Withdrawal from chronic morphine, but not cocaine induce marked upregulation of mGluR5 binding in the mouse brain

Alexis Bailey, Vanessa Viegas, Elisa Martignoni, Ian Kitchen. University of Surrey, Guildford, United Kingdom.

Evidence shows that the mGluR5 receptor plays an important role in opiate and cocaine addiction (Kalivas 2004). To determine whether chronic morphine and/or cocaine or acute or chronic withdrawal from morphine and/or cocaine alters mGlu5 density, we carried out quantitative autoradiographic mapping of the mGlu5 receptor labelled with [3H]MPEP in brains of mice treated with chronic morphine or cocaine and of mice acutely and chronically withdrawn from morphine or cocaine. Male C57BL/6J mice (20-25gr) were injected with saline or morphine i.p. twice a day at 8h interval (2 x 20mg/kg on days 1 and 2, 2 x 40 mg/kg on days 3 and 4, 2 x 80 mg/kg on days 5 and 6 and 2 x 100 mg/kg for days 7 and 8) or cocaine three times a day at 1h intervals (3 x 15 mg/kg for 15 days) or withdrawn from morphine or cocaine for 1 day (acute withdrawal) or 7 or 14 days for morphine and cocaine respectively (chronic withdrawal). Two way ANOVA carried out on the saline, morphine and morphine 1day withdrawal data revealed a significant effect of treatment (P<0.001). Chronic morphine caused a small but significant overall increase in mGlu5 binding which persisted during acute withdrawal in many brain regions (P<0.05, LSD post hoc test, n = 6-7). Two way ANOVA carried out on the saline 7day withdrawal and morphine 7day withdrawal data revealed a significant treatment (P<0.001) and treatment x region interaction (P<0.001). A dramatic 2-3 fold increase in [3H]MPEP binding was found in almost all the brain regions of chronically morphine withdrawn mice compared to controls (P<0.001, LSD post hoc test, n = 6-7) . In contrast, chronic cocaine treatment or acute or chronic withdrawal from cocaine had no significant effect on mGlu5 binding in any of the regions analysed (P>0.05, Two way ANOVA, n = 6-8) suggesting that the alterations in mGlu5 density are drug dependent. These data suggest that chronic opioid treatment, but especially chronic withdrawal from opioids, triggers alterations in the mGlu5 system which might play an important role in the mechanism of opioid craving after opioid abstinence followed by relapse. In addition, the results suggest that this effect is not observed for the psychostimulant cocaine.

Kalivas, P.W. (2004) Glutamate systems in cocaine addiction. Curr Opin Pharmacol, 4, 23-29.