Non‐subtype‐selective opioid receptor antagonism in treatment of levodopa‐induced motor complications in Parkinson's disease

Fox, Susan H.; Silverdale, Monty; Kellett, Mark; Davies, Rhys; Steiger, M. J.; Fletcher, Nicholas; Crossman, Alan R.; Brotchie, Jonathan M.

doi:10.1002/mds.10693

Cited by 59 publications

(30 citation statements)

References 51 publications

(51 reference statements)

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“…In PD patients, a low dose of naltrexone failed to have any effect (Rascol et al, 1994), whereas a high dose resulted in a minimal reduction in dyskinesia (Manson et al, 2001). A clinical trial using intravenous infusion of naloxone failed to reduce dyskinesia, but it did show an extension in the duration of levodopa action (Fox et al, 2004).…”

Section: The Opioid Systemmentioning

confidence: 97%

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

Jiménez-Urbieta

Gago

Riva

et al. 2015

Neuroscience & Biobehavioral Reviews

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Section: The Opioid Systemmentioning

confidence: 97%

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

Jiménez-Urbieta

Gago

Riva

et al. 2015

Neuroscience & Biobehavioral Reviews

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“…A trial using i.v . infusion of 0.3 mg/kg/min naloxone, a dose known to block central opioid receptors, also failed to demonstrate any reduction in dyskinesia, but did show an extension in the duration of action of levodopa (Fox et al, 2004). This disparity has produced two conflicting concepts that endogenous opioids can either: a) cause dyskinesia, or b) be part of a homeostatic response to dopamine depletion that may be beneficial.…”

Section: Introductionmentioning

confidence: 99%

Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease

et al. 2011

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In Parkinson's disease (PD), the consequence of dopaminergic denervation is an imbalance in the activity of the direct and indirect striatofugal pathways, which include potentially important changes in opioid peptide expression and/or activity. The systemic administration of a novel glycosylated opioid peptide MMP-2200 (a.k.a. lactomorphin) was shown to have potent effects in two standard models of PD: 1) amphetamine-induced rotations in the hemi-Parkinsonian 6-hydroxydopamine (6-OHDA)-treated rat and 2) locomotion in the reserpine-treated rat. MMP-2200, an opioid mu and delta receptor agonist, reduced amphetamine-induced rotations in severely-lesioned hemi-Parkinsonian rats; this effect was fully blocked by naloxone, an opioid receptor antagonist. The selective δ-opioid receptor antagonist naltrindole only partially blocked the effect of MMP-2200. MMP-2200 alone did not induce rotations. This effect was also observed in a mild progressive rat 6-OHDA-lesion model. In animals treated with reserpine, profound akinesia was induced that was reversed with apomorphine. There was a prominent overshoot in animals that received apomorphine compared to non-reserpine treated animals, reflecting the well described phenomenon of dopamine supersensitivity indicating that apomorphine not only reversed akinesia but induced hyper-kinesia. The opioid peptide MMP-2200 blocked the apomorphine-induced hyper-kinesia. This effect of MMP-2200 was prevented by pre-administration of naloxone. MMP-2200 had no effect in preventing the reserpine-induced akinesia, nor did it affect locomotion in control animals. Taken together, the results from these two models are consistent with the glycopeptide opioid agonist MMP-2200 having a potent effect on movements related to dopaminergic hyper-stimulation following striatal dopamine depletion that are best explained by a reduction in the downstream effects of dopamine agonists in these models.

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“…The nonselective opioid receptor agonist morphine reduces dyskinetic movements in patients with Parkinson's disease and also in primates with LIDs (Berg et al, 1999,Samadi et al, 2004. Nonselective opioid receptor antagonists, such as naloxone and naltrexone, have also been tested with variable effects in monkeys and humans including no change, increases or decreases in LIDs (Rascol et al, 1994,Klintenberg et al, 2002,Samadi et al, 2003,Fox et al, 2004,Samadi et al, 2004. These conflicting results with the nonselective opioid antagonists may be due to activation of varying subtypes in the different studies.…”

Section: Discussionmentioning

confidence: 99%

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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Non‐subtype‐selective opioid receptor antagonism in treatment of levodopa‐induced motor complications in Parkinson's disease

Cited by 59 publications

References 51 publications

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

Dyskinesias and impulse control disorders in Parkinson's disease: From pathogenesis to potential therapeutic approaches

Effects of the novel glycopeptide opioid agonist MMP-2200 in preclinical models of Parkinson's disease

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

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