Dopamine reuptake inhibition in the rostral agranular insular cortex produces antinociception.

We provide evidence for an antinociceptive effect of dopamine in the rat cerebral cortex that is mediated through descending nociceptive inhibition of spinal neurons. Injection of the dopamine reuptake inhibitor GBR-12935 in the rostral agranular insular cortex (RAIC), a cortical area that receives a dense dopaminergic projection and is involved in descending antinociception (Burkey et al.,1996), resulted in dose-dependent inhibition of formalin-induced nociceptive behavior, without any alteration of motor function. Injection of the dopamine reuptake inhibitor in the surrounding cortical areas had no effect on nociceptive behaviors. GBR-12935 also produced a reduction in noxious stimulus-induced c-fos expression in nociceptive areas of the spinal dorsal horn, suggesting that dopamine in the RAIC acts in part through descending antinociception. Electrophysiological recording from single wide dynamic range-type spinal dorsal horn neurons confirmed the descending nociceptive inhibitory effect. GBR-12935 in the RAIC significantly reduced neuronal responses evoked by noxious thermal stimulation of the skin, an effect that was reversed by local administration of the selective D1 receptor antagonist SCH-23390. Finally, administration of SCH-23390 alone in the RAIC decreased paw withdrawal latencies from noxious heat, suggesting that dopamine acts tonically in the cortex to inhibit nociception.