Grant: Project Grant

Nausea is a distressing condition that occurs commonly and is very hard to treat. Currently available treatments for nausea and vomiting more effectively control vomiting than nausea. Overall, nausea is currently reported as the most distressing side effect of chemotherapy, and one that often leads patients to discontinue treatment. Nausea is reduced by the active ingredient in marihuana, delta-9-Tetrahydrocannabinol (THC), by its action on cannabinoid 1 (CB1) receptors. The CB1 receptors are naturally activated by chemicals produced in the brain, called endocannabinoids. The action of endocannabinoids, however, is very short, because enzymes break them down rapidly. Drugs which inhibit these degrading enzymes dramatically prolong the action of the endocannabinoids and also suppress nausea in rats. The area of the cerebral cortex that regulates nausea is the interoceptive insular cortex, a region that receives neural input from the gut. Serotonin in this region triggers nausea and drugs that act on CB1 receptors in this region reduce nausea. The primary effect of activating CB1 receptors is to reduce the release of neurotransmitters, including serotonin. As well, the primary non-psychoactive cannabinoid in marihuana, cannabidiol (CBD), also reduces nausea by reducing forebrain release of serotonin. We will test the hypothesis that the sensation of nausea is triggered by serotonin release within the interoceptive insular cortex, and the anti-nausea effect of endocannabinoids and CBD is the result of "turning off" the release of serotonin in this region. The results of these experiments will provide a better understanding of the neural regulation of nausea, and will lead to new treatments of this difficult to control condition.