Enhanced Preproenkephalin-B–Derived Opioid Transmission in Striatum and Subthalamic Nucleus Converges Upon Globus Pallidus Internalis in L-3,4-dihydroxyphenylalanine–Induced Dyskinesia

Aubert, Incarnation; Guigoni, Céline; Li, Qin; Doveró, Sandra; Bioulac, Bernard; Gross, Christian E.; Crossman, Alan R.; Bloch, Bertrand; Bézard, Erwan

doi:10.1016/j.biopsych.2006.06.038

Cited by 83 publications

(83 citation statements)

References 55 publications

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“…The animals used for the Western blotting study have been presented in previous publications. Their motor behavior (Bezard et al, 2003), the extent of lesion (Guigoni et al, 2005a) and various postmortem indexes have been published using this brain bank (Aubert et al, 2005(Aubert et al, , 2007 (Table 1).…”

Section: The Macaque Model Of Pd and Lidmentioning

confidence: 99%

RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

Gold¹,

Hoang²,

Potts³

et al. 2007

J. Neurosci.

115

104

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Chronic L-dopa treatment of Parkinson's disease (PD) often leads to debilitating involuntary movements, termed L-dopa-induced dyskinesia (LID), mediated by dopamine (DA) receptors. RGS9 -2 is a GTPase accelerating protein that inhibits DA D2 receptor-activated G proteins. Herein, we assess the functional role of RGS9 -2 on LID. In monkeys, Western blot analysis of striatal extracts shows that RGS9 -2 levels are not altered by MPTP-induced DA denervation and/or chronic L-dopa administration. In MPTP monkeys with LID, striatal RGS9 -2 overexpression -achieved by viral vector injection into the striatum -diminishes the involuntary movement intensity without lessening the anti-parkinsonian effects of the D1/D2 receptor agonist L-dopa. In contrasts, in these animals, striatal RGS9 -2 overexpression diminishes both the involuntary movement intensity and the anti-parkinsonian effects of the D2/D3 receptor agonist ropinirole. In unilaterally 6-OHDA-lesioned rats with LID, we show that the time course of viral vector-mediated striatal RGS9 -2 overexpression parallels the time course of improvement of L-dopa-induced involuntary movements. We also find that unilateral 6-OHDA-lesioned RGS9 Ϫ/Ϫ mice are more susceptible to L-dopa-induced involuntary movements than unilateral 6-OHDA-lesioned RGS9 ϩ/ϩ mice, albeit the rotational behavior -taken as an index of the anti-parkinsonian response -is similar between the two groups of mice. Together, these findings suggest that RGS9 -2 plays a pivotal role in LID pathophysiology. However, the findings also suggest that increasing RGS9 -2 expression and/or function in PD patients may only be a suitable therapeutic strategy to control involuntary movements induced by nonselective DA agonist such as L-dopa.

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Section: The Macaque Model Of Pd and Lidmentioning

confidence: 99%

RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

Gold¹,

Hoang²,

Potts³

et al. 2007

J. Neurosci.

115

104

View full text Add to dashboard Cite

show abstract

“…Extensive studies in both rodent and nonhuman primate models, as well as studies in humans, suggest a role for the striatal opioid system in the development of LIDs (Morissette et al, 1997,Cenci et al, 1998,Duty et al, 1998,Henry et al, 1999,Johansson et al, 2001,Quik et al, 2002,Tel et al, 2002,Winkler et al, 2002,Henry et al, 2003,Carta et al, 2005,Aubert et al, 2006. Evidence for this possibility stems from results showing that enhanced PPE-B transcript levels correlate well with LIDs in experimental parkinsonian models and Parkinson's disease (Duty et al, 1998,Henry et al, 1999,Tel et al, 2002,Henry et al, 2003,Aubert et al, 2006.…”

Section: Discussionmentioning

confidence: 99%

“…Evidence for this possibility stems from results showing that enhanced PPE-B transcript levels correlate well with LIDs in experimental parkinsonian models and Parkinson's disease (Duty et al, 1998,Henry et al, 1999,Tel et al, 2002,Henry et al, 2003,Aubert et al, 2006.…”

Section: Discussionmentioning

confidence: 99%

“…Extensive studies have shown that the enkephalinergic system is altered both with nigrostriatal damage and subsequent treatments to alleviate the functional consequences of dopaminergic denervation, such as L-dopa administration. For instance, nigrostriatal degeneration increases preproenkephalin-A (PPE-A) mRNA levels in the indirect pathway, that is, striatal neurons projecting to the external globus pallidus; this contrasts with effects on PPE-B mRNA levels that are decreased in striatal outputs to the internal globus pallidus, or the direct pathway (Morissette et al, 1997,Cenci et al, 1998,Duty et al, 1998,Henry et al, 1999,Quik et al, 2002,Tel et al, 2002,Henry et al, 2003,Aubert et al, 2006. LIDs, on the other hand, are linked to increases in PPE-B transcript levels, while changes in PPE-A do not correlate well with the development of dyskinesias (Cenci et al, 1998,Duty et al, 1998,Henry et al, 1999,Quik et al, 2002,Tel et al, 2002,Henry et al, 2003,Aubert et al, 2006.…”

Section: Introductionmentioning

confidence: 99%

“…These receptors are present throughout the basal ganglia and are modulated both by nigrostriatal damage and L-dopa treatments in various basal ganglia regions (Johansson et al, 2001,Aubert et al, 2006, with a decline in κ-and/or μ-opioid receptor binding in different basal ganglia regions with LIDs (Johansson et al, 2001,Aubert et al, 2006. The lower receptor levels may indicate that function is not optimal at these opioid receptor subtypes, and that their stimulation may lead to a reduction in LIDs.…”

Section: Introductionmentioning

confidence: 99%

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The selective κ-opioid receptor agonist U50,488 reduces l-dopa-induced dyskinesias but worsens parkinsonism in MPTP-treated primates

Cox

Togasaki

Chen

et al. 2007

Experimental Neurology

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Several lines of evidence demonstrate that the striatal enkephalinergic system may be involved in the development of LIDs. Preproenkephalin-B (PPE-B) transcript levels are elevated with LIDs and there are also declines in κ-and other opioid receptors in different regions of the basal ganglia. If reduced κ-opioid receptors are linked to LIDs, it is possible that drugs that stimulate this subtype may decrease dyskinesias. We therefore initiated experiments to investigate the effect of κ-opioid receptor activation on LIDs. We first tested the selective κ-agonist U50,488 in rats with unilateral lesions of the nigrostriatal pathway. Chronic L-dopa treatment induced abnormal involuntary movements, including axial, orolingual and forelimb dyskinesias contralateral to the lesion. U50,488 administration prior to L-dopa treatment reduced these movements by 70%, suggesting that U50,488 has potential as an anti-dyskinetic treatment. We next tested its effect in a parkinsonian nonhuman primate model, which offers the advantage that parkinsonism and LIDs can clearly be differentiated and that the dyskinesias are similar to those in parkinsonian patients. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were treated with L-dopa (5 mg/kg, p.o.) twice daily for 3 weeks to induce dyskinesias. As in the rodent model, U50,488 (0.1-1.0 mg/kg, i.m.) decreased LIDs in a dose-dependent fashion. However the anti-parkinsonian effect of L-dopa was similarly reduced, and side effects developed, including sedation and vomiting. These data suggest that κ-opioid agonists such as U50,488 may not be clinically useful antidyskinetic agents because they also reverse the anti-parkinsonian effect of L-dopa.

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Dual κ‐agonist/μ‐antagonist opioid receptor modulation reduces levodopa‐induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease

Potts

Park

Woo

et al. 2015

Annals of Neurology

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Objective: Effective medical management of L-dopa induced dyskinesia (LID) remains an unmet need for patients with Parkinson’s disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed antagonist/agonist analgesic nalbuphine in reducing LID and its molecular markers in the non-human primate model. Methods: MPTP-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline s.c. as: 1) monotherapy, 2) acute co-administration with L-dopa, and 3) chronic co-administration for a month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma L-dopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses. Results: Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-parkinson effect of L-dopa or changing plasma L-dopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine co-administered with L-dopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine co-therapy blocks several molecular correlates of LID including over-expression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5 (Cdk5), and increased phosphorylation of DARPP-32 at Threonine34. Interpretation: Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.

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Enhanced Preproenkephalin-B–Derived Opioid Transmission in Striatum and Subthalamic Nucleus Converges Upon Globus Pallidus Internalis in L-3,4-dihydroxyphenylalanine–Induced Dyskinesia

Cited by 83 publications

References 55 publications

RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

RGS9–2 Negatively Modulates l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia in Experimental Parkinson's Disease

The selective κ-opioid receptor agonist U50,488 reduces l-dopa-induced dyskinesias but worsens parkinsonism in MPTP-treated primates

Dual κ‐agonist/μ‐antagonist opioid receptor modulation reduces levodopa‐induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease

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