Chronic morphine exposure and spontaneous withdrawal are associated with modifications of dopamine receptor and neuropeptide gene expression in the rat striatum

Abstract

The influence of chronic morphine and spontaneous withdrawal on the expression of dopamine receptors and neuropeptide genes in the rat striatum was investigated. Morphine dependence was induced by subcutaneous implantation of two morphine pellets for 6 days. Rats were made abstinent by removal of the pellets 1, 2 or 3 days before they were killed. The mRNA levels coding for D1- and D2-dopamine receptors, dynorphin, preproenkephalin A and substance P were determined by quantitative in situ hybridization. The caudate putamen and the nucleus accumbens showed equivalent modifications in dopamine receptor and neuropeptide gene expression. After 6 days of morphine, a decrease in D2-dopamine receptor and neuropeptide mRNA levels was observed (-30%), but there was no change in D1-dopamine receptor mRNA. In abstinent rats, both D1- and D2-dopamine receptor mRNA levels were decreased 1 day after withdrawal (-30% compared with chronic morphine). In contrast, neuropeptide mRNA levels were unaffected when compared with those observed after 6 days of morphine. During the second and third day of withdrawal, there was a gradual return to the levels seen in the placebo-treated group, for both dopamine receptor and neuropeptide mRNAs. Phenotypical characterization of striatal neurons expressing mu and kappa opioid receptor mRNAs showed that, in striatonigral neurons, both mRNAs were colocalized with D1-receptor and Dyn mRNAs. Our results suggest that during morphine dependence, dopamine and morphine exert opposite effects on striatonigral neurons, and that effects occurring on striatopallidal neurons are under dopaminergic control. We also show that withdrawal is associated with a down regulation of the postsynaptic D1 and D2 receptors.

μ Opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers

“…Thus, the reduction of PENK mRNA expression in the NAc would seem to reflect the long-term chronic state of heroin use. Multiple rat studies have reported similar reduced striatal PENK mRNA levels after repeated morphine exposure (31,32). The repeated presence of heroin in the brain is expected to function as ''endogenous enkephalin'' and lead to a counterbalance of decreased PENK expression.…”

Adolescent Cannabis Exposure Alters Opiate Intake and Opioid Limbic Neuronal Populations in Adult Rats

“…The discrete THC-induced impairment of NAc PENK appears to be unique since alterations of the enkephalin system associated with repeated intake of other substances of abuse (Uhl et al, 1988) or highly rewarding food (Kelley et al, 2003) is normally widespread throughout the striatum. The apparent relative enhancement of NAc shell PENK gene expression in THC animals even after repeated opiate exposure, which generally decreases PENK transcription (Georges et al, 1999;Uhl et al, 1988), suggests a persistent disturbance of the enkephalin reward system with early THC exposure. Long-term disturbance of the PENK system appears a common feature of early THC exposure since we have recently observed a similar selective increased PENK mRNA expression in the NAc of adult offspring with THC exposure limited to the prenatal period; these animals also showed increased heroin intake (Spano et al, 2006).…”

Expression of Neural RGS-R7 and Gβ5 Proteins in Response to Acute and Chronic Morphine

“…Long-term haloperidol administration or irreversible blockade of D2 dopamine receptors decreases m receptor mRNA and protein density in the striatum (Chen et al, 1994;Delfs et al, 1994;Bower et al, 2000). Regulation in the other direction has also been described: chronic morphine exposure and spontaneous withdrawal produce reductions in striatal D1 and D2 dopamine receptor mRNA (Georges et al, 1999). In m-opioid receptor knockout mice, dopamine receptor D1/D2 mRNA expression is increased in the striatum (Park et al, 2001).…”