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176 Chronic Pain: New Molecular Insights into Pain and Treatment
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demonstrating ATP P2Y receptor-mediated outward potassium currents.
Furthermore, local synaptic activation that triggers excitatory synaptic
responses showed no response at all in microglia cells [36]. LTP also did
not cause activation of microglia. Thus, it is likely that microglia do not
significantly contribute to fast synaptic transmission and synaptic plasticity. Similar results were found in the spinal cord dorsal horn [37].
Consistent with this finding, minocycline, an inhibitor of microglial activation, was not found to have any effect on two different forms of LTP
in the ACC of adult animals [38]. It is more likely that microglia or
microglia-related chemical factors may be involved in chronic brain
injury.
Enhancement of ACC top-down facilitation
Spinal sensory transmission occurs under descending biphasic modulation, and descending facilitation is believed to contribute to chronic pain
[39]. In addition to descending modulation from the brainstem rostral
ventromedial medulla (RVM), top-down facilitatory modulation of spinal
nociceptive transmission has been reported from the ACC [40]. Stimulation
of the ACC-potentiated spinal excitatory synaptic transmission and this
modulation is independent of the RVM. Peripheral nerve injury enhanced
the spinal synaptic transmission and occluded the ACC-spinal cord facilitation. Inhibition of ACC reduced the enhanced spinal synaptic transmission caused by nerve injury [40]. These findings indicate that ACC-spinal
top-down facilitation is enhanced after the injury in an RVM-independent
manner and that such top-down facilitation may contribute to the process
of chronic neuropathic pain.
Conclusions
Cortical synapses activated by painful signals are highly plastic and their
potentiation likely encodes the unpleasantness of pain and pain-related
emotional sufferings. Calcium-dependent signaling pathways play important roles in the induction and expression of such potentiation.
Cortical Sensitization and Reorganization 177
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Chapter 8
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NMDA NR2B
Study: Rodents’ Higher IQ May Come at Painful Price
By Rick Weiss, January 29, 2001
It hurts to be smart
That’s one conclusion from the latest study of so-called Doogie mice —
“smart” rodents that are genetically engineered to have enhanced memory
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and learning skills. Along with those extra IQ points, researchers have
found, comes an added sensitivity to some kinds of pain.
The new work offers a sobering lesson about the difficulty of enhancing certain brain functions without simultaneously taking a toll on others.
It also may temper whatever momentum there is to engineering genetic
enhancements in people. “Beware what you ask for,” said James L.
McGaugh, a neuroscientist at the University of California at Irvine. “And
when you get it, look carefully and see what else you got.” Doogie
mice— named after the precocious television character Doogie Howser,
MD — made a big splash when they were introduced to the world in
September 1999. Having been endowed with extra copies of a gene
involved in memory formation, the animals outperformed their normal
counterparts on a variety of tasks. They were better at recognizing objects
they had seen before, remembered painful experiences longer, recalled
with greater accuracy the location of submerged platforms in milky water,
and were better at “unlearning” old associations that were no longer true.
Some scientists sniffed at the suggestion that the mice were particularly brainy, noting that intelligence is much more than a collection of four
or five mental skills. Nonetheless, the work was surprising because it was
the first to show that by adding a few extra copies of a single gene to an
embryo, researchers could improve an animal’s performance on a range of
memory and learning tasks. Some suggested that drugs designed to mimic
the gene’s effects might help Alzheimer’s patients or even make sharp
people sharper. The new work hints that it won’t be that easy.
Min Zhuo and his colleagues at Washington University School of
Medicine in St. Louis assessed how the Doogie mice responded to tissue
damage and inflammation. They suspected that sensations of pain caused
by those types of injury may be controlled by the same “NR2B receptor”
that Doogie mice are overendowed with and that gives the animals their
superior memories. NR2B receptors are proteins that act as “coincidence
detectors” in the brain. They recognize, for example, when a certain sound
is linked to the arrival of food and help consolidate such coincidences into
learned associations.
The researchers subjected the mice to stimuli that cause either shortterm or long-term pain. They heated the animals’ tails, poked their foot
pads with stiff fibers, and injected their paws with irritating solutions.
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Then they used molecular and neurological tests to see how the animals’
brains responded and tracked the animals’ behavior, measuring, for example, how long they licked the site of injury.
Those tests indicated that, compared with normal mice, Doogie mice
are equally sensitive to short-term pain. But chronic inflammatory pain,
such as that caused by the injected irritants, lasts significantly longer in
Doogie mice. The team reported in today’s issue of the journal of Nature
Neuroscience: “Our results suggest that a genetic manipulation conferring
enhanced cognitive abilities may also provide unintended traits, such as
increased susceptibility to persistent pain.” Other scientists conceded that
it is difficult to know what mice are experiencing because they cannot
talk. Even in people, the physical and cognitive components of pain are
deeply integrated. Still, several scientists have now said that the new study
offers strong substantiation that a Doogie mouse’s pain is real. “This is
very convincing evidence” that the mice have prolonged chronic pain
responses, said McGaugh, who directs U.C. Irvine’s center for the neurobiology of learning and memory. Moreover, he said, the finding makes
sense. “Most of our brain regions are multipurpose. These things are all
intertwined.”
Indeed, as others have said, evolution rewards creatures that find more
than one use for things, especially things as useful as a neural coincidence
detector. “When nature finds an effective mechanism, it’s used and
reused,” said Ira Black, chairman of neuroscience and cell biology at the
Robert Wood Johnson Medical School in Piscataway, N.J. That’s why so
many drugs have unwanted side effects, and the same will probably prove
to be true for new drugs that may someday take aim at NR2B, Black said.
People who try to make smarter babies with NR2B genes, or boost their
own memory with NR2B drugs, may have to accept some level of chronic
pain. Alternatively, those who seek to kill their pain with NR2B-blocking
drugs may also have to accept some cognitive side effects.
“You can’t have it both ways,” Black said.
Summary
The NMDA receptor is known to be critical for learning-related central
plasticity. Recent evidence indicates that NMDA receptor-dependent
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plasticity is not unique to cognition-related plasticity. NMDA receptors,
located in pain-related sensory synapses, are important for injury-related
plasticity, from the spinal dorsal horn to the cortical synapse. Furthermore,
injury triggered not only changes in glutamate AMPA receptor-mediated
responses but also NMDA receptor-mediated responses, including NMDA
NR2B receptors. Therefore, targeting NMDA NR2B receptors as a potential target for chronic pain may serve dual functions, first to prevent
injury-induced new plasticity and, second, to reduce established plasticity
mediated by NMDA NR2B receptors.
Keywords: NMDA receptor; NR2B (GluN2B); ACC; IC; LTP; smart
mice; chronic pain; AC1
Introduction
The NMDA receptor is a major type of ionotropic glutamate receptor in
the CNS and plays a fundamental role in both synaptic transmission and
plasticity [1–4]. NMDA receptor-dependent synaptic plasticity is a key
cellular model for studying central brain functions, including learning and
memory, chronic pain, and drug addiction. For example, NMDA receptordependent LTP in the hippocampus contributes to the formation of longterm memory. In the ACC, NMDA receptor-dependent LTP plays an
important role in injury-triggered cortical excitation and plastic changes.
In this short review, we will review the progress made in NMDA receptordependent, and -independent, synaptic plasticity in the ACC, including
LTP and LTD. The contribution of different types of NMDA receptors will
be discussed. We believe that foundational knowledge of cortical plasticity will provide novel protein targets for better treatment of different
forms of brain disease, including chronic pain, anxiety, and memory loss.
NMDA receptors and their subtypes
NMDA receptors are 5–10 times more permeable to Ca2+ than to Na+ or
K+ and are a critical intracellular signaling molecule for triggering postsynaptic, and possible presynaptic, plastic changes. The NMDA receptor
subunits consist of three families: GluN1, GluN2 (GluN2A, -2B, -2C,
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and -2D), and GluN3 (GluN3A and GluN3B). Structural studies have
already reported that NMDA receptors are assembled in tetrameric form,
in which two GluN1 subunits and two GluN2 and/or GluN3 subunits are
combined together as di-heteromeric or tri-heteromeric receptors. The
subunit composition varies during neurodevelopment and determines the
channel properties of NMDA receptors [5,6]. In general, NMDA receptors demonstrate slower kinetics which enables relatively longer permeability of Ca2+ once activated in the presence of glutamate and the
co-agonist glycine. Depolarization relieves the block of Mg2+ in a voltagedependent manner and then Ca2+ influxes through the NMDA receptor
channel, triggering a cascade of intracellular events that cause the change
of synaptic plasticity. Aside from the postsynaptic NMDA receptors,
presynaptic NMDA receptors have also been reported to modulate glutamate release, and extra-synaptic NMDA receptors are involved in synaptic plasticity [7–11].
NMDA receptor in the ACC neurons
Glutamate is the major excitatory neurotransmitter in the ACC. NMDA
receptor plays a significant role in the ACC [4,12,13]. In the ACC, an
NMDA receptor-mediated field potential was recorded after applying
antagonists of AMPA and KA receptors. This potential was sensitive to
the antagonist of NMDA receptor, AP-5 [14]. Similarly, an electrically
evoked NMDA receptor-dependent calcium signal was recorded in the
ACC neurons [12,15]. In addition, it was found that NMDARs act as key
molecules in the synaptic plasticity of the ACC neurons. Application of
AP-5 completely blocked the induction of pairing training and TBSinduced LTP in the ACC of adult mice [16]. Interestingly, after the LTP
induction, NMDA receptor-mediated currents were decreased, which suggests that the expression of LTP in the ACC is NMDA receptor-independent. On the other hand, NMDA receptors in the ACC have also been
reported to be involved in another form of synaptic plasticity: LTD. LTD
induced by a ‘pairing training’ protocol can be blocked by applying AP-5
[17]. Therefore, NMDA receptors in the ACC neurons are a crucial part of
the physiological process.
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