Hypothetical Mechanisms of Abnormal Pain Processing

While the preceding findings are intriguing, the fact is that the exact mechanism of enhanced nociception in fibromyalgia remains a matter of debate and continuing inquiry. Accordingly, the following represents a synopsis of some hypothetical considerations regarding the potential pathologies that might contribute to the phenomenon of enhanced nociception.

There exists a school of thought that considers the pain of fibromyalgia to represent a primarily psychic phenomenon. Accordingly, those who ascribe to this perspective consider the enhanced nociception displayed by fibromyalgia patients to represent a form of secondary hyperalgesia, attributed to such processes as hypervigilance or increased attention to somatosensory stimulation suggesting a perceptual style of amplification.

This conclusion is derived in part from the consistent observation of increased activation of the anterior cingulate cortex, which plays a role in both the attentional and affective, or emotional, dimensions of pain perception. Enhanced activation of the anterior cingulate cortex in response to stimulation has also been demonstrated in another stress-related disorder characterized by enhanced somatosensory perception: irritable bowel syndrome.

On the other hand, the hyperalgesia and other forms of polymodal sensitivity that characterize the disorder have been conceptualized as a form of central sensitization in which elements of the central nervous system have become pathologically sensitive to stimulation, thereby making stimuli that were previously innocuous (light touch, for example) excruciating.

The phenomenon of central sensitization has been demonstrated to depend on the plasticity in function of N-methyl-D-aspartate (NMDA) subtype glutamate receptors, which play a fundamental role in the flow of information within the brain and spinal cord. In support of this notion, it has been demonstrated that a large subgroup of patients respond to very small doses of the anesthetic ketamine, which at sufficient doses antagonizes NMDA receptors, with dramatic reductions in the painful symptoms.

It is then intriguing that NMDA receptors play a critical role in pain perception, specifically within the hippocampus and anterior cingulate cortex, wherein a variety of stress-related factors such as corticotropin-releasing hormone, cortisol, norepinephrine, substance P, and histamine contribute to neuronal excitability specifically by enhancing NMDA receptor activity.

Thus, the pain of fibromyalgia (and perhaps other related disorders) might stem from stress- related changes within brain centers involved in overlapping mechanisms of nociception (i.e., attentional and affective dimensions), in which stress-related factors reduce the threshold for excitation. As such, these changes provide a credible organic basis for what might otherwise be appreciated as psychic phenomena.

A relative increase in the amount of information flowing out of the body and toward the brain might also result in enhanced pain perception. One naturally expects this in scenarios involving tissue damage, whether related to mechanical causes (as in an injury or a degenerative condition such as arthritis) or a chemical or thermal exposure.

Likewise, inflammatory processes result in the release of various chemicals within affected tissues that sensitize peripheral pain receptors (nociceptors), thereby amplifying the flow of information from the area of inflammation.

The adaptive value of such an increased amount of painful information originating from injured tissue is clear: the organism protects the area and allows it to heal. On the other hand, no such peripheral pathology has been described in fibromyalgia; therefore, an area of intense focus regarding the potential source of increased information flowing toward the brain has been potential pathological changes within the dorsal root ganglion and dorsal horn of the spinal column, which collectively represent the interface between the peripheral and central nervous systems.

Both of these regions contain high densities of NMDA receptors, which are thought to contribute substantially the phenomenon of wind-up, and both have been demonstrated to undergo pathological transformation under certain conditions, thereby resulting in hyperalgesia and allodynia in the affected area. Intriguingly, recent investigations using rat models have demonstrated that stress exposure results in increased metabolic activity within the dorsal horn. However, the relevance of these findings to fibromyalgia remains unknown.

Somatosensory information processing represents a two-way flow of information within the spinal cord: information concerning the status of the body is transferred from the peripheral nervous system to the central nervous system and ascends the spinal cord toward the brain, while a variety of filtering mechanisms descend from the brain to modulate the amount of information transferred specifically within the dorsal horn.

The vast majority of neurons that carry descending inhibition run along tracks within the dorsal spinal column (i.e., the part furthest toward the back). Research has demonstrated that interruption of the dorsal descending systems leads to hyperactivity of pain-related neurons within the spinal cord characterized by an increase in background activity, lowering in stimulation threshold, and increase in response magnitude to noxious stimuli.

Collectively, the findings suggest that if such an interruption were to occur in humans, such impairment would likely result in spontaneous deep pain, tenderness to palpation, and hyperalgesia of deep tissues - all of which characterize patients with fibromyalgia.

Accordingly, some researchers are focused on determining the potential contribution of restrictive lesions, specifically within the cervical spinal cord, to the experience of chronic widespread pain. Likewise, an increase in descending facilitation involving medullary brain centers might also contribute to the amplification of sensory information.

The apparent dysregulation of the sympathetic nervous system detailed previously has led to the hypothesis that fibromyalgia might represent a sympathetically maintained pain syndrome. In support of this notion, proponents of the hypothesis observe that, like other so-called sympathetically maintained pain conditions (e.g., complex regional pain syndrome, or reflex sympathetic dystrophy), the pain associated with fibromyalgia may be characterized by its frequent posttraumatic onset and by the presence of chronic stimuli-independent pain accompanied by allodynia, paresthesias, and distal vasomotor changes.

Limited reports suggest that fibromyalgia pain may be aggravated by peripheral administration of epinephrine. Historically speaking, it has been generally considered that sympathetically maintained pain is alleviated by maneuvers intended to block sympathetic activity, and there are (again, limited) reports reflecting that fibromyalgia patients respond to these as well.

More recently, however, the contribution of sympathetic activity to those conditions traditionally considered to represent sympathetically maintained pain conditions has become a matter of some contention, while the specific mechanism whereby sympathetic activation might contribute to the development of chronic widespread pain remains to be elucidated.

The most recent hypotheses concerning the nature of pain in fibromyalgia have to do with a disruption of natural analgesia within the limbic system involving the neurotransmitter dopamine. Stressful experience has been robustly demonstrated to disrupt the normal function of dopamine neurons, which in turn plays an important role in natural analgesia in such brain centers as the thalamus, basal ganglia, nucleus accumbens, insular cortex, and anterior cingulate cortex.

Recent insights regarding the pharmacology of ketamine have demonstrated that the drug activates dopamine D2 receptors, which may then explain its efficacy in relieving symptoms of fibromyalgia when given at very low doses. Intriguingly, many of the brain centers that have been shown to be involved in fibromyalgia using functional neuroimaging are among the same brain centers in which dopamine plays a role in analgesia.

Dopamine acts within the thalamus and insular cortex to recruit mechanisms of descending inhibition, while in the anterior cingulate cortex dopamine opposes the activity of NMDA receptors specifically involved in nociception. In addition, the reactivity of dopamine neurons is controlled by excitatory output from the hippocampus, which in turn is exquisitely sensitive to the effects of stress-related factors.

A stress-related increase in neuronal excitability within the hippocampus would be predicted to suppress the reactivity of dopamine neurons, thereby producing a relative increase in painful sensations. Other neurotransmitters whose dysfunction has been proposed to contribute to the development of chronic widespread pain include serotonin and norepinephrine. In general, medications that act chiefly to boost serotonergic activity have met with disappointing results, while those with mixed activity for serotonin and norepinephrine are somewhat more promising.