The Nervous System 197Subsequent evidence suggested that the analgesic effects of
hypnosis and acupuncture could also be blocked by naloxone.
These experiments indicate that neurons might be producing
their own endogenous opioids that serve as the natural ligands
of opioid receptors in the CNS. Receptor proteins for the
endogenous opioids and opioid drugs have been identified and
are widespread in the CNS. When the gene for one subtype of
opioid receptors is knocked out in mice (chapter 3), the analge-
sic effect of morphine (its ability to reduce pain) is completely
abolished, demonstrating the importance of opioids and their
receptors in reducing pain transmission.
The endogenous opioids have been identified as a family
of polypeptides produced by the brain and pituitary gland. One
member is called b - endorphin (for “endogenously produced
morphinelike compound”). Another consists of a group of five-
amino-acid peptides called enkephalins, and a third is a poly-
peptide neurotransmitter called dynorphin.
The endogenous opioid system is inactive under normal
conditions, but when activated by stressors it can block the
transmission of pain. For example, a burst in b -endorphin
secretion was shown to occur in pregnant women during partu-
rition (childbirth).
Exogenous opioids such as opium and morphine can pro-
duce euphoria, and so endogenous opioids may mediate reward
or positive reinforcement pathways. This is consistent with the
observation that overeating in genetically obese mice can be
blocked by naloxone. It has also been suggested that the feel-
ing of well-being and reduced anxiety following exercise (the
“joggers high”) may be an effect of endogenous opioids. Blood
levels of b -endorphin increase when exercise is performed at
greater than 60% of the maximal oxygen uptake (chapter 12)
and peak 15 minutes after the exercise has ended. Although
obviously harder to measure, an increased level of opioids in
the brain and cerebrospinal fluid has also been found to result
from exercise. The opioid antagonist drug naloxone, however,
does not block the exercise-induced euphoria, suggesting that
the joggers high is not primarily an opioid effect. Use of nal-
oxone, however, does demonstrate that the endogenous opioids
are involved in the effects of exercise on blood pressure, and
that they are responsible for the ability of exercise to raise the
pain threshold.
Neuropeptide Y
Neuropeptide Y is the most abundant neuropeptide in the
brain. It has been shown to have a variety of physiological
effects, including a role in the response to stress, in the regula-
tion of circadian rhythms, and in the control of the cardiovas-
cular system. Neuropeptide Y has been shown to inhibit the
release of the excitatory neurotransmitter glutamate in a part of
the brain called the hippocampus. This is significant because
excessive glutamate released in this area can cause convul-
sions. Indeed, frequent seizures were a symptom of a recently
developed strain of mice with the gene for neuropeptide Y
“knocked out.” (Knockout strains of mice have specific genes
inactivated; chapter 3, section 3.5.)
Neuropeptide Y is a powerful stimulator of appetite. When
injected into a rat’s brain, it can cause the rat to eat until it
becomes obese. Conversely, inhibitors of neuropeptide Y that
are injected into the brain inhibit eating. This research has
become particularly important in light of the discovery of leptin,
a satiety factor secreted by adipose tissue. Leptin suppresses
appetite by acting, at least in part, to inhibit neuropeptide Y
release. This topic is discussed in chapter 19, section 19.2.Endocannabinoids as Neurotransmitters
In addition to producing endogenous opioids, the brain also
produces compounds with effects similar to those of the active
ingredient in marijuana—Δ^9 -tetrahydrocannabinol (THC).
These endogenous cannabinoids, or endocannabinoids, are
neurotransmitters that bind to the same receptor proteins in the
brain as does THC from marijuana.
Perhaps surprisingly, endocannabinoid receptors are
abundant and widely distributed in the brain. The endocan-
nabinoids are lipids; they are short fatty acids ( anandamide
and 2-arachidonoyl glycerol ), and the only lipids known to act
as neurotransmitters. As lipids, the endocannabinoids are not
stored in synaptic vessicles; rather, they are produced from
the lipids of the neuron plasma membrane and released from
the dendrites and cell body. Because lipophilic neurotransmit-
ters such as the endocannabinoids and nitric oxide (discussed
next) pass easily through plasma membranes, they are not
stored but are released as they are synthesized by the neurons.
The endocannabinoids function as retrograde
neurotransmitters —they are released from the postsynap-
tic neuron and diffuse backward to the axons of presynaptic
neurons. Once in the presynaptic neuron, the endocannabi-
noids bind to their receptors and inhibit the release of neu-
rotransmitter from the axon. This can reduce the release of
either the inhibitory neurotransmitter GABA or the excitatory
neurotransmitter glutamate from presynaptic axons. Endocan-
nabinoids thereby modify the actions of a number of other
neurotransmitters in the brain.
These actions may be important in strengthening synap-
tic transmission during learning. For example, suppose that a
postsynaptic neuron receives inhibitory GABA input from one
presynaptic axon and excitatory glutamate from a different pre-
synaptic axon. If the postsynaptic neuron has just been stim-
ulated by glutamate, the glutamate produces a depolarization
that causes a rise in the cytoplasmic Ca^2 1 concentration. This
promotes the release of endocannabinoids from the postsynap-
tic neuron, which in turn act as retrograde neurotransmitters to
reduce the release of GABA from the other presynaptic axon.
Such depolarization-induced suppression of inhibition could
facilitate the use of that synapse, perhaps for learning and mem-
ory. This is a type of long-term depression of synaptic transmis-
sion, a form of synaptic plasticity described in section 7.7.
In contrast to the role played by endocannabinoids in
learning and memory, exogenous THC obtained by smoking