Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome

Document Type

Journal Article

Publication Date



Brain : a journal of neurology




dopamine; endogenous opioid system; iron; pro-opiomelanocortin (POMC); restless legs syndrome (RLS)


Restless legs syndrome (RLS) is responsive to opioid, dopaminergic, and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, β-endorphin, and perhaps metenkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta, and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS, and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anemia, and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic Hormone (ACTH) and α-Melanocyte Stimulating Hormone (α-MSH) are derived from Pro-opiomelanocortin (POMC) as is β-endorphin. However, they cause RLS-like symptoms and Periodic Limb Movements (PLMS) when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.