A pain-signaling pathway in the brain, modulated by the neurotransmitter GABAB, could be the source of a potential therapy for controlling chronic pain, according to a recent study partly funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS).

The study by Luc Jasmin, M.D., of the University of California, San Francisco and his colleagues from Harvard Medical School and Catholic University (Milan, Italy), looked at two pain-signaling pathways in animal models: communication between the RAIC (rostral agranular insular cortex, a small region of the cerebral cortex) and the amygdala (a brain area involved in pain, fear and attention), and between the RAIC and the locus coeruleus (an area involved in inhibiting pain signals from the brain to the rest of the body). Their work showed that signals from the RAIC to the amygdala--inhibited by GABAB --might be involved in chronic pain. When the RAIC sends signals to the amygdala, pain is experienced; equally, communication between the RAIC and the locus coeruleus increases pain. Therefore, increasing GABAB in the RAIC silences the pathway to the amygdala or the locus and decreases pain. Making matters more complicated, both signaling pathways act independently, and the one to the amygdala predominates. One can first decrease pain by blocking the pathway to the locus coeruleus and then increase pain by activating the pathway to the amygdala. Anesthetizing the amygdala then restores the initial condition of pain inhibition.

The RAIC employs two different GABA receptors--GABAA and GABAB--to communicate with the locus coeruleus and the amygdala, respectively. It might be possible, say the scientists, to inhibit the signals from the RAIC to the amygdala by manipulating GABAB receptors in the cerebral cortex. This might benefit patients who experience chronic pain. Most current therapies work "from the bottom up," focusing on peripheral areas where the pain is experienced. This research points toward an approach "from the top down": blocking the signals from the brain to the peripheral areas affected by pain.

Chronic pain is a debilitating feature of fibromyalgia and other rheumatic diseases of concern to the NIAMS. The National Institute of Neurological Disorders and Stroke (NINDS) also provided support for the study. NIAMS and NINDS are part of the National Institutes of Health within the Department of Health and Human Services. The study was published in the July 17, 2003, issue of Nature.

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Jasmin L, Rabkin SD, Granato A, Boudah A, Ohara PT. Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex. Nature 2003; 424 (6946): 316-20.

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