Using a genetic murine model for opioid addiction and linkage analysis, we identified a chromosome 10 locus (later defined as the mu opioid receptor [OPRM] gene) that determines 50% of the variance in how much morphine a mouse consumes during a two-bottle choice paradigm experiment. If the murine addiction model partially reflects a human genetic vulnerability to opioid dependence (OD), then study of the human OPRM gene will reveal DNA sequence variants which predispose individuals to OD. This application proposes to study-200 OD patients with parents, to examine OPRM gene sequence variants as potential susceptibility factors for OD. OPRM gene variants which predispose to OD should be transmitted to OD individuals by their parents more often than expected by chance in a haplotype relative risk analysis. Single-stranded conformational polymorphism (SSCP) and DNA sequencing has been used to examine exons one and two of the human OPRM gene. OPRM exonic nucleotide variation (which alters amino acid sequence) was seen in exons 1 and 2 among 55 OD individuals. One or more of these exonic variants may represent a genetic susceptibility factor for OD. These data indicate that exonic variation in the human OPRM gene exists, and a more extensive examination of the OPRM gene sequence may be useful in understanding genetic susceptibility to OD. Genes for dopamine neurotransmission will also be studied, because independent lines of evidence suggest that dopamine neurotransmission in the mesocorticolimbic pathway is important in the rewarding aspects of opioid drugs.
