RGS9‐2 differentially regulates adenylyl cyclase signaling by opioid and cannabinoid receptors in the mouse CNS

Abstract

Regulators of G‐protein signaling (RGS) proteins accelerate G‐protein inactivation. RGS9‐2 is expressed in the CNS, and we have reported that this RGS regulates mu opioid receptor function in vivo. Here we report effects of RGS9 knockout on inhibition of adenylyl cyclase by opioid and cannabinoid receptors in the CNS. Results showed increased inhibition of adenylyl cyclase by the opioid partial agonist morphine, but not the full mu agonist DAMGO, in nucleus accumbens of RGS9 knockout compared to wild‐type mice. Similarly, inhibition by the cannabinoid agonist WIN55,212‐2 was increased in this region. Thus, RGS9 negatively regulates opioid and cannabinoid receptor signaling in a brain region important in drug reward. The periaqueductal gray (PAG) and spinal cord are two regions important in antinociception by these drugs. Mu opioid but not cannabinoid receptor‐mediated inhibition of adenylyl cyclase was significantly greater in PAG of RGS9 knockout mice, whereas inhibition by either receptor was not different in spinal cord. Antinociception testing showed greater sensitivity to morphine, but not the cannabinoid Δ9‐tetrahydrocannabinol, in RGS9 knockout mice. These results demonstrate differential effects of RGS9 knockout on opioid and cannabinoid receptor function in brain regions that mediate drug reward and antinociception. Supported by NID A.