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

number of afferent fibers (but apparently no pain fibers)
from the viscera into the medulla; the cell bodies of these
fibers lie mainly in the nodose ganglion.
The parasympathetic sacral outflow consists of
axons that arise from cells in the second, third, and
fourth segments of the sacral cord and proceed as
preganglionic fibers to form the pelvic nerves (nervi
erigentes). They synapse in terminal ganglia lying near
or within the bladder, rectum, and sexual organs. The
vagal and sacral outflows provide motor and secretory
fibers to thoracic, abdominal, and pelvic organs, as indicated
in Figure 8–1.
Enteric Nervous System. The processes of mixing,
propulsion, and absorption of nutrients in the GI tract
are controlled locally through a restricted part of the
peripheral nervous system called the enteric nervous
system (ENS). The ENS is involved in sensorimotor
control and thus consists of both afferent sensory neurons
and a number of motor nerves and interneurons
that are organized principally into two nerve plexuses:
the myenteric (Auerbach’s) plexus and the submucosal
(Meissner’s) plexus. The myenteric plexus, located
between the longitudinal and circular muscle layers,
plays an important role in the contraction and relaxation
of GI smooth muscle (Kunze and Furness, 1999). The
submucosal plexus is involved with secretory and
absorptive functions of the GI epithelium, local blood
flow, and neuroimmune activities (Cooke, 1998).
Although originally classified by Langley in the 1920s as a
third division of the autonomic nervous system, the ENS is actually
comprised of components of the sympathetic and parasympathetic
nervous systems and has sensory nerve connections through the
spinal and nodose ganglia (see Chapter 46).
Parasympathetic preganglionic inputs are provided to the GI
tract via the vagus and pelvic nerves. Acetylcholine is released from
preganglionic neurons and activates nicotinic acetylcholine receptors
(nAChRs) on postganglionic neurons within the enteric ganglia.
Excitatory preganglionic input activates both excitatory and
inhibitory motor neurons that control processes such as muscle contraction
and secretion/absorption. Postganglionic sympathetic nerves
also synapse with intrinsic neurons and generally induce relaxation
by inhibiting the release of ACh. Sympathetic input can also be excitatory
at some sphincter muscles.
There are intrinsic primary afferent neurons with cell bodies
in the enteric ganglia and processes that extend into the lamina propria
of the mucosa. These neurons respond to luminal chemical stimuli,
mechanical deformation of the mucosa, and to stretch (Costa
et al., 2000). Nerve endings of the primary afferents can be activated
by numerous endogenous substances, the most important of which
is serotonin 5-hydroxy tryptamine, 5-HT, which is secreted from
enterochromaffin cells within the mucosa. Enterochromaffin cells
likely provide the primary sensory transduction mechanism that activates
the afferent neurons.
Information from afferent and preganglionic neural inputs to
the enteric ganglia is integrated and distributed by a network of
interneurons. These cells provide both ascending and descending
pathways within the enteric plexuses that are involved in generating
stereotypical GI reflexes such as ascending inhibition and descending
(receptive) relaxation. ACh is the primary neurotransmitter providing
excitatory inputs between interneurons, but other substances
such as ATP (via postjunctional P2X receptors), substance P (by NK 3
receptors), and serotonin (using 5-HT 3
receptors) are also important
in mediating integrative processing via interneurons.
The muscle layers of the GI tract are dually innervated by
excitatory and inhibitory motor neurons with cell bodies primarily in
the myenteric ganglia (Kunze and Furness, 1999). ACh, in addition
to being a neurotransmitter released from preganglionic neurons in
ganglia, also serves as a primary excitatory motor neurotransmitter
released from postganglionic neurons. ACh activates M 2
and M 3
receptors in postjunctional cells to elicit motor responses.
Pharmacological blockade of muscarinic cholinergic (mAChRs)
receptors does not block all excitatory neurotransmission, however,
because neurokinins (neurokinin A and Substance P) are also stored
and released by excitatory motor neurons and contribute to postjunctional
excitation via NK 1
and NK 2
receptors (Costa et al., 1996).
Inhibitory motor neurons are also abundant in the GI tract
and regulate important motility events such as accommodation,
sphincter relaxation, and descending receptive relaxation. Inhibitory
responses are elicited by at least two major transmitters, used to
varying degrees depending upon the region of the gut and the
species. A purine substance, either ATP or β-nicotinamide adenine
dinucleotide (β-NAD) (Mutafova-Yambolieva, 2007), elicits relaxation
via postjunctional P2Y 1
receptors. Nitric oxide is also an
important transmitter that activates production of cyclic GMP and
downstream effector phosphorylation by activation of PKG.
Inhibitory neuropeptides, such as vasoactive intestinal polypeptide
(VIP) and pituitary adenylyl cyclase-activating peptide (PACAP),
may also be released from inhibitory motor neurons under conditions
of strong stimulation (Kunze and Furness, 1999).
In general, motor neurons do not directly innervate smooth
muscle cells in the GI tract. Nerve terminals make synaptic connections
with interstitial cells of Cajal (ICCs), and these cells make electrical
connections (gap junctions) with smooth muscle cells (Ward
et al., 2000). Thus, the ICCs are the receptive, postjunctional transducers
of inputs from enteric motor neurons, and loss of these cells
has been associated with conditions that appear like neuropathies.
ICCs have all of the major receptors and effectors necessary to transduce
both excitatory and inhibitory neurotransmitters into postjunctional
responses (Chen et al., 2007).
Differences Among Sympathetic, Parasympathetic, and
Motor Nerves. The sympathetic system is distributed to
effectors throughout the body, whereas parasympathetic
distribution is much more limited. Furthermore, the
sympathetic fibers ramify to a much greater extent. A
preganglionic sympathetic fiber may traverse a considerable
distance of the sympathetic chain and pass
through several ganglia before it finally synapses with
a postganglionic neuron; also, its terminals make contact
with a large number of postganglionic neurons. In some
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CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS