How receptors govern inflammatory pain

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How receptors govern inflammatory pain

http://www.medicalnewstoday.com/medicalnews.php?newsid=16535 18 Nov 2004

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, A. Heppenstall, R. Lewin,

Claus Schott, Thilo Borchardt, 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.