2. • Introduction
• History of neurons and
neurotransmission
• Scientists and their experiments
• Introduction to Autonomic
nervous system
• ANS Receptor functions
• Physiological Effects of ANS
• References
3. Neurons And Synapses
• Until 1838 – Globules in the
tissue.
• In Retrospect – 3 long steps.
1st Step : Discovery of
neuron, dendrites and axons.
2nd Step : Neuron doctrine
3rd Step : Discovery of
synapse and chemical
transmission
4.
5. 1st –Neurons, Dendrites and Axons
1. Anton Van Leeuwenhoek (1632-
1723)
Built notable microscope, able to
slice specimens of cow optical
nerve(1674).
2. Robert Hooke (1635-1703)
Used the word cell to describe
smaller elements.
7. 4.Jan Evangelista Purkinje
(1787-1869)
• Studied nuerons in
cerebellum, coined term
protoplasm.
• Described drop like cells
have elongated fibre
like processes in their
vicinity -1837.
• Proposed that there
should be some
connection between
these processes and
nucleated cell bodies.
8. 5. Robert Remak (1815-1865)
• Described nervous tissue is
entirely suffused with very fine
and complex mesh of
filamentous processes(1836).
• Described existence of two
types of nerve processes-
myelinated and unmyelinated
6. Theodor schwann(1810-
1882)
• Described myelin sheath
covers nerve fibres
• Organic tissues are composed
of cells
9. 7.Alfonso Corti (1822-1876)
• Obtained carmine red bright strain from
insects(1850).
• Become famous for his descriptions of inner ear
organ of hearing which bears his name.
8. Joseph Von Gerlach (1820-
1886)
• Obtained clearest images of
neural cells and its
filaments.
• Improved fixatives for
nervous tissue
10. 9. Otto Friedrich Karl Deiters (1834-
1883)
• Developed micro dissection
technique.
• Isolated neurons under microscope
• Found two different branching
processes attached to soma
Tree like full fine branching -
protoplasmic extensions.
Long fibre- axis cylinder.
11. 20 Years Later…
Protoplasmic extensions Dendrites –
Wilhelm His(1889)
Axis cylinder Axons – Rudolph A Von
Kolliker(1896)
Cell Neuron – Wilhelm Von
Waldeyer(1891)
12. Second Big Step: Neuron
Doctrine
SANTIAGO RAMON Y
CAJAL (1852-1934)
CAMILLO GOLGI
(1843- 1926)
13. 10. Camillo Golgi(1843-1926)
• Specific staining technique – The reazione
nera (The black reaction).
• Exceedingly clear and well contrasted
picture of neuron against an yellow
background.
• Technique was unreliable as it didn’t stain
all neurons.
• Defended Reticularist hypothesis
14. 11. Santiago Ramon Y Cajal (1852-1934)
• Improved Golgi technique - Used younger brains
and brains of birds.
• Saw individual neurons and stated that no
continuity between axons and neurons.
• Wilhelm His and Cajal gave embryological
evidence about growth of neurons.
• Action currents propagate in neuronal network in
direction of dendrites to axons/soma – Dynamic
Polarisation.
• Increase in number of synapses could be
mechanism of learning and memory.
15. THE NEURONAL DOCTRINE HAD
FOUR TENETS
The neuron is the structural and functional unit
of nervous system.
Neurons are individual cells, which are not
continues to other neurons.
The neuron has three parts : Dendrites, Soma,
Axon.
Conduction takes place in direction from
dendrites to soma, to the end arborization of the
axon.
16.
17. 3rd STEP:Discovery of SYNAPSE &
Neurotransmission
12. George Palade -
Morphological proof of
synapse (1954).
13.Emil Dubois Raymond -
Existence of synapse, could
be electrical or chemical
(1846).
Unidirectional flow of
information.
Excitatory and
inhibitory synapses.
Delay in transmission.
18. 14. John Newport Langley
(1852-1925)
Coined the term autonomic
nervous system.
Discovered function of
sympathetic and
parasympathetic components.
Laid foundation for humoral
neurotransmission and concept
of receptor substance.
Action of jaborandi
(Pilocarpine) on heart - 1875
19. Deduced that pilocarpine slowed heart rate by
acting on inhibitory fibres in vagus nerve to the heart,
stimulated salivation.
With Dickinson Nicotine has ganglion blocking
property – 1889.
With sherrington established distribution of
sympathetic fibres innervating skin and relation with
sensory fibres of associated spinal nerve- 1890.
Leewandowsky(1889) and Langley(1901) noted
independently the similarity between effects of
injection of extract of adrenal gland and stimulation of
sympathetic nerves.
20. 15. Sir Charles S
Sherrington (1852-1952)
Coined the term
SYNAPSE- To Clasp
Physiology of simple and
complex motor reflexes –
concept of integrative action
of the nervous system.
Interplay of central
excitation and inhibition are
fundamental for the
integration – Awarded Nobel
prize 1921.
21. 16. Thomas Renton Elliot
(1877-1961)
Concept of chemical neuro
transmission.
Demonstrated effects of
sympathetic innervation and
exogenous epinephrine on
bladder.
Adrenaline chemical stimulant
liberated on each occasion when
impulse arrived at the periphery –
1904.
Postulated epinephrine acted at
myoneural junction not at the
nerve endings or muscle fibres.
22. 17. Walter Ernest Dixon(1871-
1938)
Interested in effect of drugs on
nerves & nerve endings
Opposed Erhlich statement and
showed that strychnine was not
bound , while it acted at the site
Investigated action of vagus
nerve on heart
Argued against retention of heroin in clinical
practice
Practiced to induce labour, showed that ovarian
secretion caused uterine contraction via an indirect
effect by release of pituitrin
23. 18. Sir Henry Hallet Dale(1875-1968)
• Distinguished muscarinic and nicotinic receptor
• First to identify acetylcholine(1914)
• Proposed term cholinergic and adrenergic
synapses
• Dale’s law: each neuron releases only one type of
neurotransmitter.
• Dale’s vasomotor reversal phenomenon: only fall
in BP occurs when an alpha blocker is given before
injecting adrenaline. He demonstrated in cats and
used ergot alkaloids as alpha blockers.
24. Two kinds of effects produced by Ach.
A. Ach causes a fall in BP due to vasodilation.
B. A larger dose of Ach also produces bradycardia, further reducing BP.
C. Atropine blocks the effect of Ach in lowering BP.
D. Still under the influence of atropine, a much larger dose of Ach causes a rise in BP and
tachycardia.
Sir Henry Hallett Dale
(Nobel laureate, 1936)
A, B: Muscarinic effects of Ach (M3, M2)
C: Muscarinic antagonistic effect (M)
D. Stimulation of sympathetic ganglia (NN)
(Arterial pressure of an
anesthetized cat was
measured)
25. 19.Otto Loewi (1873-1961)
• Proved the chemical
transmission of the nerve
impulses and received Nobel
prize with Henry Dale
• Idea of experiment in a dream
and become a prototype for all
investigations of chemical
factors in the nervous system.
• Coined term Neurohumoral
transmission
26.
27. • Findings of Experiment:
1. stimulation of vagus caused appearance of a
substance in perfusated heart capable of
producing in the second heart, an inhibitory
effect resembling vagus stimulation.
2. stimulation of sympathetic nervous system
caused appearance of a substance capable of
accelerating the second heart, later concluded
that substance was adrenaline.
28. 3.Atropine prevented the inhibitory action of
vagus on the heart but did not prevent release of
vagusstof.
4.physostigmine(eserine) potentiated the effect of
vagus stimulation on the heart, prevented
destruction of vagusstof by heart muscle, due to
inhibition of cholinesterase which normally
destroys acetylcholine.
29. 20.Wilhelm Feldberg & Otto Krayer
first long experiment on role of Ach
Stimulated vagus nerve of dog and cat, measured
Ach in venous outflow of heart
effect of parasympathetic out flow in contraction of
tongue muscle
30. 21.Walter Bradford
Cannon(1871-1945):
Discovery of adrenaline &
concept of autoreceptor
• With Uridil: stimulation of
sympathetic hepatic nerve in
mammals release adrenaline
like substance that increase
blood pressure and heart rate.
31. • With Bacq: idea of Autoreceptor
• With Rosenblueth: hepatic nerve
stimulation caused rise in BP which
persisted after administration of
ergotoxin
• Sympathin E- excitatory effects
• Sympathin I- inhibitory effects of
adrenaline
• Studied effects of pituitrin on uterus and
practiced to induce labour.
32. 22.Ulf Von Euler(1905-1983):
• Discovered active biological
agent from intestine: substance P
• Prostaglandin & vesiglandin-
1935, piperidine-1942,
noradrenaline-1946
• Studied about NA distribution in nerves &
organs, excretion during various physiological
and pathological conditions
• Researched about uptake, storage and release
from nerve granules as well as
neurotransmission process.
33. 23.Raymond Ahlquist (1914-1983)
• Effects of adrenaline, noradrenaline
& isoproternol in variety of target
tissues.
• In 1948 divided adrenoceptors
into α- and β-adrenoceptor subtypes
• The pharmacology of the sympathetic nervous
system.
• In 1958, dichloroisoprenaline the first clinically
useful beta-blocker.
• Discovered that the peristalsis is enhanced by α-
adrenoceptors and conversely inhibited by β-
adrenoceptors.
34. • Nobel Laureate, 1970
• His discoveries concern the
mechanisms which regulate the
formation of norepinephrine in
the nerve cells and the
mechanisms which are
involved in the inactivation of
this important neurotransmitter.
24. Julius Axelrod (1912-2004)
35. 25. Sir Bernard Katz:
• Study of neuromuscular
junction with intracellular
electrodes, role of Ach in
synapse was
demonstrated.
• Discovered that small
fluctuations in basement
membrane potential due to
release of synaptic vesicles
36. 26. Sir John Carew Eccles:
• Believed that Synapses
had electrical
transmission
• 1951-Inserted
microelectrodes into
nerve cells , recorded
electrical responses
produced by synapses
40. Neurohumoral Transmission
• Nerves that transmit their message across
synapses and neuroeffector junctions by release
of humoral (chemical) messengers.
• Criteria's for transmitter :
a. Presynaptic neurone with synthesizing
enzymes
b. Released following nerve stimulation
c. Produce response identical to nerve stimulated
response
d. Potentiated or antagonized by other substances
41. Steps Of Neurohumoral Transmission
I. Impulse conduction:
Resting transmembrane potential -70mv,
high k+ & low Na+ concentration,
Impulse ↑↑↑Na+ depolarize overshoot,+20
mv
Normalize by activation of Na+ K+ pump.
II. Transmitter Release
Stored in vesicles prejunctionally,
Fusion of vesical & axonal membrane through Ca+
influx.
42. III. Transmitter action on post junctional membrane
EPSP: increase in cation permeability
depolarisation followed k+ efflux
IPSP: increase anion permeability
hyperpolarisation
IV. Post junctional activity
V. Termination of transmitter action:
parasympathetic Ach- hydrolyzed by AchE
VIP- degrades by peptidases
sympathetic NA- acts at junction, diffuses & recycles
NPY- diffuses & degrades
Gaba-ergic GABA- acts , diffuses & recycles
43. • Graded in
magnitude
• Have no threshold
• Cause
depolarization
o Movement of
Na+ and K+
• Summate
• Have no
refractory period
Excitatory post synaptic potential
44. Inhibitory Post Synaptic Potential
• Cause
hyperpolarization
o K+ or Cl-
• Small in magnitude
• Makes membrane
less excitable
45. Synthesis & Storage
Action
potential
Metabolism
Recognition
(action)
Key Steps in Neurotransmission:
Strategies for Pharmacological
Intervention:
Block synthesis and storage: Usually rate-limiting steps; produce long- term effects
Block release: Rapid action and effective
Block reuptake increases synaptic neurotransmitter concentrations
Can be selective or non-selective
Interfere with metabolism: Can be reversible or irreversible; blocking metabolism
increases effective neurotransmitter concentrations
Interfere with recognition: Receptor antagonists & agonists; high specificity
Release
Reuptake
46.
47. Parsympathetic Nervous System
• Cholinergic system
• Craniosacral out flow- CN III, VII, IX, X & S2,3,4
• Preganglionic fibres myelinated, long
• Post ganglionic fibres non myelinated, short
• Parasympathetic ganglia: ciliary ganglia
Sphenopalatine ganglia, submaxillary ganglia,
otic ganglia.
• EXCEPTION: ciliary post ganglionic fibres are
myelinated
48.
49. PARA SYMPATHETIC
NEUROTRANSMITTERS:
Acetylcholine(Ach)- Neurotransmitter
a. Somatic motor neuron to skeletal muscle(NMJ)
b. Preganglionic parasympathetic/ sympathetic fibres
c. Post ganglionic parasympathetic fibres to NEJ
EXCEPTION: postganglionic sympathetic fibres to
sweat glands of palm and sole are cholinergic
Hypothalamus is major controlling centre for PNS
51. Synthesis, storage and release of acetylcholine:
Pre-synaptic
cell
Post-synaptic
cell
Ach
Ca2+
Na+
Choline
(10 mM)
Choline
Recognition
by receptors
Ca2+
Ach
Ach
Ach
Nerve
impulse
NN
NM
Ach
Ac-CoA
ChAT
Ach
AchE
AchE
choline
+ acetic acid
CAT = choline acetyltransferase
AchE = acetylcholinesterase
Synaptic
cleft
Antiporter
52. CH3COOH+
AchE
(CH3)3 N+–CH2–CH2–OH(CH3)3 N+–CH2–CH2–O–C–CH3
O
H2
O
OH(-)
AchE
Glu202
Tyr337
Ser203
Glu334
His447
Degradation of acetylcholine:
Steps involved in the action of acetylcholinesterase:
1. Binding of substrate (Ach)
2. Formation of a transient intermediate (involving -OH on Serine 203, etc.)
3. Loss of choline and formation of acetylated enzyme
4. Deacylation of AchE (regeneration of enzyme)
600,000 Ach molecules / AchE / min
= turnover time of 150 microseconds
Choline Acetic acid
53. Sympathetic Nervous System
• Adrenergic system
• Thoracolumber outflow
• Preganglionic neurons leave spinal nerve and
communicate with paravertebral chain of 22
sympathetic ganglia
• 3 cervical and sacral ganglia run upward or
downward making no synapse in between
• T1- T4 preganglionic fibres synapse with post
ganglionic fibres in paravertebral ganglia
• T5-T11 preganglionic fibres -Coeliac ganglia
54. • T12-L1 preganglionic fibres - superior mesentric
ganglia.
• L2-L3 preganglionic fibres- inferior mesentric
ganglia.
• T10- T11 some preganglionic fibres terminate in
chromaffin cells of adrenal gland i.e no post
ganglionic fibres.
• Pre ganglionic fibres: myelinated , shorter or
equal with post ganglionic fibres
• Post ganglionic fibres: non myelinated
• Vasomotor centre in major controlling centre for
SNS.
55.
56. SYMPATHETIC NEUROTRANSMITTERS:
• Neurotransmitter at sympathetic ganglia is
acetylcholine
• Sympathetic post ganglionic fibres release
Norepinephrine(NE) at neuroeffector junction.
• EXCEPTION:
i. Postganglionic sympathetic fibres to sweat gland
ii. Some post ganglionic sympathetic fibres to
arterioles of skeletal muscle
iii. Some post ganglionic sympathetic fibres at
splanchnic and renal blood vessels are
dopaminergic in nature.
iv. Preganglionic sympathetic nerve fibres to adrenal
medulla neurotransmitter is Ach but on
stimulation cells secrete Epinephrine.
59. Rules & Exceptions of Autonomic
innervations
• Parasympathetic nervous system: energy storing and
restorative system
• Sympathetic nervous system: Prepares for
E- situations i.e.. Emergency, exercise, embarrssment
• Only sympathetic no parasympathetic innervations:
radial muscle of iris, smooth muscle of eyelids,
nictating membrane
pilomotor muscle, ventricular myocardium
bladder neck(trigone), seminal vesical &
vas deferens
60. • Only parasympathetic no sympathetic
innervations:
circular muscles of iris, ciliary muscle
lacrimal glands, mucus membrane of GIT
bronchial tree, pancreatic exocrine glands
detrusor muscle of bladder, erectile
tissue of penis
• Only Adrenergic receptors no sympathetic
innervations:
Adipocytes – lipolysis
Liver cells –gluconeogenesis,
skeletal muscle cells –glycolysis
61. • Only cholinergic receptors no parasympathetic
inervations:
Blood vessels
• Sympathetic in nature but cholinergic in
character:
Sweat galnds, arterioles of skeletal muscles
• Sympathetic system is antagonist to
parasympathetic system:
On salivary glands its stimulatory
63. PNS Receptors - Pharmacological Classification:
Cholinergic R
Adrenergic R
Dopamine R
Muscarinic R
Nicotinic R
M1, M3, M5 (Gq coupled)
M2, M4 (Gi coupled)
NM (neuromuscular, or muscle type)
NN (neuronal, or ganglion type)
b1,
a2a1,
b2, b3
D1, D2, D3, D4, D5
Other receptors (receptors for NANC transmitters,
e.g. nitric oxide, vasoactive intestinal peptide,
neuropeptide Y)
(mAChR)
(nAChR)
64.
65. “Nicotinic actions” -- similar to those induced by nicotine; action
mediated by nicotinic cholinergic receptors:
• stimulation of all autonomic ganglia (NN)
• stimulation of voluntary muscle (NM)
• secretion of epinephrine from the adrenal
medulla (NN)
Cholinergic receptors: Nicotinic
Nicotiana tabacum
(cultivated tobacco)
66. Nicotinic acetylcholine receptor: Function
Ligand-gated ion (Na+)
channel - an
“Ionotropic Receptor”
• Acetylcholine binds to the α-
subunits of the receptor making
the membrane more permeable to
cations (Na+) and causing a local
depolarization. The local
depolarization spreads to an
action potential, or leads to
muscle contraction when
summed with the action of other
receptors. The ion channel is open
during the active state.
• Nicotine in small doses stimulates
autonomic ganglia and adrenal medulla.
When large doses are applied, the
stimulatory effect is quickly followed by a
blockade of transmission.
67. “Muscarinic actions” -- reproduced
by injection of muscarine, from
Amanita muscaria (fly agaric).
Similar to those of
parasympathetic stimulation
Cholinergic Receptors: Muscarinic
Multiple muscarinic cholinergic
receptors distributed in different
tissues. Therefore, the “muscarinic
actions” are dependent on the
receptors in different tissues and
cells.
70. Intracellular signaling triggered by acetylcholine in
the Heart
Main molecular players: M2, heterotrimeric G Protein Gi, Adenylyl cyclase
71. Clinical manifestation of excessive cholinergic effects
D – Defecation
U – Urination
M – Miosis
B – Bradycardia
E – Emesis
L – Lacrimation
S – Salivation
(DUMBELS)
72. Classification of adrenergic receptors by agonist
potency
a -- NE Epi > Iso
b -- Iso > Epi > NE
NE = norepinephrine
Epi = epinephrine
Iso = isoproterenol
HO
HO
CH2
NHCH3
OH
CH
Epi
HO
HO
CH2
NH2
OH
CH
NE
HO
HO
CH2
NH
OH
CH
Iso
CH(CH3)2
74. Gs and Gi proteins have different functions
Agonist
bg
as
Agonist
bg
ai
AC
as
bg
ai
bg
Gs = stimulatory G protein
Gi = inhibitory G protein
AC = adenylyl cyclase (convert ATP to cAMP)
Beta1 receptor Alpha2 receptor
75. a1: Postsynaptic effector cells, especially smooth
muscle, salivary glands, liver cells
Vasoconstriction, relaxation of intestine,
salivary secretion, hepatic glycogenolysis
a2 : Presynaptic adrenergic nerve terminals
(autoreceptor), platelets, lipocytes, smooth
muscle, β pancreatic cells
Inhibition of transmitter release, platelet
aggregation, contraction of vascular smooth
muscle, inhibition of insulin release
Distribution and Functions of Adrenergic Receptors:
78. Dopaminergic receptors in the periphery
Dopamine receptors play important roles in CNS. Notably,
dopamine neurotransmission is involved in several
diseases including Parkinson’s disease, schizophenia, and
attention deficiency disorder.
There are 5 types of dopamine receptors (D1 – D5). In
periphery, D1 dopamine receptor mediates renal
vasodilation, and increased myocardial contractility.
Agonist Agonist
D2,3,4D1,5
GiGs
cAMP cAMP
84. Cardiovascular effects of intravenous infusion of epinephrine, norepinephrine, and isoproterenol
in man. Norepinephrine (predominantly a-agonist) causes vasoconstriction and increased systolic
and diastolic BP, with a reflex bradycardia. Isoproterenol (b-agonist) is a vasodilator, but strongly
increases cardiac force and rate. Mean arterial pressure falls. Epinephrine combines both actions.
85. Intracellular signaling triggered by acetylcholine in the
endothelium
eNOS
●NO
L-Arg
L-Citruline
Major molecular players: M3, heterotrimeric G Protein Gq, Ca(2+)-CaM, eNOS, NO
eNOS
Nitric oxide synthase
86. Nitric oxide (NO) signaling pathway for SMC relaxation
Second
messenger
91. Lens
Pupillary dilator muscle (a1)
Pupillary constrictor muscle (M3)
Secretion of aqueous humor (b)
(M3)
Cholinergic effects: Adrenergic effects:
• Contraction of pupillary constrictor muscle
-- miosis
• Contraction of ciliary muscle - bulge of lens
-- near vision, outflow of aqueous humor
• Contraction of pupillary dilator muscle
-- mydriasis
• Stimulation of ciliary epithelium
-- production of aqueous humor
Trabecular meshwork
(opened by pilocarpine)
92.
93. Enteric nervous system
• Collection of well organised neurons in wall of
GIT with pupose of controlling its functions
• Integrative capability to function independently
of CNS
• Major network of nerve fibres
myentric (Auerbach’s) plexus:
between longitudinal and circular muscle layers
submucosal (meissner’s) plexus:
between circular muscle layer and the mucosa
• Nuerotransmitters: Ach, NE, neuropeptide,
substance P, serotonin, dopamin,
cholecystokinin.
94. References:
• Goodman & Gilman’s The pharmacological basis of
therapeutics: 10th 12th edition
• Rang and Dale’s pharmacology: 6th edition
• Sharma & Sharma’s principles of pharmacology: 1st
edition
• KD Tripathi’s essentials of medical pharmacology:
7th edition
• Katzung’s basic &clinical pharmacology:12th edition
• Golan’s principles of pharmacology: 3rd edition
• Internet sources….