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ABSTRACT Despite several years of research, the aetiology of Parkinson's disease (PD) is quite far from being solved. In PD, as well as in other neurodegenerative disorders, it has been proposed that the combination of multiple factors might contribute to the onset of the disease. Indeed, several authors have suggested that environmental factors, such as pollutants and chemicals, might be associated with the onset of several neurodegenerative disorders. On the other hand, several studies have described that the nociceptin/orphanin-NOP and prodynorphin-KOP opioid systems are implicated in the pathology of Parkinson's disease. Considering the nonrestricted commercial availability and common use of several pesticides, such as paraquat and maneb, in agriculture of less developed countries, the aim of our study was to investigate the involvement of nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Our results showed that after paraquat/maneb (5/15 mg kg−1) treatment, a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis, was observed. Also, the association of paraquat and maneb (5/15 mg kg−1) induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after both treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these agrochemicals might be implicated in the mechanisms underlying sporadic Parkinson's disease. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 656-663, 2015. [ABSTRACT FROM AUTHOR]

Several studies demonstrated the role of the endogenous opioid system in the development of susceptibility to alcohol dependence. Recently, we reported that binge intragastric administration of ethanol induces selective alterations of pronociceptin and prodynorphin gene expression in the rat amygdala complex depending on the days of exposures and on the development of tolerance and dependence. The aim of the present study was to investigate the potential epigenetic mechanisms leading to these alcohol-induced changes in gene expression. Specific histone modifications and DNA methylation at opioid peptide precursor promoters were analyzed by chromatin immunoprecipitation and real-time methylation-specific PCR, respectively. We found a linkage between gene expression alterations and epigenetic modulation at pronociceptin and prodynorphin promoters following alcohol treatment. In animals treated for 1 day, we observed a reversed correlation, with a decrease of histone 3 lysine 27 trimethylation (repressive mark) and an increase of histone 3 lysine 9 acetylation (activating mark), associated with both gene expression up-regulation. In rats treated with alcohol for up to 5 days, we found an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter providing further evidence of the already proposed possible role for histone deacetylases for addiction treatment. No significant alterations in DNA methylation and histone 3 lysine 4 trimethylation following different alcohol exposures were present, suggesting the selectivity of epigenetic effects induced by alcohol. These data demonstrate that ethanol induces selective epigenetic changes, thus better defining the role of opioid peptides in the ethanol-induced effects in the amygdala complex. [ABSTRACT FROM AUTHOR]

The amphetamine analogue 3,4-methylendioxymetamphetamine (MDMA, Ecstasy) causes complex adaptations at the molecular and cellular levels altering the activity of different brain neurotransmitters. The present study aims to verify the effects of single and repeated injections of MDMA on dynorphin and nociceptin systems gene regulation in the brainstem, an area rich in neurons containing serotonin. Both acute and chronic (twice a day for 7 days) MDMA (8 mg/kg) induced a marked increase in prodynorphin mRNA levels as well as in cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation, without causing any effect on kappa opioid receptor or nociceptin system (both pronociceptin and its receptor) genes expression, in this brain region. The blockade of 5HT1/5HT2 receptors by methysergide abolished the acute MDMA-induced increase in prodynorphin. Moreover, the concomitant chronic administration of both methysergide and MDMA (7 days) induced a significant increase in all the dynorphin or nociceptin system genes expression and in CREB and ERK phosphorylation. Our data suggest the involvement of dynorphin in the effects evoked by MDMA in the brainstem, possibly via CREB and ERK1/2 cascade activation, since the ERK inhibitor PD98059 prevented the MDMA-induced prodynorphin gene expression, and, acutely, also through the involvement of serotoninergic mechanisms. Chronically, it is also possible to hypothesize a general inhibitor role of serotonin in the effects evoked by MDMA. Moreover, these findings strengthen the hypothesis, already proposed, of a neuroprotective role for both CREB and dynorphin. [ABSTRACT FROM AUTHOR]

Abstract: It has been suggested that the opioid-like neuropeptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOPr) may contribute to Parkinson''s disease. Based on this idea, the aim of our study was to investigate the involvement of the N/OFQ–NOPr system in an animal model of Parkinson''s disease and to evaluate if this neuropeptidergic system is acting through mechanisms involving glutamate and/or GABA. We injected the neurotoxins MPP+ or 6-OHDA into the cerebral ventricles and 10 days later measured N/OFQ and NOPr gene expression in caudate putamen (CP) and substantia nigra (SN), by RT-PCR. A large reduction in N/OFQ and NOPr mRNAs was observed in the CP of rat treated with either MPP+ or 6-OHDA, MPP+ being more effective than 6-OHDA. Both the neurotoxins induced an increase in N/OFQ gene expression in the SN, but only MPP+ evoked a significant down-regulation of NOPr in this area, showing a slight trend of reduction in 6-OHDA treated rats. Moreover, a reduction in the levels of glutamic acid decarboxylase (GAD65/67), an enzyme that converts the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA), was also observed in the SN following 6-OHDA. These data suggest that DA modulates N/OFQ–NOPr system gene expression in SN and CP, strengthening the hypothesis that this neuropeptidergic system could be implicated in the mechanisms underlying Parkinson''s disease. Our data might also suggest that the GABAergic system plays a role in the regulation of nigral function, although further studies are necessary to confirm this hypothesis. In agreement with previous studies, we also support the hypothesis of a potential value for NOP receptor antagonists to attenuate symptoms related to the degeneration of nigrostriatal dopaminergic pathway. [Copyright &y& Elsevier]

Abstract: DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) is a potent endogenous inhibitor of protein phosphatase-1, which plays an important role in dopaminergic transmission. A large body of evidence supports the key role of DARPP-32-dependent signalling in mediating the actions of multiple drugs of abuse, including cocaine, which, when acutely administered, increases the Thr34 phosphorylation of DARPP-32 in the striatal and cortical areas. In this study, we have examined the contribution of the kappa opioid system to the regulation of DARPP-32 phosphorylation at Thr34, following acute cocaine administration, in selected rat brain areas. Results showed that a single injection of cocaine induces a significant increase in DARPP-32 phosphorylation at Thr34 in the hippocampus, caudate putamen and prefrontal cortex. In addition, pretreatment with the kappa opioid receptor agonist U-69593 prevented cocaine effects in all the investigated areas. These data could be considered consistent with the ability of kappa opioid agonists to attenuate many behavioural and neurochemical effects of cocaine. [Copyright &y& Elsevier]

Cocaine binds to dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters blocking the reuptake of these monoamines into presynaptic terminals. As previously reported, continuous infusion of cocaine for seven days or GBR 12909, a selective dopamine uptake inhibitor, produced significant decreases in prodynorphin (PDYN) gene expression in the hypothalamus. Cocaine also produced a significant increase in PDYN mRNA in the caudate putamen, whereas GBR12909 has no effect and the selective serotonin uptake inhibitor fluoxetine decreases PDYN mRNA in the same brain region. The effect of the selective norepinephrine uptake inhibitor nisoxetine was examined on PDYN gene expression. Nisoxetine or vehicle was infused continuously for 7 days via osmotic minipump into male rats. This treatment produced significant increases in PDYN gene expression in the hypothalamus (183% of control), nucleus accumbens (142% of control) and hippocampus (124% of control) and a significant decrease in the caudate putamen (69% of control). These data suggest that nisoxetine affects PDYN gene expression and support a role for NE in the mechanisms underlying the effects of chronic exposure to psychoactive drugs. Moreover, nisoxetine, as well as fluoxetine, decreases PDYN mRNA in the caudate putamen, in contrast to the up-regulation produced by cocaine. Thus, the inhibition of NE uptake alone cannot account for the cocaine-induced increase of PDYN gene expression. These findings suggest that PDYN gene expression regulation by cocaine in the caudate putamen might be due to a combination of effects on two or three monoamine transporters, or to a mechanism unrelated to transporters inhibition. [Copyright &y& Elsevier]

DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) is a potent endogenous inhibitor of protein phosphatase-1, which plays an important role in dopaminergic transmission. A large body of evidence supports the key role of DARPP-32-dependent signalling in mediating the actions of multiple drugs of abuse, including cocaine, which, when acutely administered, increases the Thr(34) phosphorylation of DARPP-32 in the striatal and cortical areas. In this study, we have examined the contribution of the kappa opioid system to the regulation of DARPP-32 phosphorylation at Thr(34), following acute cocaine administration, in selected rat brain areas. Results showed that a single injection of cocaine induces a significant increase in DARPP-32 phosphorylation at Thr(34) in the hippocampus, caudate putamen and prefrontal cortex. In addition, pretreatment with the kappa opioid receptor agonist U-69593 prevented cocaine effects in all the investigated areas. These data could be considered consistent with the ability of kappa opioid agonists to attenuate many behavioural and neurochemical effects of cocaine.

The effects of kappa-opioid agonist treatment on kappa-opioid receptor density and on dynorphin A levels in the rat brain were studied. Rats were treated with the selective kappa-opioid agonist U-69593 or vehicle for 5 d. Dynorphin A levels and kappa-opioid receptor binding were measured on day 8 (3 d after the last injection) or 22 (17 d after the last injection). On day 8, kappa-opioid receptor density was increased in the hypothalamus of rats treated with U-69593; there were no changes in the frontal cortex or caudate putamen. In contrast, there was an increase in dynorphin A levels in the frontal cortex and no changes in hypothalamus and caudate putamen in response to U-69593. On day 22, Bmax was decreased in frontal cortex and caudate putamen of U-69593-treated rats, whereas dynorphin A levels were increased in the caudate putamen and in the frontal cortex. These findings suggest that kappa-opioid receptor agonist treatment has long-term, continually changing effects on the kappa-opioid system.