The Delta-Opioid System in the Brain: A Neglected Element in Parkinson’s Disease?

Abstract

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease resulting from the death of dopaminergic neurons in the substantia nigra pars compacta (SNc) which innervate all of the neuclei of the basal ganglia. Cell loss in the SNc causes a consequent striatal dopamine (DA) deficiency, leading to a cascade of functional changes in basal ganglia circuitry and ultimately the development of the cardinal features of PD, including resting tremor, bradykinesia, postural instability and rigidity, along with non-motor symptoms including cognitive, affective, psychiatric, and autonomic problems. DA replacement with the Levodopa (L-DOPA) is still a gold standard for symptomatic therapy of PD. However, the side effects of long-term use of L-DOPA are obvious. The emerging non-dopaminergic treatments for PD are becoming a scheduling program for the pipe-lines of drug development and clinical trials. The abundant expression of opioid receptors and their endogenous ligands, especially those for the δ-opioid system within the basal ganglia, has attracted much attention for its contribution to neurodegenerative diseases such as PD. In this article, we first discussed the relevant functional neuroanatomy and circuitry of the basal ganglia, and the evolving PD models of the basal ganglia. We then retrospected the studies on the location and expression of the δ-opioid system within the basal ganglia in health and PD, opioid-induced regulation of neurotransmitter release in basal ganglia, effects of pharmacological δ-opioid receptor (DOR) manipulation on PD and levodopa-induced dyskinesia (LID), and the effects of DOR activation on dopaminergic neuron injury/cellular model of PD. Based on these analyses, we believe that δ-opioid signaling is generally a beneficial, not detrimental factor for motor complications in PD. However, more in-depth investigations are expected to provide more solid and direct evidence for this benefit and to develop therapeutic strategies against PD by targeting δ-opioid system.