Novel therapeutic strategies for treatment of motor abnormalities in Parkinson’s disease: focus on opioid receptors

The opioid receptor family encompasses three classical receptors (mu, delta and kappa, renamed MOP, DOP and KOP according to the IUPHAR recommendations) and a novel entity termed ORL-1 (NOP) receptor. These receptors display structural and functional homologies, but unique pharmacological properties and selectivity for endogenous opioid peptides. Moreover, they show uneven distribution in the CNS. Opioid peptide and receptor expression is altered in animal and human PD brains. Preclinical evidence indicates that KOP and DOP receptor agonists and NOP receptor antagonists attenuate parkinsonian-like akinesia induced by dopamine depletion. KOP receptor agonists are reported to enhance 6-OHDA-induced neurodegeneration of nigral DA cells while DOP receptor agonists are neuroprotective. Indirect evidence that blockade of NOP receptor may also be neuroprotective has been produced. Despite such positive data, clinical attempts to attenuate motor symptoms in PD patients with opioid receptor ligands were made (with KOP receptor agonist and non selective opioid receptor antagonists) and proven unsuccessful. Changes in opioid peptide and receptor expression are also observed in models of levodopa-induced dyskinesia (LID) and in the brain of dyskinetic patients. Preclinical studies aimed at testing the effect of selective or non selective opioid receptor ligands in LID models gave conflicting results either supporting a compensatory or a pathogenetic role of endogenous opioids. Clinical studies failed to prove that non selective opioid receptor antagonists are effective in reducing LID. However, whether these compounds affect the priming process underlying LID development remains to be investigated