterial pressure, and often, a slowing of heart rate.
NEGATIVE FEEDBACK RESPONSE is present.
B. Presynaptic Regulation
Autoreceptors |
Presynaptic receptors that respond to the primary transmitter substance released by the nerve ending |
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usually inhibitory, but in addition to the excitatory β receptors on noradrenergic fibers, many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors. |
Heteroreceptors |
respond to many other substances |
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activated by substances released from other nerve terminals that synapse with the nerve ending. |
Principle of negative feedback control is also found at the presynaptic level of autonomic function.
-have been shown to exist at most nerve endings
C. Postsynaptic Regulation
Can be considered from two perspectives: |
1. Modulation by previous activity at the primary receptor |
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2. Modulation by other simultaneous events. |
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FIRST MECHANISM |
Up-regulation and down-regulation are known to occur in response to decreased or increased activation, respectively, of the receptors. |
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Extreme form of up-regulation occurs after denervation of some tissues, resulting in denervation supersensitivity of the tissue* to activators of that receptor type. |
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ex: Nicotinic receptors are normally restricted to the end plate regions underlying somatic motor nerve terminals. |
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ex: Prolonged administration of large doses of reserpine, a norepinephrine depleter, can cause increased sensitivity of the smooth muscle and cardiac muscle effector cells |
SECOND MECHANISM |
Involves modulation of the primary transmitter-receptor event by events evoked by the same or other transmitters acting on different postsynaptic receptors. |
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ex: Ganglionic transmission |
Postganglionic cells are activated (depolarized) due to binding of an appropriate ligand to a neuronal nicotinic (NN) acetylcholine receptor.
Resulting:
a. Fast excitatory postsynaptic potential (EPSP) evokes a propagated action potential if threshold is reached.
Continued
b. Often followed by a small and slowly developing but longer-lasting hyperpolarizing afterpotential—a slow inhibitory postsynaptic potential (IPSP).**
1. Hyperpolarization involves opening of potassium channels by M2 cholinoceptors.
2. Small, slow excitatory postsynaptic potential caused by closure of potassium channels linked to M1 cholinoceptors.
3. Late, very slow EPSP may be evoked by peptides released from other fibers.
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