The Role of Opioids on Motor Activity in Physio-pathological Conditions

To date, four principal classes of opioid peptide receptors, μ (MOP), κ (KOP), δ (DOP) and ORL- 1 (NOP) have been identified and cloned. The experimental and clinical importance of this receptor family has been amply demonstrated in many diseases, though historically they have mainly been associated with antinociception (pain relief). The current work described herein discusses the impact of opioid systems on movement disorders, namely Parkinson’s disease (PD). PD is a relatively common neurological disease in which the motor symptoms result from the death of a particular dopamine (DA) containing cell population in the substantia nigra pars compacta (SNc). This inevitably results in a dysregulation of the activity of basal ganglia (BG); a set of midbrain structures responsible for normal movement programming and execution. The BG structures highly express opioid receptors and their endogenous peptides and, throughout the course of PD, opioidergic transmission appears dysregulated. The view that opioids are involved in compensatory or pathogenic mechanisms following loss of DA neurons lends support to the notion that they may represent a suitable target for the treatment of PD. The work contained herein describes the benefits of opioid receptor ligand administration under physiological or pathological conditions (e.g. in experimental models of PD). For instance, we discovered that the endogenous MOP receptor peptide endomorphin-1 (EM-1), when injected or perfused into the substantia nigra pars reticulata (SNr) of naïve rats facilitates and inhibits spontaneous locomotion depending on dose. Additionally, we have tested DOP receptor agonists in an experimental model of PD (i.e. 6- hydroxydopamine hemilesioned rats). These studies demonstrated the ability of the selective nonpeptide DOP receptor agonist SNC-80 to alleviate symptoms in experimental PD, such as akinesia and poor coordinated movement. We have also showed that when administered systemically, the novel peptide agonist UFP-512 causes both facilitation and inhibition of movement depending on the dose used. Lastly, we demonstrated a functional relationship between NOP and DOP receptors in SNr. We showed that in SNr, blockade of NOP receptors with the selective antagonist J-113397 and activation of DOP receptors with SNC-80 synergistically enhances motor performance in experimental PD. In addition to demonstrating the behavioral outcome of opioid receptor stimulation or blockade on a variety of movement-related parameters, we have correlated these behaviors with novel neurochemical findings in each of the presented studies. The overall findings of the work presented shed additional light on the subject of opioidergic systems and movement disorders and may contribute to future therapeutics for diseases such as PD.