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

and known or unknown transmitters. In knockout mice, compensatory
mechanisms or transmitter redundancy may disguise even welldefined
actions (Hökfelt et al., 2000). Finally, it should be recognized
that the putative co-transmitter may have primarily a trophic function
in maintaining synaptic connectivity or in expressing a particular
receptor.
ATP and ACh coexist in cholinergic vesicles
(Dowdall et al., 1974) and ATP, NPY, and catecholamine
are found within storage granules in nerves
and the adrenal medulla (see above). ATP is released
along with the transmitters, and either it or its metabolites
have a significant function in synaptic transmission
in some circumstances (see below). Recently,
attention has focused on the growing list of peptides
that are found in the adrenal medulla, nerve fibers, or
ganglia of the autonomic nervous system or in the structures
that are innervated by the autonomic nervous system.
This list includes the encephalin, substance P and
other tachykinins, somatostatin, gonadotropin-releasing
hormone, cholecystokinin, calcitonin gene–related
peptide, galanin, pituitary adenylyl cyclase–activating
peptide, VIP, chromogranins, and NPY (Hökfelt et al.,
2000). Some of the orphan GPCRs discovered in the
course of genome-sequencing projects may represent
receptors for undiscovered peptides or other co-transmitters.
The evidence for widespread transmitter function
in the autonomic nervous system is substantial for
VIP and NPY, and further discussion is confined to
these peptides. The possibility that abnormalities in
function of neuropeptide co-transmitters, in type 2 diabetes,
e.g., contribute to disease pathogenesis remains
of interest (Ahren, 2000).
Co-transmission in the Autonomic Nervous System.
The evidence is substantial that ATP plays a role in
sympathetic nerves as a co-transmitter with norepinephrine
(Silinsky et al., 1998; Westfall et al., 1991,
2002). For example, the rodent vas deferens is supplied
with a dense sympathetic innervation, and stimulation
of the nerves results in a biphasic mechanical response
that consists of an initial rapid twitch followed by a sustained
contraction. The first phase of the response is
mediated by ATP acting on postjunctional P2X receptors,
whereas the second phase is mediated mainly by
norepinephrine acting on α 1
receptors (Sneddon and
Westfall, 1984). The co-transmitters apparently are
released from the same types of nerves because pretreatment
with 6-hydroxydopamine, an agent that
specifically destroys adrenergic nerves, abolishes both
phases of the neurogenically induced biphasic contraction.
It has been assumed that the sympathetic nerves
store ATP and NE in the same synaptic vesicles, and
therefore, on release, the two co-transmitters are
released together (Stjärne, 1989). This may not always
be the case, and ATP and NE may be released from separate
subsets of vesicles and subject to differential regulation
(Todorov et al., 1996).
While part of the metabolism of ATP, once released into the
neuroeffector junction, is by extracellularly directed membranebound
nucleotidases to ADP, AMP, and adenosine (Gordon, 1986),
the majority of the metabolism occurs by the action of releasable
nucleotidases. There is also evidence that ATP and its metabolites
exert presynaptic modulatory effects on transmitter release by P2
receptors and receptors for adenosine. In addition to evidence showing
that ATP is a co-transmitter with norepinephrine, there is also
evidence that ATP may be a co-transmitter with ACh in certain postganglionic
parasympathetic nerves, such as in the urinary bladder.
The NPY family of peptides is distributed widely
in the central and peripheral nervous systems and
consists of three members: NPY, pancreatic polypeptide,
and peptide YY. NPY has been shown to be colocalized
and core-leased with NE and ATP in most
sympathetic nerves in the peripheral nervous system,
especially those innervating blood vessels (Westfall,
2004). There is also convincing evidence that NPY
exerts prejunctional modulatory effects on transmitter
release and synthesis. Moreover, there are numerous
examples of postjunctional interactions that are consistent
with a co-transmitter role for NPY at various sympathetic
neuroeffector junctions. Thus, it seems that
NPY, together with NE and ATP, is the third sympathetic
co-transmitter. The functions of NPY include 1)
direct postjunctional contractile effects; 2) potentiation
of the contractile effects of the other sympathetic cotransmitters;
and 3) inhibitory modulation of the nerve
stimulation–induced release of all three sympathetic cotransmitters.
Studies with selective NPY-Y 1
antagonists provide evidence
that the principal postjunctional receptor is of the Y 1
subtype,
although other receptors are also present at some sites and may exert
physiological actions. Studies with selective NPY-Y 2
antagonists suggest
that the principal prejunctional receptor is of the Y 2
subtype both
in the periphery and in the CNS. Again, there is evidence for a role
for other NPY receptors, and clarification awaits the further development
of selective antagonists. NPY also can act prejunctionally to
inhibit the release of ACh, CGRP, and substance P. In the CNS, NPY
exists as a co-transmitter with catecholamine in some neurons and
with peptides and mediators in others. A prominent action of NPY is
the presynaptic inhibition of the release of various neurotransmitters,
including NE, DA, GABA, glutamate, and 5-HT, as well as inhibition
or stimulation of various neurohormones such as gonadotropinreleasing
hormone, vasopressin, and oxytocin. Evidence also exists
for stimulation of NE and DA release. NPY also acts on autoreceptors
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CHAPTER 8
NEUROTRANSMISSION: THE AUTONOMIC AND SOMATIC MOTOR NERVOUS SYSTEMS