Modulation of Opioid and NMDA Receptors in Preclinical Models of Parkinson’s Disease and Levodopa-Induced Dyskinesia

Abstract

Dopamine (DA)-replacement therapy utilizing L-DOPA is the mainstay of symptomatic treatment for Parkinson’s disease (PD). A critical complication of this therapy is the development of L-DOPA-induced dyskinesia (LID), which occurs in the majority of patients. Endogenous opioid peptides, including enkephalins and dynorphins, are co-transmitters of dopamine, gamma-aminobutyric acid (GABA), and glutamate neurotransmission in the direct and indirect striatal output pathways, which are disrupted in PD. Alterations in levels of expression of these peptides and their precursors have been implicated both in PD and in the subsequent development and expression of LID. Alterations in N-methyl-D-aspartate (NMDA) glutamate transmission have also been implicated in LID; the NMDA receptor antagonist amantadine is the only drug currently approved for the clinical treatment of LID.⁠ We utilized pharmacological techniques to investigate the role of altered opioid and NMDA neurotransmission occurring in the direct and indirect striatopallidal output pathways in preclinical models of PD and LID. In the first study presented (Chapter 2), we show that the antidyskinetic effects of the NMDA receptor antagonist MK-801 are preferential to the indirect pathway. Specifically, we show that MK-801 is capable of suppressing hyperkinetic abnormal involuntary movements (AIMs) induced by a selective D2R agonist, quinipirole but not those induced by a selective D1R agonist, SKF81297. Importantly, MK-801 is capable of suppressing AIMs induced by L-DOPA (levodopa, L-3,4-dihydroxyphenylalanine), which is the most effective clinical treatment for PD, even though this agent likely activates both outflow pathways, and quinpirole, but not those induced by SKF81297. This finding of MK-801 also indicates that the contribution of NMDA receptor-mediated glutamatergic transmission to the expression of LID may be specific to the indirect striatopallidal output pathway. In Chapter 3, we have investigated the effects of a novel opioid glycopeptide agonist MMP-2200 which has high affinities and activities for mu and delta opioid receptors on AIMs induced separately by L-DOPA, quinpirole, and SKF81297. We also investigated the combined effects of MMP-2200 and MK-801. It was shown that the opioid glycopeptide MMP-2200 reduced AIMs induced by a D2R selective agonist quinpirole, and MMP-2200 modified the effect of MK-801 to result in a potent reduction of L-DOPA-induced AIMs without induction of parkinsonism. In the studies presented in Chapter 4, we show that the selective kappa opioid receptor antagonist nor-BNI accelerates the rate of development of levodopa-induced AIMs (as opposed to the expression of established AIMs) in a mild striatal 6-OHDA lesion model in a paradigm of chronic gradual dose escalation of L-DOPA to prime LID. Functional restorative effects of nor-BNI on parkinsonian motor deficits were not observed. Together, the studies described here investigated the roles of alterations in NMDA receptor glutamate transmission and opioid peptide transmission occurring in the direct and indirect striatal output pathways in the context of PD and LID. These findings, using a standard preclinical model of PD and LID may point toward new therapeutic targets and drug candidates for the clinical treatment of LID.