Stimulation of delta opioid receptors located in substantia nigra reticulata but not globus pallidus or striatum restores motor activity in 6-hydroxydopamine lesioned rats: new insights into the role of delta receptors in parkinsonism

J Neurochem. 2008 Dec;107(6):1647-59. doi: 10.1111/j.1471-4159.2008.05727.x.


The delta opioid peptide (DOP) receptor has been proposed as a target in the symptomatic therapy of Parkinson's disease. However, the circuitry underlying the antiparkinsonian action of DOP receptor agonists and their site of action have never been adequately investigated. Systemic administration of the DOP receptor agonist (+)-4-[(alphaR)-alpha-(2S,5R)-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N-N-diethylbenzamide (SNC-80) attenuated akinesia/bradykinesia and improved motor activity in 6-hydroxydopamine hemilesioned rats. Opposite effects were produced by the selective DOP receptor antagonist naltrindole (NTD), suggesting that endogenous enkephalins tonically sustain movement under parkinsonian conditions. Microdialysis revealed that SNC-80 reduced GABA release in globus pallidus (GP) while NTD elevated it. Moreover, SNC-80 reduced GABA and glutamate release in substantia nigra reticulata (SNr) whereas NTD reduced GABA without affecting glutamate release. The bar test coupled to microdialysis showed that perfusion with NTD in SNr but not GP or striatum prevented the antiakinetic effect of systemic SNC-80 and its neurochemical correlates. Consistently, microinjections of SNC-80 into SNr or bicuculline in GP attenuated parkinsonian-like symptoms while SNC-80 microinjections in GP or striatum were ineffective. This study demonstrates that nigral DOP receptors mediate antiparkinsonian actions of SNC-80 and challenges the common view that DOP receptor agonists solely attenuate parkinsonism via pallidal mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Benzamides / administration & dosage
  • Bicuculline / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Chromatography, High Pressure Liquid / methods
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • GABA Antagonists / pharmacology
  • Glutamic Acid / metabolism
  • Hindlimb Suspension / methods
  • Male
  • Microdialysis / methods
  • Motor Activity / drug effects
  • Motor Activity / physiology*
  • Oxidopamine
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / pathology*
  • Parkinsonian Disorders / physiopathology
  • Piperazines / administration & dosage
  • Psychomotor Performance / drug effects
  • Psychomotor Performance / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / antagonists & inhibitors
  • Receptors, Opioid, delta / physiology*
  • Substantia Nigra / drug effects
  • Substantia Nigra / pathology*
  • Substantia Nigra / physiopathology*
  • Thiophenes / pharmacology
  • Time Factors
  • gamma-Aminobutyric Acid / metabolism


  • 6-(4-nitrophenyl)-2-phenyl-4-(thiophen-2-yl)-3,5-diazabicyclo(3.1.0)hex-2-ene
  • Benzamides
  • Bridged Bicyclo Compounds, Heterocyclic
  • GABA Antagonists
  • Piperazines
  • Receptors, Opioid, delta
  • Thiophenes
  • 4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Oxidopamine
  • Bicuculline