Opioids protect against substantia nigra cell degeneration under conditions of iron deprivation: a mechanism of possible relevance to the Restless Legs Syndrome (RLS) and Parkinson's disease

J Neurol Sci. 2011 May 15;304(1-2):93-101. doi: 10.1016/j.jns.2011.02.003. Epub 2011 Mar 3.


Hypofunction of the endogenous opioid, dopamine and iron systems are implicated in the pathogenesis of Restless Legs Syndrome (RLS). Therefore, we probed the interrelationship of these 3 systems in an in vitro model. Cell cultures of the substantia nigra (SN) of Sprague-Dawley rats were established and the cells were determined to be primarily dopaminergic. The numbers of cells surviving under different concentrations of the iron chelator desferoxamine were reduced in a concentration and time dependent manner (p<0.01 at day 10, n=19). The cell death was determined to be apoptotic and DNA analysis revealed that 48-hour 100 μM desferoxamine exposure caused DNA fragmentation of the cells. Pre-administration of the δ-opioid peptide [D-Ala2, D-Leu5]Enkephalin (DADLE) significantly protected the SN cells from damage by iron deficiency (n=6, p<0.01). Our previous studies indicate that the DNA-damage induced apoptosis family gene P53 is activated in this model and that pre-exposure to DADLE prevents this activation. The implications of this model are that in RLS patients with iron deficiency, dopaminergic system dysfunction may result and an intact endogenous opioid system or opioid treatment may protect the dopamine system from dysfunction. Implications of this model for Parkinson's Disease are also briefly discussed.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Analgesics, Opioid / therapeutic use*
  • Anemia, Iron-Deficiency / complications
  • Anemia, Iron-Deficiency / drug therapy
  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Cytoprotection* / drug effects
  • Cytoprotection* / physiology
  • Enkephalin, Leucine-2-Alanine / pharmacology
  • Enkephalin, Leucine-2-Alanine / therapeutic use
  • Iron Chelating Agents / pharmacology
  • Iron Deficiencies*
  • Parkinson Disease / drug therapy
  • Parkinson Disease / etiology
  • Parkinson Disease / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Restless Legs Syndrome / drug therapy
  • Restless Legs Syndrome / etiology
  • Restless Legs Syndrome / pathology*
  • Substantia Nigra / drug effects
  • Substantia Nigra / pathology*


  • Analgesics, Opioid
  • Iron Chelating Agents
  • Enkephalin, Leucine-2-Alanine