DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

182 While these criteria are applicable for most neurotransmitters,
including norepinephrine and ACh, there
are now exceptions to these general rules. For instance,
NO has been found to be a neurotransmitter, in a few
postganglionic parasympathetic nerves, in nonadrenergic,
noncholinergic (NANC) neurons in the periphery, in
the ENS, and in the CNS. However, NO is not stored in
neurons and released by exocytosis. Rather, it is
synthesized when needed and readily diffuses across
membranes.
Chemical rather than electrogenic transmission at
autonomic ganglia and the neuromuscular junction of
skeletal muscle was not generally accepted for a considerable
period because techniques were limited in time
and chemical resolution. Techniques of intracellular
recording and microiontophoretic application of drugs,
as well as sensitive analytical assays, have overcome
these limitations.
Neurotransmission in the peripheral and central
nervous systems once was believed to conform to the
hypothesis that each neuron contains only one transmitter
substance. However, peptides such as enkephalin,
substance P, neuropeptide Y, VIP, and somatostatin;
purines such as ATP and adenosine; and small molecules
such as NO have been found in nerve endings.
These substances can depolarize or hyperpolarize nerve
terminals or postsynaptic cells. Furthermore, results of
histochemical, immunocytochemical, and autoradiographic
studies have demonstrated that one or more of
these substances is present in the same neurons that
contain one of the classical biogenic amine neurotransmitters.
For example, enkephalins are found in postganglionic
sympathetic neurons and adrenal medullary
chromaffin cells. VIP is localized selectively in peripheral
cholinergic neurons that innervate exocrine glands,
and neuropeptide Y is found in sympathetic nerve endings.
These observations suggest that synaptic transmission
in many instances may be mediated by the release
of more than one neurotransmitter (see the next section).
SECTION II
NEUROPHARMACOLOGY
Steps Involved in Neurotransmission
The sequence of events involved in neurotransmission
is of particular importance because pharmacologically
active agents modulate the individual steps.
The term conduction is reserved for the passage
of an impulse along an axon or muscle fiber; transmission
refers to the passage of an impulse across a synaptic
or neuroeffector junction. With the exception of the
local anesthetics, very few drugs modify axonal conduction
in the doses employed therapeutically. Hence
this process is described only briefly.
Axonal Conduction. At rest, the interior of the typical
mammalian axon is ~70 mV negative to the exterior.
The resting potential is essentially a diffusion potential
based chiefly on the 40 times higher concentration of
K + in the axoplasm as compared with the extracellular
fluid and the relatively high permeability of the resting
axonal membrane to K + . Na + and Cl – are present in
higher concentrations in the extracellular fluid than in
the axoplasm, but the axonal membrane at rest is considerably
less permeable to these ions; hence their contribution
to the resting potential is small. These ionic
gradients are maintained by an energy-dependent active
transport mechanism, the Na + , K + -ATPase (Hille, 1992).
In response to depolarization to a threshold level,
an action potential or nerve impulse is initiated at a local
region of the membrane. The action potential consists
of two phases. Following a small gating current resulting
from depolarization inducing an open conformation
of the channel, the initial phase is caused by a rapid
increase in the permeability of Na + through voltagesensitive
Na + channels. The result is inward movement
of Na + and a rapid depolarization from the resting potential,
which continues to a positive overshoot. The second
phase results from the rapid inactivation of the Na +
channel and the delayed opening of a K + channel, which
permits outward movement of K + to terminate the depolarization.
Inactivation appears to involve a voltage-sensitive
conformational change in which a hydrophobic
peptide loop physically occludes the open channel at the
cytoplasmic side. Although not important in axonal conduction,
Ca 2+ channels in other tissues (e.g., L-type
Ca 2+ channels in heart) contribute to the action potential
by prolonging depolarization by an inward movement
of Ca 2+ . This influx of Ca 2+ also serves as a stimulus to
initiate intracellular events (Catterall, 2000; Hille, 1992),
and Ca 2+ influx is important in excitation-exocytosis
coupling (transmitter release).
The transmembrane ionic currents produce local
circuit currents around the axon. As a result of such
localized changes in membrane potential, adjacent resting
channels in the axon are activated, and excitation
of an adjacent portion of the axonal membrane occurs.
This brings about propagation of the action potential
without decrement along the axon. The region that has
undergone depolarization remains momentarily in a
refractory state. In myelinated fibers, permeability
changes occur only at the nodes of Ranvier, thus causing
a rapidly progressing type of jumping, or saltatory,
conduction.
The puffer fish poison, tetrodotoxin, and a close
congener found in some shellfish, saxitoxin, selectively