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

172 regulation of sacral parasympathetic outflow. In general, visceral
afferents that enter the spinal nerves convey information concerned
with temperature as well as nociceptive visceral inputs related to
mechanical, chemical, and thermal stimulation. The primary pathways
taken by ascending spinal visceral afferents are complex and
controversial (Saper, 2002). Most probably converge with musculoskeletal
and cutaneous afferents and ascend by the spinothalamic
and spinoreticular tracts. Others ascend by the dorsal column. An
important feature of the ascending pathways is that they provide collaterals
that converge with the cranial visceral sensory pathway at
virtually every level (Saper, 2000). At the brainstem level, collaterals
from the spinal system converge with the cranial nerve sensory
system in the STN, the ventrolateral medulla, and the parabrachial
nucleus. At the level of the forebrain, the spinal system appears to
form a posterolateral continuation of the cranial nerve visceral sensory
thalamus and cortex (Saper, 2000).
The neurotransmitters that mediate transmission from sensory
fibers have not been characterized unequivocally. Substance P
and calcitonin gene–related peptide (CGRP), which are present in
afferent sensory fibers, in the dorsal root ganglia, and in the dorsal
horn of the spinal cord, are leading candidates for neurotransmitters
that communicate nociceptive stimuli from the periphery to the
spinal cord and higher structures. Other neuroactive peptides, including
somatostatin, vasoactive intestinal polypeptide (VIP), and cholecystokinin,
also have been found in sensory neurons (Hökfelt et al.,
2000), and one or more such peptides may play a role in the transmission
of afferent impulses from autonomic structures. ATP appears
to be a neurotransmitter in certain sensory neurons, including those
that innervate the urinary bladder. Enkephalins, present in interneurons
in the dorsal spinal cord (within an area termed the substantia
gelatinosa), have antinociceptive effects that appear to arise from
presynaptic and postsynaptic actions to inhibit the release of substance
P and diminish the activity of cells that project from the spinal
cord to higher centers in the CNS. The excitatory amino acids glutamate
and aspartate also play major roles in transmission of sensory
responses to the spinal cord.
SECTION II
NEUROPHARMACOLOGY
Central Autonomic Connections. There probably are no purely autonomic
or somatic centers of integration, and extensive overlap
occurs. Somatic responses always are accompanied by visceral
responses, and vice versa. Autonomic reflexes can be elicited at the
level of the spinal cord. They clearly are demonstrable in experimental
animals or humans with spinal cord transection and are manifested
by sweating, blood pressure alterations, vasomotor responses
to temperature changes, and reflex emptying of the urinary bladder,
rectum, and seminal vesicles. Extensive central ramifications of the
autonomic nervous system exist above the level of the spinal cord.
For example, integration of the control of respiration in the medulla
oblongata is well known. The hypothalamus and the STN generally
are regarded as principal loci of integration of autonomic nervous
system functions, which include regulation of body temperature,
water balance, carbohydrate and fat metabolism, blood pressure,
emotions, sleep, respiration, and reproduction. Signals are received
through ascending spinobulbar pathways, the limbic system,
neostriatum, cortex, and to a lesser extent other higher brain centers.
Stimulation of the STN and the hypothalamus activates bulbospinal
pathways and hormonal output to mediate autonomic and motor
responses (Andresen and Kunze, 1994; (see Chapter 14). The
hypothalamic nuclei that lie posteriorly and laterally are sympathetic
in their main connections, whereas parasympathetic functions
evidently are integrated by the midline nuclei in the region of the
tuber cinereum and by nuclei lying anteriorly.
The CNS can produce a wide range of patterned autonomic
and somatic responses from discrete activation of sympathetic or
parasympathetic neurons to more generalized activation of these
nerves with highly integrated patterns of response. There are highly
differentiated patterns of activity during a wide range of physiological
conditions consistent with the need for modulation of different
organ functions. There is evidence for organotropical organization of
neuronal pools at multiple levels of the CNS that generate these
various patterns of sympathetic and parasympathetic responses. The
pattern generators at these different levels of the neuroaxis are often
organized in a hierarchical manner that allows individual response or
larger responses made up of multiple individual units.
Highly integrated patterns of response generally are organized
at a hypothalamic level and involve autonomic, endocrine, and
behavioral components. On the other hand, more limited patterned
responses are organized at other levels of basal forebrain, brainstem,
and spinal cord.
Divisions of the Peripheral Autonomic System. On the
efferent side, the autonomic nervous system consists of
two large divisions: (1) the sympathetic or thoracolumbar
outflow and (2) the parasympathetic or craniosacral
outflow. A brief outline of those anatomical features is
necessary for an understanding of the actions of autonomic
drugs.
The arrangement of the principal parts of the
peripheral autonomic nervous system is presented
schematically in Figure 8–1. The neurotransmitter of
all preganglionic autonomic fibers, most postganglionic
parasympathetic fibers, and a few postganglionic sympathetic
fibers is acetylcholine (ACh). Some postganglionic
parasympathetic nerves use nitric oxide (NO)
as a neurotransmitter; nerves that release NO are
referred to as nitrergic (Toda and Okamura, 2003). The
adrenergic fibers comprise the majority of the postganglionic
sympathetic fibers; here the primary transmitter
is norepinephrine (NE, noradrenaline, levarterenol).
The terms cholinergic and adrenergic were proposed
originally by Dale to describe neurons that liberate
ACh or norepinephrine, respectively. Not all the transmitter(s)
of the primary afferent fibers, such as those
from the mechano- and chemoreceptors of the carotid
body and aortic arch, have been identified conclusively.
Substance P and glutamate are thought to mediate many
afferent impulses; both are present in high concentrations
in the dorsal spinal cord.
Sympathetic Nervous System. The cells that give rise
to the preganglionic fibers of this division lie mainly
in the intermediolateral columns of the spinal cord
and extend from the first thoracic to the second or