Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion

Andrew J. Flores, Mitchell J. Bartlett, Blake T. Seaton, Grace Samtani, Morgan R. Sexauer, Nathan C. Weintraub, James R. Siegenthaler, Dong Lu, Michael L. Heien, Frank Porreca, Scott J. Sherman, Torsten Falk

Research output: Contribution to journalArticlepeer-review

Abstract

Levels of the opioid peptide dynorphin, an endogenous ligand selective for kappa-opioid receptors (KORs), its mRNA and pro-peptide precursors are differentially dysregulated in Parkinson's disease (PD) and following the development of L-DOPA-induced dyskinesia (LID). It remains unclear whether these alterations contribute to the pathophysiological mechanisms underlying PD motor impairment and the subsequent development of LID, or whether they are part of compensatory mechanisms. We sought to investigate nor-BNI, a KOR antagonist, 1) in the dopamine (DA)-depleted PD state, 2) during the development phase of LID, and 3) via measuring of tonic levels of striatal DA. While nor-BNI (3 mg/kg; s.c.) did not lead to functional restoration in the DA-depleted state, it affected the dose-dependent development of abnormal voluntary movements (AIMs) in response to escalating doses of L-DOPA in a rat PD model with a moderate striatal 6-hydroxdopamine (6-OHDA) lesion. We tested five escalating doses of L-DOPA (6, 12, 24, 48, 72 mg/kg; i.p.), and nor-BNI significantly increased the development of AIMs at the 12 and 24 mg/kg L-DOPA doses. However, after reaching the 72 mg/kg L-DOPA, AIMs were not significantly different between control and nor-BNI groups. In summary, while blocking KORs significantly increased the rate of development of LID induced by chronic, escalating doses of L-DOPA in a moderate-lesioned rat PD model, it did not contribute further once the overall severity of LID was established. While we observed an increase of tonic DA levels in the moderately lesioned dorsolateral striatum, there was no tonic DA change following administration of nor-BNI.

Original languageEnglish (US)
Article number148613
JournalBrain Research
Volume1821
DOIs
StatePublished - Dec 15 2023

Keywords

  • 6-hydroxydopamine (6-OHDA)
  • Parkinson's disease
  • Striatal lesion
  • Tonic dopamine
  • norbinaltorphimine (nor-BNI)
  • κ-opioid receptor (KOR)

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

Fingerprint

Dive into the research topics of 'Antagonism of kappa opioid receptors accelerates the development of L-DOPA-induced dyskinesia in a preclinical model of moderate dopamine depletion'. Together they form a unique fingerprint.

Cite this