Abstract
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.
Keywords
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Article info
Publication history
Published online: January 27, 2009
Accepted:
December 15,
2008
Received in revised form:
December 10,
2008
Received:
November 12,
2008
Identification
Copyright
© 2008 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
