Neurobiology of Fibromyalgia Syndrome
In our review, the neurobiology of fibromyalgia syn-
drome (FM) is discussed in the context of what is known
about neural mechanisms of nociception and central
mechanisms of persistent pain conditions. We present a
general view of mechanisms of nociception, central tem-
poral summation, and central sensitization, and as well
compare sensory tests that examine these mechanisms in
normal pain-free human subjects. We then show how
amplification and other alterations of these mechanisms
apply to patients with FM.
NOCICEPTION, ACUTE PAIN, PERSISTENT PAIN
Pain is usually related to impulse input that originates
from nociceptors in somatic or visceral tissues. The
impulses travel in myelinated (A-delta) and unmyelinated
(C) peripheral nerves, which first project to dorsal horn
nociceptor-specific neurons and wide dynamic range neu-
rons, before these second-order neurons transmit noci-
ceptive information to brain regions involved in pain,
including the thalamus, anterior cingulate cortex (ACC),
anterior insular cortex, and somatosensory cortex.
Nociceptor-specific neurons are so termed because they
respond predominantly to specific stimulus intensities
that either cause tissue damage or would cause tissue
damage if maintained over time. Wide dynamic range
neurons respond differentially over a very broad range of
stimulus intensities, from very gentle touch to stimuli that
cause tissue damage. Brain regions that receive input
from nociceptor-specific and wide dynamic range neu-
rons are related to sensory-discriminative, cognitive-eval-
uative, and affective processing of somatosensory noci-
ceptive input. The activation of these brain regions is
associated with pain experience and subsequent reflex
and protective behaviors. Importantly, the same brain
areas are likely to be involved in both acute and persist-
ent pain conditions.
Reflex and reflective behaviors that are aimed at elimi-
nating acute pain are not operative in chronic pain syn-
dromes including FM. Patients with FM, like most
chronic pain sufferers, do not display pain behaviors usu-
ally seen in acute pain, including increased perspiration,
hypertension, hyperthermia, and tachycardia. FM
patients have abnormal pain thresholds (hyperalgesia)
and report amplified pain with a variety of nociceptive
stimuli, including pressure, heat, and cold. Because no
consistent tissue abnormalities have been detected in FM,
central pain processing abnormalities need to be consid-
ered as important contributors to the heightened pain
sensitivity of these patients.
In our review, we also discuss recent evidence that the
clinical pain of patients with FM is related to abnormal
central temporal summation of pain, or “windup,”
evoked by repetitive stimulation of peripheral nociceptive
afferent neurons. Sensory testing experiments can be used
to demonstrate that abnormal windup of FM patients is
related to central nervous system (CNS) mechanisms of
central sensitization and persistent pain.
As background to the central sensory abnormalities of
FM patients, we discuss the normal role of nociceptors
and the central consequences of repetitive stimulation of
nociceptive neurons, and also describe how these mecha-
nisms appear to be distorted in FM patients.
DONALD D. PRICE and ROLAND STAUD
ABSTRACT. Accumulating evidence suggests that fibromyalgia syndrome (FM) pain is maintained by tonic impulse
input from deep tissues, such as muscle and joints, in combination with central sensitization mechanisms.
This nociceptive input may originate in peripheral tissues (trauma and infection) resulting in hyperalge-
sia/allodynia and/or central sensitization. Evidence for abnormal sensitization mechanisms in FM includes
enhanced temporal summation of delayed pain in response to repeated heat taps and repeated muscle taps,
as well as prolonged and enhanced painful after-sensations in FM patients but not control subjects.
Moreover, magnitudes of enhanced after-sensations are predictive of FM patients’ ongoing clinical pain.
Such alterations of relevant pain mechanisms may lead to longterm neuroplastic changes that exceed the
antinociceptive capabilities of affected individuals, resulting in ever-increasing pain sensitivity and dysfunc-
tion. Future research needs to address the important role of abnormal nociception and/or antinociception
for chronic pain in FM. (J Rheumatol 2005;32 Suppl 75:22-28)
Key Indexing Terms:
TEMPORAL SUMMATION CHRONIC PAINFIBROMYALGIA
From the Department of Neuroscience and Department of Medicine,
University of Florida, Gainesville, Florida, USA.
The authors have no conflict of financial interest related to the contents
of this article.
D.D. Price, PhD, Departments of Oral and Maxillofacial Surgery and
Neuroscience, Colleges of Dentistry and Medicine; R. Staud MD,
McKnight Brain Institute, University of Florida.
Address reprint requests to D.D. Price, Claude Denson Pepper Center,
PO Box 100416, Gainesville, FL 32610-0416. E-mail:
22 The Journal of Rheumatology 2005, Volume 32 Supplement 75
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