Modulatory Effects Of Midbrain κ-opioid Receptor System On Morphine-induced Dependence In Rat

Opioid dependence remains a serious medical and social issue.Neurobiological and pharmacological studies have revealed that there is a direct correlation between the mesocorticolimbic system and opioid dependence.Opioids,such as morphine, disinhibit the dopaminergic neurons by activating theμ-opioid receptor on the GABAergic interneurons in ventral tegmental area(VTA).The subsequent DA efflux in the dopaminergic projecting targets(such as nucleus accumbens,medial prefrontal cortex) is believed to be initial events that trigger reward and dependence.In addition, exposure to opioids results in activation of some transcription factors,such as CREB and Fos family.ΔFosB,a truncated splice variant of full-length FosB,is considered to be a molecular switch of addiction.Kappa-opioid receptor,as well as its endogenous ligand dynorphin,hss a wide distribution in central nervous system.Activation of theκ-receptor antagonizes variousμ-receptor-mediated actions in the brain.κ-agonists inhibit the DA neurons and DA release,whileμ-agonists activate the dopaminergic neurotransmission.μ-agonists produce euphoria and function as positive reinforcers.In contrast,κ-agonists produce dysphoria and function as negative reinforcers.Taking together,μ-andκ-receptor act as an opposing pair in opioid signaling in the brain.Evidence is increasing to indicate that activation ofκ-opioid receptor suppress the morphine dependence.U-50488,a selectiveκ-agonist,abolishes the reinforcing effects of morphine in both self-administration and conditioned place preference paradigms.Without any effect by its self,selective-antagonist nor-BNI blocks the inhibitory effects of U-50488 on the morphine dependence.On the other hand,DA release stimulated by addictive drugs is exacerbated inκ-receptor knockout mice.The dual modulations of the midbrain dopaminergic system byμ- andκ-receptors may underlie the mechanism through whichκ-agonist inhibits the morphine dependence.It has long been recognized that drug dependence processing relies heavily on mesocorticolimbic DA systems,comprising DA neurons in VTA and their projections to NAc,mPFC and other forebrain regions.Recently,major efforts have attempted to specify what functionκ-receptor contribute in VTA.Doesκ-receptor exist in VTA? Doesκ-receptor in VTA exert an inhibitory effect of DA neurotransmission? Does intra-VTA administration ofκ-agonist inhibit morphine dependence and what is the mechanism? We are now trying to explore these issues.Using the real-time quantitative PCR and western blot tequniques,we measure theκ-receptor mRNA and protein levels in mPFC,NAc and VTA.Acute exposure to morphine increases the mRNA levels in all three regions,but have no significant effects on protein levels.After chronic exposure to morphine,whereasκ-receptor mRNA returns to basal level in NAc and VTA,the relatively modest induction in mPFC persists.Moreover,κ-receptor protein levels decrease in mPFC and VTA,but remain unchanged in NAc.These results suggest the involvement of mesocorticolimbicκ-receptors in the development of morphine dependence.Given the findings metioned above,we speculate that intra-VTA administration ofκ-agonist might influence the morphine dependence.Thus,the effects of U-50488 following VTA microinjetion on the morphine dependence were evaluated in behavior models of conditioned place preference and locomotor sensitization.Intra-VTA administraion of U-50488,at the doses we tested,did not produce significant effects on place conditioning and locomotor activity in naive rats.However,the morphine-induced place preference and locomotor sensitization were attenuated in U-50488-treated rats,suggesting a VTAκ-receptor-mediated mechanism in the modulation of morphine depedence.In further studies,we explored the neurochemical and neurobiological mechanisms through whichκ-agonist inhibit the morphine dependence.We found that acute exposure to morphine elevated the DA turnover in NAc and mPFC extracts. These elevations were significantly suppressed in extracts obtained from the rats treated with U-50488.A similar tendency was observed in animals received chronic drug administration,although there were no significant changes in DA turnover.In microdialysis study,U-50488,following microinjection into VTA,also attenuated the morphine-induced elevation of DA metabolite(HVA) and 5-HT metabolite(5-HIAA). In addition,the number of FosB-positive neurons significantly increased in mPFC and NAc during the development of locomotor sensitization.U-50488,following microinjection into VTA,reduced the number of FosB-positive neurons significantly, indicating that the inhibitory effects of intra-VTA U-50488 on morphine dependence might be related to its modulatory effects on expression of the transcription factor FosB.In conclusion,κ-opioid receptor in VTA was found to be involved in the morphine dependence.Activation of theκ-opioid receptor in VTA exhibits inhibitory effects on morphine-induce place preference and locomotor sensitization.The mechanism is related to its modulation on DA release and FosB expression.