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Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex


It is known that pain perception can be altered by mood, attention and cognition, or by direct stimulation of the cerebral cortex1, but we know little of the neural mechanisms underlying the cortical modulation of pain. One of the few cortical areas consistently activated by painful stimuli is the rostral agranular insular cortex (RAIC) where, as in other parts of the cortex, the neurotransmitter γ-aminobutyric acid (GABA) robustly inhibits neuronal activity. Here we show that changes in GABA neurotransmission in the RAIC can raise or lower the pain threshold—producing analgesia or hyperalgesia, respectively—in freely moving rats. Locally increasing GABA, by using an enzyme inhibitor or gene transfer mediated by a viral vector, produces lasting analgesia by enhancing the descending inhibition of spinal nociceptive neurons. Selectively activating GABAB-receptor-bearing RAIC neurons produces hyperalgesia through projections to the amygdala, an area involved in pain and fear. Whereas most studies focus on the role of the cerebral cortex as the end point of nociceptive processing, we suggest that cerebral cortex activity can change the set-point of pain threshold in a top-down manner.

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Figure 1: Cortical injection sites and nociceptive heat paw-withdrawal responses.
Figure 2: Immunocytochemistry of the RAIC, amygdala and brainstem.
Figure 4: Summary of the main findings of the present study.
Figure 3: Nociceptive threshold and Fos immunoreactivity after drug treatment.


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We thank J. D. Levine for critical comments, H. J. Ralston for support and encouragement, K. New for constructing the viral vector, U. MacGarvey for assistance with histochemistry, and G. Janni for editorial assistance. This work was funded by NIH (L.J.), NINDS (S.D.R.) and the Koret Foundation (P.T.O.).

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Correspondence to Luc Jasmin or Peter T. Ohara.

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The authors declare that they have no competing financial interests.

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Jasmin, L., Rabkin, S., Granato, A. et al. Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex. Nature 424, 316–320 (2003).

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