Ganong's Review of Medical Physiology, 23rd Edition

CHAPTER 7Neurotransmitters & Neuromodulators 143

Anesthesia

Although general anesthetics have been used for millennia, lit-
tle 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 recep-
tors and specifically on GABAA and glycine receptors to in-
crease Cl– conductance. Regional variation in anesthetic
actions in the CNS seems to parallel the variation in subtypes
of GABAA receptors. Other inhaled anesthetics do not act by
increasing GABA receptor activity, but appear to act by inhib-
iting 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 polypep-
tide, 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 post-
translational processing.
There are three neurokinin receptors. Two of these, the sub-
stance P and the neuropeptide K receptors, are G protein-cou-

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 proba-

bly the mediator at the first synapse in the pathways for pain

transmission in the dorsal horn. It is also found in high con-

centrations in the nigrostriatal system, where its concentra-

tion 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 func-

tions 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 7–3 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)

TABLE 7–4 Opioid peptides and their precursors.

Precursor

Opioid

Peptides Structures

Proenkephalin Met-

enkephalin

Tyr-Gly-Gly-Phe-Met

Leu-

enkephalin

Tyr-Gly-Gly-Phe-Leu

Octapeptide Tyr-Gly-Gly-Phe-Met-Arg-Gly-

Leu

Heptapeptide Tyr-Gly-Gly-Phe-Met-Arg-Phe

Proopiomel-

anocortin

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

Prodynorphin Dynorphin

1–8

Tyr-Gly-Gly-Phe-Leu-Arg-Arg-lle

Dynorphin

1–17

Tyr-Gly-Gly-Phe-Leu-Arg-Arg-

lle-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