Advertisement

Drugs & Aging

, Volume 9, Issue 3, pp 149–158 | Cite as

Potential of Opioid Antagonists in the Treatment of Levodopa-Induced Dyskinesias in Parkinson’s Disease

Leading Article

Summary

Current treatments for Parkinson’s disease (PD) rely on dopamine-replacing strategies, and centre around dopamine precursors (e.g. levodopa) or directly acting dopamine agonists. With long-term therapy these agents lose much of their clinical utility due to the appearance of adverse effects such as dyskinesias and/or a wearing off of efficacy. Although dyskinesias in Huntington’s disease, hemiballism and experimental animals are thought to be associated with reductions in amino acid transmission within the lateral and medial segments of the globus pallidus, the neural mechanisms underlying treatment-related dyskinesias in PD are poorly understood.

Recent evidence suggests that, within these regions of the brain, the opioid peptides enkephalin and dynorphin, acting at δ and κ opioid receptors, respectively, can reduce the release of amino acid transmitters. Furthermore, the synthesis of these peptides appears to be enhanced in neurons projecting to the pallidal complex in animal models of PD following repeated treatment with dopamine-replacing agents that also cause dyskinetic adverse effects (e.g. levodopa and apomorphine). In contrast, dopamine receptor agonists such as bromocriptine and lisuride do not cause dyskinetic adverse effects following long-term treatment, and do not elevate peptide synthesis when given de novo. These data, together with recent data on the behavioural effects of opioid antagonists in a rodent model of levodopa-induced dyskinesia in PD, suggest the possibility that antagonists of opioid receptors may prove useful as adjuncts to levodopa. By limiting the severity of dyskinetic adverse effects, these drugs may help extend the time for which the antiparkinsonian effects of such compounds can be usefully exploited.

Keywords

Levodopa Naloxone Opioid Receptor Bromocriptine Naltrexone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Marsden CD, Parkes JD, Quinn N. Fluctuations of disability in Parkinson’s disease — clinical aspects. In: Marsden C, Fahn S, editors. Movement disorders. London: Butterworth Scientific, 1982: 96–122Google Scholar
  2. 2.
    Cotzias GC, Papavasiliou PS, Gellene R. Modification of parkinsonism: chronic treatment with L-dopa. N Engl J Med 1969; 280: 337–45PubMedCrossRefGoogle Scholar
  3. 3.
    Yhar MD, Duvosin RC, Schear MJ, et al. Treatment of parkinsonism with L-dopa. Arch Neurol 1969; 280: 343–54CrossRefGoogle Scholar
  4. 4.
    Barbeau A. L-dopa therapy in Parkinson’s disease — a critical review of nine years experience. Can Med Assoc J 1969; 101: 791–800Google Scholar
  5. 5.
    Marsden CD, Parkes JD. ‘On-off’ effects in patients with Parkinson’s disease on chronic levodopa therapy. Lancet 1976; I: 292–6CrossRefGoogle Scholar
  6. 6.
    Barbeau A. The clinical physiology of side effects in long-term L-dopa therapy. Adv Neurol 1974; 5: 347–65PubMedGoogle Scholar
  7. 7.
    Shaw KM, Lees AJ, Stern GM. The impact of treatment with levodopa in Parkinson’s disease. Q J Med 1980; 49: 283–93PubMedGoogle Scholar
  8. 8.
    Barbeau A. High-level levodopa therapy in severely akinetic parkinsonism patients: twelve years later. In: Rinne VK, Klinger M, Stamm G, editors. Parkinson’s disease: current progress, problems and management. Amsterdam: Elsevier, 1980: 229–39Google Scholar
  9. 9.
    Nutt JG. Levodopa-induced dyskinesia. Neurology 1990; 40: 340–5PubMedCrossRefGoogle Scholar
  10. 10.
    Crossman AR. Primate models of dyskinesia: the experimental approach to the study of basal ganglia-related involuntary movement disorders. Neuroscience 1987; 21: 1–40PubMedCrossRefGoogle Scholar
  11. 11.
    Crossman AR. A hypothesis on the pathophysiological mechanisms that underlie levodopa — or dopamine agonist-induced dyskinesias in Parkinson’s disease: implications for future strategies in treatment. Mov Disord 1990; 5(2): 100–8PubMedCrossRefGoogle Scholar
  12. 12.
    Mitchell IJ, Jackson A, Sambrook MA, et al. Common neural mechanisms in experimental chorea and hemiballismus in the monkey: evidence from 2-deoxyglucose autoradiography. Brain Res 1985; 339: 346–50PubMedCrossRefGoogle Scholar
  13. 13.
    Burton K, Calne DB. Dopamine agonists and Parkinson’s disease. Clin Neurol Neurosurg 1984; 86(3): 172–7PubMedCrossRefGoogle Scholar
  14. 14.
    Le Witt PA, Ward CD, Larsen TA, et al. Comparison of pergolide and bromocriptine therapy in parkinsonism. Neurology 1983; 33: 1009–14CrossRefGoogle Scholar
  15. 15.
    Pezzoli G, Martignoni E, Pacchetti C, et al. Pergolide compared with bromocriptine in Parkinson’s disease: a multicenter, crossover, controlled study. Mov Disord 1994; 9(4): 431–6PubMedCrossRefGoogle Scholar
  16. 16.
    Rabey JM, Nissipeanu P, Inzelberg R. Beneficial effects of cabergoline, new long-lasting D2 agonist in the treatment of Parkinson’s disease. Clin Neurol 1994; 17(3): 286–93Google Scholar
  17. 17.
    Rinne UK. Lisuride, a dopamine agonist in the treatment of early Parkinson’s disease. Neurology 1989; 39: 336–9PubMedCrossRefGoogle Scholar
  18. 18.
    Lieberman A, Kupersmith M, Estey E, et al. Treatment of Parkinson’s disease with bromocriptine. N Engl J Med 1976; 295(25): 1400–4PubMedCrossRefGoogle Scholar
  19. 19.
    Bedard PJ, Di Paolo T, Falardeau P, et al. Chronic treatment with L-DOPA, but not bromocriptine induces dyskinesia in MPTP-parkinsonian monkeys: correlation with [3H]spiperone binding. Brain Res 1986; 379: 294–9PubMedCrossRefGoogle Scholar
  20. 20.
    Lees AJ, Stern GM. Sustained bromocriptine therapy in previously untreated patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1981; 44: 1020–3PubMedCrossRefGoogle Scholar
  21. 21.
    Calne DB, Teychenne PF, Claveria LE, et al. Bromocriptine in parkinsonism. BMJ 1974; 4: 442–4PubMedCrossRefGoogle Scholar
  22. 22.
    Parkes JD, Debono AG, Marsden CD. Bromocriptine in parkinsonism: long-term treatment dose response, and comparison with levodopa. J Neurol Neurosurg Psychiatry 1976; 39: 1101–8PubMedCrossRefGoogle Scholar
  23. 23.
    Kartzinel R, Teychenne P, Gillespie MM, et al. Bromocriptine and levodopa (with or without carbidopa) in parkinsonism. Lancet 1976 Aug 7; II: 272–5CrossRefGoogle Scholar
  24. 24.
    Lees AJ. Comparison of therapeutic effects of levodopa, levodopa and selegiline, and bromocriptine in patients with early, mild Parkinson’s disease: three year interim report. BMJ 1993; 307: 469–72CrossRefGoogle Scholar
  25. 25.
    Calne DB, Plotkin C, Williams AC, et al. Long-term treatment of parkinsonism with bromocriptine. Lancet 1978 Apr 8; I: 735–7CrossRefGoogle Scholar
  26. 26.
    Hoehn MM. Result of chronic levodopa therapy and its modification by bromocriptine in Parkinson’s disease. Acta Neurol Scand 1985; 71: 97–106PubMedCrossRefGoogle Scholar
  27. 27.
    Rinne UK. Early combination of bromocriptine and levodopa in the treatment of Parkinson’s disease: a 5-year follow-up. Neurology 1987; 37: 826–8PubMedCrossRefGoogle Scholar
  28. 28.
    Tolosa ES, Martin WE, Cohen HP, et al. Patterns of clinical response and plasma dopa levels in Parkinson’s disease. Neurology 1975; 25: 177–83PubMedCrossRefGoogle Scholar
  29. 29.
    Tolosa ES, Martin WE, Cohen HP. Dyskinesias during levodopa therapy. Lancet 1975 Jun 21; I: 1381–2CrossRefGoogle Scholar
  30. 30.
    Muenter MD, Sharpless NS, Tyce GM, et al. Patterns of dystonia (‘I-D-I’ and ‘D-I-D’) in response to L-dopa therapy for Parkinson’s disease. Mayo Clin Proc 1977; 52: 163–74PubMedGoogle Scholar
  31. 31.
    Tolosa E, Alom J. Drug-induced dyskinesias. In: Jankovic J, Tolosa E, editors. Parkinson’s disease and movement disorders. Baltimore: Urban and Schwarzenberg, 1988: 327–47Google Scholar
  32. 32.
    Martin JP. Hemichorea resulting from a local lesion of the brain (syndrome of body of Luys). Brain 1927; 50: 637–51CrossRefGoogle Scholar
  33. 33.
    Whittier JR, Mettler FA. Studies on the subthalamus of rhesus monkey: II. Hyperkinesia and other physiological effects of subthalamic lesions, with special reference to the subthalamic nucleus of Luys. J Comp Neurol 1949; 90: 319–72PubMedCrossRefGoogle Scholar
  34. 34.
    Hammond C, Feger J, Biolac B, et al. Experimental hemibal-lismus produced by unilateral kanic acid lesion in the corpus Luysii. Brain Res 1979; 191: 577–80CrossRefGoogle Scholar
  35. 35.
    Mitchell IJ, Jackson A, Sambrook MA, et al. The role of the subthalamic nucleus in experimental chorea: evidence from 2-deoxyglucose metabolic mapping and horseradish peroxidase tracing studies. Brain 1989; 112: 1533–48PubMedCrossRefGoogle Scholar
  36. 36.
    Mitchell IJ, Crossman AR, Liminga U, et al. Regional changes in 2-deoxyglucose uptake associated with neuroleptic-induced tardive dyskinesia in the cebus monkey. Mov Disord 1992; 7: 32–7PubMedCrossRefGoogle Scholar
  37. 37.
    Cuello AC, Paxinos G. Evidence for a long leu-enkephalin striopallidal pathway in the rat brain. Nature 1978; 271: 178–80PubMedCrossRefGoogle Scholar
  38. 38.
    Del Fiacco M, Paxinos G, Levanti MC. Neostriatal enkephalin immunoreactive neurons project to the globus pallidus. Brain Res 1982; 231: 1–17PubMedCrossRefGoogle Scholar
  39. 39.
    Gerfen CG, Young III WS. Distribution of striatonigral and striatopallidal peptidergic neurons in both patch and matrix compartments: an in situ hybridisation histochemistry and fluorescent retrograde tracing study. Brain Res 1988; 460: 161–7PubMedCrossRefGoogle Scholar
  40. 40.
    Vincent SR, Hokfelt T, Christensson I, et al. Immunohistochemical evidence for a dynorphinergic immunoreactive strionigral pathway. Eur J Pharmacol 1982; 85: 251–2PubMedCrossRefGoogle Scholar
  41. 41.
    Maneuf YP, Mitchell IJ, Crossman AR, et al. On the role of enkephalin cotransmission in the GABAergic striatal efferents to the globus pallidus. Exp Neurol 1994; 125: 65–71PubMedCrossRefGoogle Scholar
  42. 42.
    Maneuf YP, Mitchell IJ, Crossman AR, et al. Functional implications of kappa opioid receptor-mediated modulation of glutamate transmission in the output regions of the basal ganglia in rodent and primate models of Parkinson’s disease. Brain Res 1995; 683: 102–8PubMedCrossRefGoogle Scholar
  43. 43.
    Hill MP, Brotchie JM. Modulation of glutamate release by a κ-opioid receptor agonist in rodent and primate striatum. Eur J Pharmacol 1995; 281: Rl–2CrossRefGoogle Scholar
  44. 44.
    Hille CJ, Hill MP, Brotchie JM. Modulation of glutamate transmission in the basal ganglia by enadoline, a selective kappa-opioid receptor agonist, in the marmoset and rat. In: Ohye O, Kimura M, McKenzie J, editors. The basal ganglia V. Plenum. In pressGoogle Scholar
  45. 45.
    Abou-Khalil B, Young AB, Penney JB. Evidence for the presynaptic localisation of opiate binding sites on striatal efferent fibres. Brain Res 1984; 323: 21–9PubMedCrossRefGoogle Scholar
  46. 46.
    Goldstein A, Naidu A. Multiple opioid receptors: ligand selectivity profiles and binding site signatures. Mol Pharmacol 1989; 36(2): 265–72PubMedGoogle Scholar
  47. 47.
    Ungerstedt U. 6-hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 1968; 5: 107–10PubMedCrossRefGoogle Scholar
  48. 48.
    Marsden CD, Duvoisin C, Jenner P, et al. Relationship between animal models and clinical parkinsonism. Adv Neurol 1975; 9: 165–75PubMedGoogle Scholar
  49. 49.
    DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990; 13(7): 281–5PubMedCrossRefGoogle Scholar
  50. 50.
    Waters CM, Peck R, Rossor M, et al. Immunocytochemical studies on the basal ganglia and substantia nigra in Parkinson’s disease and Huntington’s chorea. Neuroscience 1988; 25(2): 419–38PubMedCrossRefGoogle Scholar
  51. 51.
    Gerfen CR, McGinty JF, Young III WS. Dopamine differentially regulates dynorphin, substance P and enkephalin expression in striatal neurons: in situ hybridisation histochemical analysis. J Neurosci 1991; 11: 1016–31PubMedGoogle Scholar
  52. 52.
    Engber TM, Susel Z, Kuo S, et al. Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output neurons of 6-hydroxydopamine lesioned rats. Brain Res 1991; 552: 113–8PubMedCrossRefGoogle Scholar
  53. 53.
    Mocchetti I, Naranjo J, Costa E. Regulation of striatal enkephalin turnover in rats receiving antagonists of specific dopamine subtypes. J Pharmacol Exp Ther 1987; 241: 1120–4PubMedGoogle Scholar
  54. 54.
    Young III WS, Bonner TI, Brann MR. Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc Natl Acad Sci U S A 1986; 83: 9827–31PubMedCrossRefGoogle Scholar
  55. 55.
    Li SJ, Jiang HK, Stachowiak MS, et al. Influence of nigrostriatal dopaminergic tone on the biosynthesis of dynorphin and enkephalin in rat striatum. Brain Res Mol Brain Res 1990; 8: 219–25PubMedCrossRefGoogle Scholar
  56. 56.
    Carey RJ. Naloxone reverses L-DOPA induced overstimulation effects in a Parkinson’s disease animal model analogue. Life Sci 1991; 48: 1303–8PubMedCrossRefGoogle Scholar
  57. 57.
    Henry B, Crossman AR, Brotchie JM. Opioid peptide involvement in L-DOPA-induced dyskinesias: molecular and behavioural studies following long-term treatment in the 6-OHDA—lesioned rat model of Parkinson’s disease [abstract P 204]. 4th International Congress of Movement Disorders: Vienna: 1996 Jun 17–21. Mov Disord 1996; 11Suppl. 1: 61Google Scholar
  58. 58.
    Pollock J, Kornetsky C. Naloxone prevents and blocks the emergence of neuroleptic-mediated oral stereotypic behaviors. Neuropsychopharmacology 1991; 4(4): 245–9PubMedGoogle Scholar
  59. 59.
    Stoessl JA, Polanski E, Frydryszak H. The opiate antagonist naloxone suppresses a rodent model of tardive dyskinesia. Mov Disord 1993; 8(4): 445–52PubMedCrossRefGoogle Scholar
  60. 60.
    Blum I, Munitz H, Shalev A, et al. Naloxone may be beneficial in the treatment of tardive dyskinesia. Clin Neuropharmacol 1984; 7(3): 265–7PubMedCrossRefGoogle Scholar
  61. 61.
    Lindenmayer JP, Gardner E, Goldberg E, et al. High-dose naloxone in tardive dyskinesia. Psychiatry Res 1988; 26: 19–28PubMedCrossRefGoogle Scholar
  62. 62.
    Kurlan R, Majumdar L, Deeley C, et al. A controlled trial of propoxyphene and naltrexone in patients with Tourette’s syndrome. Ann Neurol 1991; 30: 19–23PubMedCrossRefGoogle Scholar
  63. 63.
    Trabucchi M, Bassi S, Frattola L. Effect of naloxone on the ‘on-off’ syndrome in patients receiving long-term levodopa therapy. Arch Neurol 1982; 39: 120–1PubMedCrossRefGoogle Scholar
  64. 64.
    Sandyk R, Snider SN. Naloxone treatment of 1-dopa-induced dyskinesias in Parkinson’s disease [letter] Am J Psychiatry 1986; 143(1): 118PubMedGoogle Scholar
  65. 65.
    Gomez-Mancilla B, Bedard PJ. Effect of nondopaminergic drugs on L-DOPA-induced dyskinesias in MPTP-treated monkeys. Clin Neuropharm 1993; 16(5): 418–27CrossRefGoogle Scholar
  66. 66.
    Rascol O, Fabre N, Blin O, et al. Naltrexone, an opiate antagonist, fails to modify motor symptoms in patients with Parkinson’s disease. Mov Disord 1994; 9(4): 437–40PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 1996

Authors and Affiliations

  1. 1.Rm 1.124, Division of Neuroscience, School of Biological SciencesUniversity of ManchesterManchesterEngland

Personalised recommendations