Metabotropic mGluR5 - and adenosine A2A - receptor interactions in opioid addiction

Sherie Smith, Nicole Pochani, Ream Al-Hasani, Lisa Wells, Susanna Hourani, Ian Kitchen, Alexis Bailey. Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH, Surrey, United Kingdom.

There is substantial amount of evidence showing that mGluR5 receptors play an important role in opioid addiction [1] and chronic morphine treatment and long term withdrawal from that treatment up-regulates mGluR5 binding in brains of mice [2]. Functional interactions between mGluR5 receptors and striatal adenosine A2A-D2 dopamine receptor heterodimers have been implicated [3]. Furthermore, these interactions are hypothesised to play an important role in opioid addiction. To further investigate the mGluR5-A2A receptor interactions in the brain, we carried out quantitative autoradiographic mapping of the mGluR5 receptor labelled with [3H]MPEP in brains of naïve male CD-1 (8-12 week) wild-type (WT) and adenosine A2A receptor knockout mice (KO). Two way ANOVA showed a significant genotype effect (P<0.0001, n = 3-6) with no significant genotype x region interaction effect (P>0.05). A significant decrease (∼50%) in [3H]MPEP binding was observed solely in the striatal areas of adenosine A2A receptor KO mice compared to WT (nucleus accumbens shell P<0.05; nucleus accumbens core P<0.01; olfactory tubercle P<0.001) (Bonferonni post hoc test).

To investigate the influence of mGluR5 - A2A -receptor interaction in opioid addiction, we treated male CD-1 (8-12 week) WT and A2A KO mice with chronic intermittent saline and escalating dose morphine ((2 × 20 mg/kg/day on days 1 and 2, 2 × 40 mg/kg/day on days 3 and 4, 2 × 80 mg/kg/day on days 5 and 6 and 2 × 100 mg/kg/day on days 7 and 8 at 8 h intervals. i.p.) administration protocol which mimics the human pattern of opioid abuse. Horizontal locomotor activity was measured in these animals every day throughout the treatment protocol. Although there was a trend for A2A KO mice to be less sensitive to the locomotor effects of morphine, three-way ANOVA showed no significant genotype effect (n = 3-10). A significant treatment effect was observed over the 8 days duration of the study (P<0.01). Whether mGluR5-A2A interactions are involved in this effect remains to be determined.

This data clearly adds to the evidence for the presence of an mGluR5-A2A receptor interaction in the striatum which might be involved in opioid addiction.

1. Kalivas, P.W., Glutamate systems in cocaine addiction. Curr Opin Pharmacol, 2004. 4(1): p.23-9.

2. Bailey, A., et al., Withdrawal from chronic morphine, but not cocaine induce marked upregulation of mGluR5 binding in the mouse brain. pA2online.org, 2009. 7(4).

3. Nishi, A., et al., Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling. Proc Natl Acad Sci U S A, 2003. 100(3): p. 1322-7.