While Dcc has not to this point been reported as a specific gene regulating pain or opioid-related phenotypes, the Dcc gene has received significant attention in addiction-related research. Much of this work has centered on the development and adult plasticity of the mesocorticolimbic dopamine system, a key neural substrate of the actions of drugs of abuse [40, 41]. In adult rodents, sensitizing regimens of amphetamine lead to up-regulation of DCC protein levels in the ventral tegmental area (VTA), the cell body regions of mesocorticolimbic dopamine neurons. Amphetamine-induced increases in VTA DCC protein levels are prevented by co-administration of NMDA receptor antagonists [32], seems to lead to changes in synaptic plasticity, and is required for the development of behavioral sensitization to stimulants [25]. Notably, adult Dcc heterozygous mice do not develop behavioral sensitization to amphetamine and fail to show reorganization of VTA synaptic connectivity [25]. Similarly, exposing adult Dcc heterozygous mice to morphine resulted in a reduced severity of opioid maladaptations. It is possible that the reduction in morphine-induced effects in the heterozygous mice is the result of impaired morphine-induced spinal synaptic plasticity especially in light of DCC’s link to the NMDA receptor, a key structure in OIH and tolerance [3].
