Unraveling glutamate-opioid receptor interactions using high-resolution electron microscopy: implications for addiction-related processes.

Adaptive responses in glutamate and opioid receptor systems in limbic circuits are emerging as a critical component of the neural plasticity induced by chronic use of abused substances. The present commentary reviews findings from neuroanatomical studies, with superior spatial resolution, that support a cellular basis for prominent interactions of glutamate and opioid receptor systems in preclinical models of drug addiction. The review begins by highlighting the advantages of high-resolution electron microscopic immunohistochemistry for unraveling receptor interactions at the synapse. With an emphasis on a recent publication describing the anatomical relationship between the μ-opioid receptor (MOR) and the AMPA-GluR2 subunit (Beckerman, M. A., and Glass, M. J., 2011. Ultrastructural relationship between the AMPA-GluR2 receptor subunit and the mu-opioid receptor in the mouse central nucleus of the amygdala. Exp Neurol), we review the anatomical evidence for opioid-induced neural plasticity of glutamate receptors in selected brain circuits that are key integrative substrates in the brain's motivational system. The findings stress the importance of glutamate-opioid interactions as important neural mediators of adaptations to chronic use of abused drugs, particularly within the amygdaloid complex.