The brain is particularly vulnerable to drugs of abuse changing the neuroreceptor functions. Opiates interact and overstimulate heterogeneous opioid receptors leading to their desensitization, internalization, and activation of recombinant opioid receptor. The molecular properties of rat and human brain recombinant mu-delta receptor were compared with those of purified mu- and delta-receptors. cDNA coding the unique fragment of recombinant mu-delta receptor was isolated and sequenced. We hypothesized that recombinant mu-delta receptor may be a hallmark of opiate abuse. Peptide fragments of the mu- (MOR), delta- (DOR), and recombinant mu-delta- (MDOR) receptors were used as antigens to assess the presence of autoantibodies in the blood of rats that self-administered heroin and cocaine, as well as drug abusers. Significant steady elevation of MDOR autoantibodies were measured in sera of rats that self-administered heroin compared to that for cocaine and vehicle animals. The appearance and increased level of MDOR autoantibodies in opiate abusers correlated with severity of the disorder and duration of drug exposure.