The development of tolerance and addiction to morphine is thought to involve 'anti-opioid' systems that include some types of glutamate receptor. In the Journal of Neuroscience, Inoue et al. show that both tolerance and dependence require a specific receptor subtype, but that they are mediated by different brain areas.

The authors investigated the effects of morphine in mice lacking the gene for the NR2A subunit (also called GluRε1) of the N-methyl-D-aspartate (NMDA) receptor. The NR2A-knockout mice showed an increase in the acute analgesic effect of morphine, but the ability of morphine to induce tolerance or dependence was reduced in these mice.

In control mice, chronic treatment with morphine that was sufficient to induce tolerance also caused an increase in levels of NR2A in certain areas of the brain: the periaqueductal grey, the ventral tegmental area and the nucleus accumbens.

To investigate the roles of these areas more fully, Inoue et al. induced expression of NR2A by electroporating the gene into specific nuclei in the brains of adult mice. Expression of NR2A in either the periaqueductal grey or the ventral tegmental area — but not the nucleus accumbens — rescued the ability of morphine to induce tolerance in the mutant mice.

Induction of dependence by a different treatment protocol also increased NR2A expression in normal mice, but in this case the increase was only in the nucleus accumbens. Consistent with this, knockout mice in which NR2A was expressed in the nucleus accumbens became susceptible to morphine dependence.

The new results support the idea that an increase in NR2A in specific brain areas might contribute to the development of tolerance and dependence by acting as part of an 'anti-opioid' system. Local electroporation of receptor genes into the brains of knockout mice could represent a useful approach for investigating these and other effects.