In our studies using adult mice we identified strong effects of DCC on three clinically important opioid maladaptations. Since none of these would be considered directly analogous to the stimulant-related phenotypes studied by other investigators, DCC would not likely have been targeted for study in relation to the effects of opioids based on the existing stimulant drug response data alone. Rather, the genetic analysis formed the basis for our hypotheses. Distinct from the results obtained using stimulant drugs, we failed to identify morphine-induced effects on Dcc expression either at the mRNA or protein levels in spinal cord tissue, a major neuronal relay station involved in opioid tolerance and opioid-induced hyperalgesia [3, 42]. However, such drug-induced changes may not be necessary if functionally important but as yet unidentified differences in CNS structure between the strains of mice exist even before drug exposure, or if different Dcc alleles cause differences in function rather than expression. The latter possibility might be caused by one of the identified SNP variants predicted to change amino acid sequence. In this respect the A713V variant is of
