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

Abstract

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 Met-enkephalin 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, anaemia 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 and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is β-endorphin. However, they cause RLS-like symptoms and periodic limb movements 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.

Keywords: dopamine; endogenous opioid system; iron; periodic limb movements in sleep (PLMS); pro-opiomelanocortin (POMC); restless legs syndrome (RLS).

Figure 1

Receptor blocking studies in RLS. Pimozide, a dopamine receptor blocker, blocks the therapeutic effect of either opioids administered alone or dopaminergic agonists administered alone to RLS patients. On the other hand, naloxone blocks only the therapeutic effect of the opioids administered alone to RLS patients. These results suggest that the effect of the endogenous opioid system upon RLS is mediated through its impact upon the dopaminergic system. It should be emphasized that these results are based upon a limited number of studies with small numbers of RLS patients and not subjects from the general population. The interaction of the endogenous opioid and dopaminergic systems can, in general, be highly varied and more complex than demonstrated here, as outlined in the ‘Conclusion’ section. Reproduced and modified from Walters with permission from Elsevier. RLS = restless legs syndrome.

Figure 2

In vitro animal model of RLS. In an in vitro rat model, iron-deprived dopaminergic cells in the substantia nigra undergo apoptosis and cell death. When the system is pretreated with the delta opioid peptide DADLE, cell death is decreased dramatically. Reproduced from Walters et al., with permission from Elsevier.

Figure 3

Pro-opiomelanocortin and its derivatives. β-Endorphin, melanocyte stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) are derived from the same parent molecule pro-opiomelanocortin (POMC). These may all play a role in the pathogenesis of RLS. CLIP = corticotropin-like intermediate peptide; RLS = restless legs syndrome. Intermediate steps in metabolism are not shown.

Figure 4

Role of the metabolites of pro-opiomelanocortin in the pathogenesis of RLS. POMC gives rise to β-endorphin, an endogenous opioid, which should improve RLS, and to α-melanocyte stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH), which cause RLS symptoms in an animal model. Intermediate steps in metabolism are not shown. RLS = restless legs syndrome.

Figure 5

Some of the principal evidence linking restless legs syndrome (RLS) to the endogenous opioid and pro-opiomelanocortin (POMC) systems. (1) Opioids treat RLS but if naloxone, an opioid receptor blocker, is given to opioid-treated RLS patients, the RLS worsens. (2) In an autopsy study of RLS patients versus control subjects, β-endorphin (and perhaps Met-enkephalin) are decreased in the thalamus. (3) Mu- and total opioid receptor knock-out mice mimic some of the clinical and biochemical features of RLS. (4) A mu-opioid receptor blocker given to wild-type (control) mice causes a decrease in serum iron. (5) The parent molecule POMC gives rise to β-endorphin, which like other opioids, should improve RLS. POMC also gives rise to ACTH and α-MSH, which cause RLS-like symptoms in an animal model. Intermediate steps in metabolism are not shown in (5). α-MSH = α-melanocyte stimulating hormone; ACTH = adrenocorticotropic hormone; RLS = restless legs syndrome.