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

• Published in: Brain research Vol. 683; no. 1; pp. 102 - 108
• Main Authors: Maneuf, Yannick P., Mitchell, Ian J., Crossman, Alan R., Woodruff, Geoffrey N., Brotchie, Jonathan M.
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 12.06.1995; Amsterdam Elsevier; New York, NY
• Subjects: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Anti-Arrhythmia Agents - pharmacology; Basal Ganglia - drug effects; Basal Ganglia - metabolism; Basal Ganglia - physiopathology; Benzofurans - pharmacology; Biological and medical sciences; Callithrix; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Glutamate transmission; Glutamic Acid - metabolism; Glutamic Acid - physiology; In Vitro Techniques; Kappa opioid; Male; Medical sciences; Motor Activity - drug effects; Naltrexone - analogs & derivatives; Naltrexone - pharmacology; Neurology; Output regions of the basal ganglia; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - physiopathology; Parkinson's disease; primates; Pyrrolidines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - physiology; Reserpine - pharmacology; Rodentia; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Kappa opioid; Parkinson's disease; Glutamate transmission; Output regions of the basal ganglia; Animal model; Nervous system diseases; Rat; Callithrix jacchus; Rodentia; Central nervous system; Parkinson disease; Basal ganglion; Glutamate; Cerebral disorder; Opiate receptor κ; Vertebrata; Mammalia; Central nervous system disease; Excitatory aminoacid; Neurotransmitter; Primates; Simioidea; Degenerative disease; Brain (vertebrata); Extrapyramidal syndrome
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/0006-8993(95)00358-W

Parkinson's disease is characterized by an increased excitatory amino acid transmission in the internal segment of the globus pallidus and the substantia nigra pars reticulata. The effects of the kappa receptor agonist enadoline (CI-977) on glutamate transmission were investigated in vitro. Enadoline reduced the K +-evoked release of glutamate from slices of substantia nigra in a concentration-dependent manner (maximum effect: 78% inhibition at 200 μM). This effect was blocked by the selective kappa receptor antagonist nor-binaltorphimine. The endogenousm ligand for kappa receptors i sthought to be dynorphin. Dynorphin released from terminals of striato-pallidal and striato-nigral pathways might thus act as an endogenous modulatory agent on glutamatergic transmission in the basal ganglia. In vivo experiments were carried out in rodent and primate models of Parkinson's disease to assess the potential of manipulating kappa receptors as a potential treatment for Parkinson's disease. Enadoline reduced reserpine-induced akinesia when injected in the entopeduncular nucleus of the rat. Similarly, injections of CI-977 in the internal segment of globus pallidus (GPi) of the MPTP-treated marmoset alleviated parkinsonian symptoms and allowed the animal to recover its locomotor activity. This suggest that reducing the overactive glutamatergic transmission in the output regions of the basal ganglia by activating kappa receptors might potentially form the basis of a novel anti-parkinsonian therapy.