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Ed. Note: The following
is a press release from Cell Press.
Researchers have shown in animal studies how receptors on nerve cells can
become altered to produce chronic pain triggered by inflammation. They say
that their findings could aid in developing new drugs to treat such
chronic pain, which is distinct from the relatively short-lived pain from
injury, which fades as the injury heals.
In their experiments, Bettina
Hartmann and her colleagues studied receptors called AMPA receptors, which
are triggered by the neurotransmitter glutamate. Such receptors are
protein switches that nestle in the membranes of nerve cells and, when
triggered, induce either short-term or long-term changes in the nerve
cells. A short-term change might be the triggering of a single nerve
impulse; but AMPA receptors have been implicated in long-lasting changes
such as adjusting the strength of nerve cell connections, or synapses, in
learning and memory. AMPA receptors regulate nerve cell response by
opening to enhance calcium flow into the cell, heightening the cells'
sensitivity to producing nerve impulses when triggered.
According to Hartmann and her
colleagues, studies of spinal cord tissue showed that AMPA receptors are
found in spinal cord regions known to be responsible for pain sensing, or
nociception. However, they said, there had been no studies that explored
what role the receptors played in whole animals.
To study that role, the
researchers genetically altered mice to lack one or another type of key
component, or subunit, of the AMPA receptor protein. Knocking out one type
of subunit, called GluR-A, would enhance AMPA permeability to calcium; and
knocking out the other, called GluR-B, would reduce its permeability.
Normally, the relative fraction of AMPA receptors with GluR-A or GluR-B on
the surfaces of nerve cells would determine the cell's permeability to
calcium.
Importantly, the researchers
found that both of the types of deficient mice showed normal response to
discomforting stimuli, such as heat. Thus, their pain responses were
otherwise normal.
However, when the researchers
used chemicals to induced an artificial inflammation in the paws of the
deficient mice, they found significant differences in responses between
the two mutant mouse strains. The strain with increased permeability of
their AMPA channels was significantly more sensitive to heat or mechanical
pressure on their inflamed paws than were either the strain of mice with
"closed" AMPA channels or the normal mice.
In similar tests, the
researchers also found that the altered mice with more permeable AMPA
channels showed evidence of greater persisting pain from inflammation,
compared with the altered mice with less permeable channels. According to
Hartmann and her colleagues, this difference "supports that acute,
short-term plasticity at central nociceptive synapses is dependent on AMPA
receptors and their composition."
The researchers also cited
evidence from other laboratories that AMPA receptors might be involved in
pain-related changes in the brain that are "involved in the perception,
memory, and emotional modulation of pain."
The researchers concluded that
"the present study demonstrates that AMPA receptors are important
determinants of pathological nociceptive sensitivity and suggests their
potential relevance in the therapeutic approaches toward the prevention
and treatment of chronic inflammatory pain.
Bettina Hartmann, Seifollah
Ahmadi, Paul A. Heppenstall, Gary R. Lewin, Claus Schott, Thilo Borchardt,
Peter H. Seeburg, Hanns Ulrich Zeilhofer, Rolf Sprengel, and Rohini Kuner:
"The AMPA Receptor Subunits GluR-A and GluR-B Reciprocally Modulate Spinal
Synaptic Plasticity and Inflammatory Pain"
Publishing in Neuron, Volume 44,
Number 4, November 18, 2004, pages 637–650.
http://www.neuron.org/.
Contact: Heidi Hardman
hhardman@cell.com
1-617-397-2879
Cell Press
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