TY - JOUR
T1 - Does the endogenous opiate system play a role in the Restless Legs Syndrome?
T2 - A pilot post-mortem study
AU - Walters, Arthur S.
AU - Ondo, William G.
AU - Zhu, Wen
AU - Le, Weidong
N1 - Funding Information:
This study was funded by an internal grant from the New Jersey Neuroscience Institute at JFK Medical Center, the Seton Hall University School of Graduate Medical Education. We would like to gratefully acknowledge the donation of tissue samples, medical histories and lists of medications from patients and controls for these studies from the Restless Legs Syndrome Foundation and the Harvard Brain Bank.
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/4/15
Y1 - 2009/4/15
N2 - 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.
AB - 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.
KW - Beta-endorphin
KW - Endogenous opioids
KW - Met-enkephalin
KW - Restless Legs Syndrome
KW - Thalamus
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U2 - 10.1016/j.jns.2008.12.022
DO - 10.1016/j.jns.2008.12.022
M3 - Article
C2 - 19167016
AN - SCOPUS:60949097459
SN - 0022-510X
VL - 279
SP - 62
EP - 65
JO - Journal of the Neurological Sciences
JF - Journal of the Neurological Sciences
IS - 1-2
ER -