484. A PhD student comes with questions. She
wants to know how dopamine and serotonin
play a role in fibromyalgia pathogenesis. You
tell her that
(A) dopamine levels directly correlate with
pain levels
(B) tryptophan, serotonin, 5-hydroxytryptophan,
and 5-hydroxyindole acetic acid
have been found to be decreased in
fibromyalgia patients
(C) the number of tender points in
fibromyalgia patients have not been
found to correlate with the concentration
of serotonin in the serum
(D) dopamine agonists have been found to
decrease pain in fibromyalgia patients
(E) B and D
484. (E)
A. and D. Dopamine is a neurotransmitter best
known for its role in the pathology of schizophrenia,
Parkinson disease, and addiction.
There is also strong evidence for a role of
dopamine in restless leg syndrome, which is
a common comorbid condition in patients
with fibromyalgia. In addition, dopamine
plays a critical role in pain perception and
natural analgesia. Accordingly, musculoskeletal
pain complaints are common among
patients with Parkinson disease, which is
characterized by drastic reductions in
dopamine owing to neurodegeneration of dopamine-producing neurons, while patients
with schizophrenia, which is thought to
arise, at least partly, from hyperactivity of
dopamine-producing neurons, have been
shown to be relatively insensitive to pain.
Interestingly, patients with restless legs syndrome
have also been demonstrated to have
hyperalgesia to static mechanical stimulation.
Fibromyalgia has been commonly
referred to as a “stress-related disorder”
owing to its frequent onset and worsening of
symptoms in the context of stressful events.
It was therefore proposed that fibromyalgia
may represent a condition characterized by
low levels of central dopamine that likely
results from a combination of genetic factors
and exposure to environmental stressors,
including psychosocial distress, physical
trauma, systemic viral infections, or inflammatory
disorders (eg, rheumatoid arthritis,
systemic lupus erythematosus). This conclusion
was based on three key observations:
(1) fibromyalgia is associated with stress;
(2) chronic exposure to stress results in a disruption
of dopamine-related neurotransmission;
and (3) dopamine plays a critical role in
modulating pain perception and central
analgesia in such areas as the basal ganglia
including the nucleus accumbens, insular
cortex, anterior cingulate cortex, thalamus,
periaqueductal gray, and spinal cord. In
support of the “dopamine hypothesis of
fibromyalgia,” a reduction in dopamine synthesis
has been reported after using positron
emission tomography (PET) and demonstrated
a reduction in dopamine synthesis
among fibromyalgia patients in several
brain regions in which dopamine plays a
role in inhibiting pain perception, including
the mesencephalon, thalamus, insular cortex,
and anterior cingulate cortex. A subsequent
PET study demonstrated that, whereas
healthy individuals release dopamine into
the caudate nucleus and putamen during a
tonic experimental pain stimulus (ie, hypertonic
saline infusion into a muscle bed),
fibromyalgia patients fail to release dopamine
in response to pain and, in some cases, actually
have a reduction in dopamine levels
during painful stimulation. Moreover, a
substantial subset of fibromyalgia patients
respond well in controlled trials to pramipexole,
a dopamine agonist that selectively
stimulates dopamine D2/D3 receptors and
is used to treat both Parkinson disease and
restless legs syndrome.
B. Tryptophan is decreased in the serum and
CSF of fibromyalgia patients. Serotonin is low
in fibromyalgia serum. 5-Hydroxytrytophan,
the intermediary between tryptophan and
serotonin, and 5-hydroxyindole acetic
acid, the by-product of serotonin metabolism,
are both low in the CSF of patients
with fibromyalgia. The excretion in urine of
5-hydroxyindole acetic acid was lower than
normal in patients with fibromyalgia, lower
in females versus males, and lower in females
with fibromyalgia versus females who don’t
have fibromyalgia.
C. The numbers of active tender points in
fibromyalgia patients directly correlated
with the concentration of serotonin in
fibromyalgia sera.