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.