However, cocaine use disorder may develop when the MOR-DOR and MOR-MOR complexes are no longer able to cause sufficient inhibition of the GABA anti-reward neurons due to an irreversible and permanent brake on the D2R signaling in the A2AR-D2R-Sigma1R complex and/or insufficient release of enkephalins from these neurons. This evidence concerns the gene OPRM1 and cocaine use disorder.