How receptors govern inflammatory pain

November 17, 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, 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.
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Cell Press

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