Research Article| Volume 279, ISSUE 1-2, P62-65, April 15, 2009

Does the endogenous opiate system play a role in the Restless Legs Syndrome?: A pilot post-mortem study

Published:January 27, 2009DOI:


      Opioids are an effective treatment for the signs and symptoms of Restless Legs Syndrome (RLS) and the signs and symptoms of RLS return when the opiate receptor blocker naloxone is given to opioid treated RLS patients in a blinded fashion. These data suggest that the opioid effect is specific to the opiate receptor in RLS and implicate the endogenous opioid system with its enkephalins and endorphins in the pathogenesis of RLS. We therefore measured Beta endorphin, Met-enkephalin and Leu-enkephalin levels in thalamus and substantia nigra of RLS patients (5 F — avg age 80.2 years) compared to controls (5 F, 1 M — avg age 76.3 years). One half of each brain was fixed in paraformaldehyde (PFA) in phosphate buffered saline (PBS) for pathologic evaluation and paraffin sections were stained with antibodies. Cell numbers were counted in a blinded fashion. In the thalamus, there were reductions of Beta-endorphin and Met-enkephalin positive cells by 37.5% (p=.006, effect size 2.16) and 26.4% (p=.028, effect size 1.58), respectively, in RLS patients compared to controls. There was no difference in Leu-enkephalin in the thalamus or changes in Beta endorphin, Met-enkephalin, Leu-enkephalin or Tyrosine Hydroxylase, the rate limiting step for dopamine synthesis, in the substantia nigra. Although one of the main hypotheses for pathogenesis has been that there is a dopaminergic hypofunction in RLS, this lack of decrease in Tyrosine Hydroxylase in substantia nigra is consistent with previously published post-mortem data in RLS. With Bonferroni correction, the decrease in thalamic Beta endorphin remained significant (p=.006×7=.042). These results suggest that there may be altered central processing of pain in RLS and these data further implicate the endogenous opioid system in the pathogenesis of RLS. The mu opiate receptor subtype may be involved in the pathogenesis of RLS as it is the target of Beta-endorphin and Met-enkephalin but not Leu-enkephalin. However, these results should be viewed as only preliminary and more advanced techniques such as stereology should be employed in future post-mortem studies. In addition, other opioid rich areas need to be explored as well as areas implicated in the pathogenesis of RLS such as the red nucleus and raphe nucleus.


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        • Walters A.S.
        • Wagner M.L.
        • Hening W.A.
        • Grasing K.
        • Mills R.
        • Chokroverty S.
        • et al.
        Successful treatment of the idiopathic restless legs syndrome in a randomized double blind trial of oxycodone versus placebo.
        Sleep. 1993; 16: 327-332
        • Walters A.S.
        • Winkelmann J.
        • Trenkwalder C.
        • Fry J.M.
        • Kataria V.
        • Wagner M.
        • et al.
        Long-term follow-up on restless legs syndrome patients treated with opioids.
        Mov Disord. 2001; 16: 1105-1109
        • Von Spiczak S.
        • Whone A.L.
        • Hammers A.
        • Asselin M.C.
        • Turkheimer F.
        • Tings T.
        • et al.
        The role of opioids in restless legs syndrome: an (11C) diprenorphine PET study.
        Brain. 2005; 128: 906-917
        • San Pedro E.C.
        • Mountz J.M.
        • Mountz J.D.
        • Liu H.-G.
        • Katholi C.R.
        • Deutsch G.
        Familial Painful restless legs syndrome correlates with pain dependent variation of blood flow to the caudate, thalamus, and anterior cingulated gyrus.
        J Rheumatol. 1998; 25: 2270-2275
        • Bucher S.F.
        • Seelos K.C.
        • Oertel W.H.
        • Reiser M.
        • Trenkwalder C.
        Cerebral generators involved in the pathogenesis of the restless legs syndrome.
        Ann Neurol. 1997; 41: 639-645
        • Etgen T.
        • Draganski B.
        • Ilg C.
        • Schroder M.
        • Geisler P.
        • Hajak G.
        • et al.
        Bilateral thalamic gray matter changes in patients with restless legs syndrome.
        Neuroimage. 2005; 24: 1242-1247
        • Hening W.
        • Walters A.
        • Kavey N.
        • Gidro-Frank S.
        • Cote L.
        • Fahn S.
        Dyskinesia while awake and periodic movements of sleep in restless legs syndrome: treatment with opioids.
        Neurology. 1986; 36: 1363-1366
        • Walters A.
        • Hening W.
        • Cote L.
        • Fahn S.
        Dominantly inherited Restless Legs with myoclonus and Periodic Movements of sleep: a syndrome related to the endogenous opiates?.
        Adv. Neurol. 1986; 43: 309-319
        • Walters A.S.
        Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome.
        Sleep Med. 2002; 3: 301-304
        • Wetter T.C.
        • Eisensehr I.
        • Trenkwalder C.
        Functional neuroimaging studies in restless legs sydrome.
        Sleep Med. 2004; 5: 401-406
        • Connor J.R.
        Pathophysiology of restless legs syndrome: evidence for iron involvement.
        Curr Neurol Neurosci Rep. 2008; 8: 162-166
        • Sun Y.-M.J.
        • Hoang-Le T.
        • Neubauer J.A.
        • Walters A.S.
        Opioids protect against substantia nigra dopaminergic cell apoptosis induced by iron deprivation: a possible model for the pathogenesis of the Restless Legs Syndrome.
        Mov Disord. 2004; 19: S39
        • Walters A.S.
        Group Organizer and Correspondent: The International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group Rating Scale for Restless Legs Syndrome.
        Sleep Med. 2003; 4: 121-132
        • Miki T.
        • Satriotomo I.
        • Li H.P.
        • Matsumoto Y.
        • Gu H.
        • Yokoyama T.
        • et al.
        Application of the physical dissector to the central nervous system: estimation of the total number of neurons in subdivisions of the rat hippocampus.
        Anat Sci Int. 2005; 80: 153-162
        • Yehuda S.
        • Youdim M.B.
        Brain iron: a lesson from animal models.
        Am J Clin Nutr. 1989; 50: 618-625
        • Smith Y.
        • Villalba R.
        Striatal and extrastriatal dopamine the basal ganglia: an overview of its anatomical organization in normal and Parkinsonian brains.
        Mov Disord. 2008; 23: S534-S547
        • Herz A.
        • Millan M.J.
        Opioids and opioid receptors mediating antinociception at various levels of the neuraxis.
        Physiol Bohemoslov. 1990; 39: 395-401
        • Clemens S.
        • Rye D.
        • Hochman S.
        Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective.
        Neurology. 2006; 67: 125-130
        • Ondo W.G.
        • He Y.
        • Rajasekaran S.
        • Le W.D.
        Clinical correlates of 6-hydroxydopamine injections into A 11 dopaminergic neurons in rats: a possible model for restless legs syndrome.
        Mov Disord. 2000; 15: 154-158
        • Qu S.
        • Le W.
        • Zhang X.
        • Xie W.
        • Zhang A.
        • Ondo W.G.
        Locomotion is increased in A11 lesioned mice with iron deprivation: a possible animal model for restless legs syndrome.
        J Neuropathol Exp Neurol. 2007; 66: 383-388
        • Winkelman J.W.
        • Sethi K.D.
        • Kushida C.A.
        • Becker P.J.
        • Koester J.
        • Cappola J.J.
        • et al.
        Efficacy and safety of pramipexole in retless legs syndrome.
        Neurology. 2006; 67: 1034-1039
        • Beard J.
        Iron deficiency alters brain development and functioning.
        J Nutr. 2003; 133: 1468S-1472S
        • Carmody J.
        Opiate receptors: an introduction.
        Anesth Intensive Care. 1987; 15: 27-37
        • Ragavan V.V.
        • Wardlaw S.L.
        • Kreek M.J.
        • Frantz A.G.
        Effect of chronic naltrexone and methadone administration on brain immunoreactive beta-endorphin in the rat.
        Neuroendocrinology. 1983; 37: 266-268
        • Rattan A.K.
        • Tejwani G.A.
        Effect of chronic treatment with morphine, midazolam, and both together on beta-endorphin levels in the rat.
        Brain Res Bull. 1996; 41: 335-341
        • Godau J.
        • Wevers A.K.
        • Gaenslen A.
        • Di Santo A.
        • Liepelt I.
        • Gasser T.
        • et al.
        Sonographic abnormalities of brainstem structures in restless legs syndrome.
        Sleep Med. 2008; 9: 782-789