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

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ORAL
4
ANAL
LM
2
6
1
3
5
+ + – – –
7
MP
CM
SM
Muc
SECTION VI
DRUGS AFFECTING GASTROINTESTINAL FUNCTION
Lumen
Figure 46–1. The neuronal network that initiates and generates the peristaltic response. Mucosal stimulation leads to release of serotonin
by enterochromaffin cells (8), which excites the intrinsic primary afferent neurons (1), which then communicate with ascending
(2) and descending (3) interneurons in the local reflex pathways. The reflex results in contraction at the oral end via the excitatory
motor neuron (6) and aboral relaxation via the inhibitory motor neuron (5). The migratory myoelectric complex (see text) is shown
here as being conducted by a different chain of interneurons (4). Another intrinsic primary afferent neuron with its cell body in the
submucosa also is shown (7). MP, myenteric plexus; CM, circular muscle; LM, longitudinal muscle; SM, submucosa; Muc, mucosa.
(Adapted from Kunze and Furness, 1999, with permission from Annual Reviews. www.annualreviews.org.)
muscle activity that is directly controlled by the motor neurons of
the myenteric plexus to provide the effector component of the
peristaltic reflex. Motor neurons receive input from ascending and
descending interneurons (which constitute the relay and programming
systems) that are of two broad types, excitatory and inhibitory.
The primary neurotransmitter of the excitatory motor neurons is
acetylcholine (ACh), although tachykinins, co-released by these
neurons, also play a role. The principal neurotransmitter in the
inhibitory motor neurons appears to be NO, although important contributions
may also be made by ATP, vasoactive intestinal peptide,
and pituitary adenylyl cyclase–activating peptide (PACAP), all of
which are variably coexpressed with NO synthase. Substantial
progress has been made in elucidating the mucosal sensor for initiating
peristalsis and other reflexes. Enterochromaffin cells, scattered
throughout the epithelium of the intestine, release serotonin
(5-HT) to initiate many gut reflexes (Gershon and Tack, 2007) by
acting locally on enteric neurons. Excessive release of 5-HT from
the gut wall (e.g., by chemotherapeutic agents) leads to vomiting
by actions of 5-HT on vagal nerve endings in the proximal small
intestine. Compounds targeting the 5-HT system are important
modulators of motility, secretion, and emesis.
This view of nerve–muscle interaction within the GI tract is
in many ways oversimplified, and other cell types are important.
One of these is the interstitial cell of Cajal, distributed within the gut
wall and responsible for setting the electrical rhythm, and hence the
pace of contractions, in various regions of the gut. These cells also
8
translate or modulate excitatory and inhibitory neuronal communication
to the smooth muscle (Ward et al., 2004).
Excitation-Contraction Coupling in GI Smooth Muscle
Control of tension in GI smooth muscle is in large part dependent on
the intracellular Ca 2+ concentration. In general, there are two types of
excitation-contraction coupling. Ionotropic receptors can mediate
changes in membrane potential, which in turn activate voltagedependent
Ca 2+ channels to trigger an influx of Ca 2+ (electromechanical
coupling); metabotropic receptors activate various
signal transduction pathways to release Ca 2+ from intracellular stores
(pharmaco-mechanical coupling). Inhibitory receptors also exist on
smooth muscle and generally act via PKA and PKG, whose kinase
activities can lead to hyperpolarization, decreased cytosolic [Ca 2+ ],
and reduced interaction of actin and myosin. As an example, NO may
induce relaxation via activation of guanylyl cyclase-cyclic GMP pathway,
and the opening of several types of K + channels.
OVERVIEW OF FUNCTIONAL AND
MOTILITY DISORDERS OF THE BOWEL
GI motility disorders are a complex and heterogeneous
group of syndromes whose pathophysiology is not completely
understood. Typical motility disorders include