Similar to the effects of methamphetamines, chronic morphine treatment increases GFAP expression in brain regions involved in addictive disorders: ventral tegmental area (VTA), NAcc, and PFC (Beitner-Johnson et al. 1993; Song et al. 2001; Marie-Claire et al. 2004). Furthermore, the gliotoxin fluorocitrate reduces morphine-induced GFAP immunoreactivity and mitigates tolerance (Song et al. 2001). Finally, morphine tolerance and blunted analgesia correlate with glutamate transporter down-regulation in the spinal cord (Mao et al. 2002). The glutamate transporter stimulator MS-153 significantly reduces conditioned place preference (CPP) in mice treated with opioids (and psychostimulants) without altering locomotion (Nakagawa et al. 2005). MS-153 also attenuates morphine tolerance and reduces the signs/symptoms of opioid dependence (Nakagawa et al. 2001). Furthermore, adenovirally mediated intra-NAcc shell EAAT2/GLT-1 transduction reduces morphine-induced CPP (Fujio et al. 2005). Therefore, astrocyte-based glutamatergic dysfunction is important in the initiation and maintenance of opioid misuse, and targeting these deficits reduces some of the core features of dependence, e.g., CPP.
