In our review, the neurobiology of fibromyalgia syndrome (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 temporal 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 neurons, before these second-order neurons transmit nociceptive 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 neurons are related to sensory-discriminative, cognitive-evaluative, and affective processing of somatosensory nociceptive 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 persistent pain conditions. Reflex and reflective behaviors that are aimed at eliminating acute pain are not operative in chronic pain syndromes including FM. Patients with FM, like most chronic pain sufferers, do not display pain behaviors usually 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 considered 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 mechanisms 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 hyperalgesia/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 dysfunction. 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
