Ganong's Review of Medical Physiology, 23rd Edition

Anesthesia
Although general anesthetics have been used for millennia, little
has been understood about their mechanisms of action.
However, it now appears that alcohols, barbiturates, and many
volatile inhaled anesthetics as well act on ion channel receptors
and specifically on GABA A and glycine receptors to increase
Cl – conductance. Regional variation in anesthetic
actions in the CNS seems to parallel the variation in subtypes
of GABA A receptors. Other inhaled anesthetics do not act by
increasing GABA receptor activity, but appear to act by inhibiting
NMDA and AMPA receptors instead.
In contrast to general anesthetics, local anesthetics produce
anesthesia by blocking conduction in peripheral nerves via
reversibly binding to and inactivating Na + channels. Na +
influx through these channels normally causes depolarization
of nerve cell membranes and propagation of impulses toward
the nerve terminal. When depolarization and propagation are
interrupted, the individual loses sensation in the area supplied
by the nerve.
LARGE-MOLECULE TRANSMITTERS:
NEUROPEPTIDES
Substance P & Other Tachykinins
Substance P is a polypeptide containing 11 amino acid residues
that is found in the intestine, various peripheral nerves, and
many parts of the CNS. It is one of a family of six mammalian
polypeptides called tachykinins that differ at the amino terminal
end but have in common the carboxyl terminal sequence of
Phe-X-Gly-LeuMet-NH 2 , where X is Val, His, Lys, or Phe. The
members of the family are listed in Table 7–3. There are many
related tachykinins in other vertebrates and in invertebrates.
The mammalian tachykinins are encoded by two genes.
The neurokinin B gene encodes only one known polypeptide,
neurokinin B. The substance P/neurokinin A gene
encodes the remaining five polypeptides. Three are formed by
alternative processing of the primary RNA and two by posttranslational
processing.
There are three neurokinin receptors. Two of these, the substance
P and the neuropeptide K receptors, are G protein-cou-
TABLE 7–3 Mammalian tachykinins.
Gene Polypeptide Products Receptors
SP/NKA Substance P Substance P (NK-1)
Neurokinin A
Neuropeptide K Neuropeptide K (NK-2)
Neuropeptide α
Neurokinin A (3–10)
NKB Neurokinin B Neurokinin B (NK-3)
CHAPTER 7 Neurotransmitters & Neuromodulators 143
pled receptors. Activation of the substance P receptor causes
activation of phospholipase C and increased formation of IP 3
and DAG.
Substance P is found in high concentration in the endings
of primary afferent neurons in the spinal cord, and it is probably
the mediator at the first synapse in the pathways for pain
transmission in the dorsal horn. It is also found in high concentrations
in the nigrostriatal system, where its concentration
is proportional to that of dopamine, and in the
hypothalamus, where it may play a role in neuroendocrine
regulation. Upon injection into the skin, it causes redness and
swelling, and it is probably the mediator released by nerve
fibers that is responsible for the axon reflex. In the intestine, it
is involved in peristalsis. It has recently been reported that a
centrally active NK-1 receptor antagonist has antidepressant
activity in humans. This antidepressant effect takes time to
develop, like the effect of the antidepressants that affect brain
monoamine metabolism, but the NK-1 inhibitor does not
alter brain monoamines in experimental animals. The functions
of the other tachykinins are unsettled.
Opioid Peptides
The brain and the gastrointestinal tract contain receptors that
bind morphine. The search for endogenous ligands for these
receptors led to the discovery of two closely related pentapeptides
(enkephalins; Table 7–4) that bind to these opioid receptors.
TABLE 7–4 Opioid peptides and their precursors.
Precursor
Proenkephalin Metenkephalin
Proopiomelanocortin
Opioid
Peptides Structures
Leuenkephalin
Prodynorphin Dynorphin
1–8
Tyr-Gly-Gly-Phe-Met
Tyr-Gly-Gly-Phe-Leu
Octapeptide Tyr-Gly-Gly-Phe-Met-Arg-Gly-
Leu
Heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Phe
β-Endorphin Tyr-Gly-Glu-Phe-Met-Thr-Ser-
Lys-Ser-Gln-Thr-Pro-Leu-Val-
Thr-Leu-Phe-Lys-Asn-Ala-Ile-Val-
Lys-Asn-Ala-His-Lys-Lys-Gly-Gln
Dynorphin
1–17
Tyr-Gly-Gly-Phe-Leu-Arg-Arg-lle
Tyr-Gly-Gly-Phe-Leu-Arg-Arglle-Arg-Pro-Lys-Leu-Lys-Trp-
Asp-Asn-Gln
α-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-
Tyr-Pro-Lys
β-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-
Tyr-Pro