A Mechanism-Based Approach to Prevention of and Therapy for Fibromyalgia

Fibromyalgia syndrome (FMS) is characterized by pain referred to deep tissues. Diagnosis and treatment of FMS are complicated by a variable coexistence with regional pain, fatigue, sleep disruption, difficulty with mentation, and depression. The widespread, deep pain of FMS can be a consequence of chronic psychological stress with autonomic dysregulation. Stress acts centrally to facilitate pain and acts peripherally, via sympathetic vasoconstriction, to establish painful muscular ischemia. FMS pain, with or without a coexistent regional pain condition, is stressful, setting up a vicious circle of reciprocal interaction. Also, stress interacts reciprocally with systems of control over depression, mentation, and sleep, establishing FMS as a multiple-system disorder. Thus, stress and the ischemic pain it generates are fundamental to the multiple disorders of FMS, and a therapeutic procedure that attenuates stress and peripheral vasoconstriction should be highly beneficial for FMS. Physical exercise has been shown to counteract peripheral vasoconstriction and to attenuate stress, depression, and fatigue and improve mentation and sleep quality. Thus, exercise can interrupt the reciprocal interactions between psychological stress and each of the multiple-system disorders of FMS. The large literature supporting these conclusions indicates that exercise should be considered strongly as a first-line approach to FMS therapy

Extreme Thermal Sensitivity and Pain-Induced Sensitization in a Fibromyalgia Patient

During the course of a psychophysical study of fibromyalgia syndrome (FMS), one of the subjects with a long history of headache and facial pain displayed an extraordinarily severe thermal allodynia. Her stimulus-response function for ratings of cutaneous heat pain revealed a sensitivity clearly beyond that of normal controls and most FMS subjects. Specially designed psychophysical methods showed that heat sensitivity sometimes increased dramatically within a series of stimuli. Prior exposure to moderate heat pain served as a trigger for allodynic ratings of series of normally neutral thermal stimulation. These observations document a case of breakthrough pain sensitivity with implications for mechanisms of FMS pain

Reliability of pain intensity clamping using response-dependent thermal stimulation in healthy volunteers

BACKGROUND: Pain intensity clamping uses the REsponse-Dependent Stimulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point which is continuously monitored from a subject's real-time pain ratings. REDSTIM blinds subjects regarding the pain intensity set-point, supporting its use for assessing intervention efficacy. By maintaining the pain intensity at a constant level, a potential decrease in pain sensitivity can be detected by an increase in thermode temperature (unknown to the subject) and not by pain ratings alone. Further, previously described sensitizing and desensitizing trends within REDSTIM provide a novel insight into human pain mechanisms overcoming limitations of conventional testing methods. The purpose of the present study was to assess the test-retest reliability of pain intensity clamping using REDSTIM during three separate sessions. METHODS: We used a method for testing changes in pain sensitivity of human subjects (REDSTIM) where the stimulus temperature is modulated to clamp pain intensity near a desired set-point. Temperature serves as the response variable and is used to infer pain sensitivity. Several measures were analyzed for reliability including average temperature and area under the curve (AUC). Intraclass correlation coefficients were calculated for each measure at pain rating set-points of 20/100 and 35/100. RESULTS: Sixteen healthy individuals (mean age = 21.6 ± 3.9) participated in three experiments two days apart at both pain rating set-points. Most reliability coefficients were in the moderate to substantial range (r's = 0.79 to 0.94) except for the negative AUC (r = 0.52), but only at the 20/100 pain rating set-point. CONCLUSIONS: The present study supports the test-retest reliability of pain intensity clamping using the REDSTIM methodology while providing a novel tool to examine human pain modulatory mechanisms and overcoming common shortcomings of conventional quantitative sensory testing methods

Age-related differences in conditioned pain modulation of sensitizing and desensitizing trends during response dependent stimulation

The current study evaluated age differences in conditioned pain modulation using a test stimulus that provided the opportunity to evaluate changes in heat pain sensitivity, sensitization, and desensitization within the same paradigm. During this psychophysical test, pain intensity clamping uses REsponse Dependent STIMulation (REDSTIM) methodology to automatically adjust stimulus intensity to maintain a desired pain rating set-point. Specifically, stimulus intensity increases until a pre-defined pain rating (the setpoint) is exceeded, and then decreases until pain ratings fall below the setpoint, with continued increases and decreases dictated by ratings. The subjects are blinded in terms of the setpoint and stimulus intensities. Younger and older subjects completed two test sessions of two REDSTIM trials, with presentation of conditioning cold stimulation between the trials of one session but not the other. The results indicated that conditioning cold stimulation similarly decreased the overall sensitivity of younger and older subjects, as measured by the average temperature that maintained a setpoint rating of 20 (on a scale of 0-100). The conditioning stimulus also significantly enhanced sensitization following ascending stimulus progressions and desensitization following descending stimulus progressions in older subjects relative to younger subjects. Thus, older subjects experienced greater swings in sensitivity in response to varying levels of painful stimulation. These results are discussed in terms of control over pain intensity by descending central modulatory systems. These findings potentially shed new light on the central control over descending inhibition and facilitation of pain

Long-term changes in purposive and reflexive responses to nociceptive stimulation following anterolateral chordotomy

Macaca nemestrina monkeys received unilateral interruption of the spinothalamic tract, producing contralateral hypalgesia and a bilateral decrease in amplitude of the flexion reflex. These effects on operant escape and reflex responses to electrocutaneous stimulation (ES) were monitored for months to evaluate relationships between the extent of each lesion and the presence or absence of recovery from the early postoperative deficits. Before surgery, the animals were trained to perform an operant response that terminated ES to the lateral calf of either leg. The durations of ES tolerated by each monkey were inversely related to stimulus intensities within the pain sensitivity range of human subjects. The vigor of operant escape responses and the frequency of intertrial pulls of the manipulandum were directly related to stimulus intensity. Following anterolateral chordotomy at an upper thoracic level, these measures revealed a contralateral hypalgesia for each animal. Operant responsivity to stimulation contralateral to the lesion recovered to control levels for 7 animals (group R). Sustained contralateral recovery of operant reactivity was not observed for 8 monkeys (group U). Most of the lesions in groups R and U were similar in extent and location, involving the classical distribution of the spinothalamic tract (in the anterolateral and ventral columns). Thus, recovery was not determined solely by lesion configuration. However, when recovery did occur, it was associated with medially extensive lesions. A subgroup of 3 unrecovered animals received superficial lesions that did not substantially involve the gray matter or the ventral columns. For all animals, reflex magnitudes were initially diminished bilaterally and then increased over months of testing. Reflex recovery was greater for the animals that demonstrated recovery of intentional reactions to nociception (group R). An ipsilateral hyperreflexia became apparent for group R. Contralateral recovery to normal levels was observed for group R but not for group U. The time course of recovery for operant and reflex responses clearly differed, indicating that different processes determined changes in these spinal and supraspinal reactions to nociceptive stimulation

Substance P-driven feed-forward inhibitory activity in the mammalian spinal cord

In mammals, somatosensory input activates feedback and feed-forward inhibitory circuits within the spinal cord dorsal horn to modulate sensory processing and thereby affecting sensory perception by the brain. Conventionally, feedback and feed-forward inhibitory activity evoked by somatosensory input to the dorsal horn is believed to be driven by glutamate, the principle excitatory neurotransmitter in primary afferent fibers. Substance P (SP), the prototypic neuropeptide released from primary afferent fibers to the dorsal horn, is regarded as a pain substance in the mammalian somatosensory system due to its action on nociceptive projection neurons. Here we report that endogenous SP drives a novel form of feed-forward inhibitory activity in the dorsal horn. The SP-driven feed-forward inhibitory activity is long-lasting and has a temporal phase distinct from glutamate-driven feed-forward inhibitory activity. Compromising SP-driven feed-forward inhibitory activity results in behavioral sensitization. Our findings reveal a fundamental role of SP in recruiting inhibitory activity for sensory processing, which may have important therapeutic implications in treating pathological pain conditions using SP receptors as targets

Relationships between Irritable Bowel Syndrome Pain, Skin Temperature Indices of Autonomic Dysregulation, and Sensitivity to Thermal Cutaneous Stimulation

This study evaluated relationships between irritable bowel syndrome (IBS) pain, sympathetic dysregulation, and thermal pain sensitivity. Eight female patients with diarrhea-predominant IBS and ten healthy female controls were tested for sensitivity to thermal stimulation of the left palm. A new method of response-dependent thermal stimulation was used to maintain pain intensity at a predetermined level (35%) by adjusting thermal stimulus intensity as a function of pain ratings. Clinical pain levels were assessed prior to each testing session. Skin temperatures were recorded before and after pain sensitivity testing. The temperature of palmar skin dropped (1.5°C) when the corresponding location on the opposite hand of control subjects was subjected to prolonged thermal stimulation, but this response was absent for IBS pain patients. The patients also required significantly lower stimulus temperatures than controls to maintain a 35% pain rating. Baseline skin temperatures of patients were significantly correlated with thermode temperatures required to maintain 35% pain ratings. IBS pain intensity was not significantly correlated with skin temperature or pain sensitivity. The method of response-dependent stimulation revealed thermal hyperalgesia and increased sympathetic tone for chronic pain patients, relative to controls. Similarly, a significant correlation between resting skin temperatures and thermal pain sensitivity for IBS but not control subjects indicates that tonic sympathetic activation and a thermal hyperalgesia were generated by the chronic presence of visceral pain. However, lack of a significant relationship between sympathetic tone and ratings of IBS pain casts doubt on propositions that the magnitude of IBS pain is determined by psychological stress

Blast Brain Injury Elevates Catecholamine Biosynthesis in the Nucleus Tractus Solitaries and Oxidative Stress in the Hypothalamus in Rats

Introduction: Traumatic Brain Injury (TBI) produces major health problems impacting the lives of both military and civilian personnel. TBI disrupts autonomic function but the nature of this disruption is unknown. Following blast brain injury, we assessed selective biochemical markers for autonomic function in adult male Sprague Dawley rats. Methods: Rats were subjected to head-directed overpressure blast injury (OBI) of 358 kPa magnitude at the target. At the same time for sham controls, rats were anesthetized as the previous group but instead of OBI were exposed just to noise being placed at ~ 2 m distance from the shock tube nozzle. Sympathetic nervous system activation of nucleus tractus solitaries and in the hypothalamus was evaluated at 6 hours following blast injury by assessing the expression of catecholamine biosynthesizing enzyme, tyrosine hydroxylase (TH) in the nucleus tractus solitaries and NADPH oxidase activity, a marker of oxidative stress,in the hypothalamus. Results: Following OBI there was a significant elevation in TH protein expression by 49% compared with control (P\u3c0.05). In addition, NADPH oxidase activity was significantly increased by 36% following OBI (P\u3c0.05). Conclusions: Collectively, the increased catecholamine biosynthesis in nucleus tractus solitaries and oxidative stress in the hypotalamus suggest that OBI results in increased sympathoexcitation in the rat brain. Such effects may be one important factor contributing to autonomic dysfunction following OBI. Acknowledgements: Supported by Department of Veteran Affairs; Rehabilitation R&D, GRECC, Medical Research Services, Banyan Biomarkers Inc, University of Florida Brain Institute, NIA, and AH

Role of primary somatosensory cortex in the coding of pain

The intensity and submodality of pain are widely attributed to stimulus encoding by peripheral and subcortical spinal/trigeminal portions of the somatosensory nervous system. Consistent with this interpretation are studies of surgically anesthetized animals, showing that relationships between nociceptive stimulation and activation of neurons are similar at subcortical levels of somatosensory projection and within the primary somatosensory cortex (in cytoarchitectural areas 3b and 1 of SI). Such findings have led to characterizations of SI as a network which preserves, rather than transforms, the excitatory drive it receives from subcortical levels. Inconsistent with this perspective are images and neurophysiological recordings of SI neurons in lightly anesthetized primates. These studies show that an extreme anterior position within SI (area 3a) receives input originating predominantly from unmyelinated nociceptors, distinguishing it from posterior SI (areas 3b and 1), long recognized as receiving input predominantly from myelinated afferents, including nociceptors. Of particular importance, interactions between these subregions during maintained nociceptive stimulation are accompanied by an altered SI response to myelinated and unmyelinated nociceptors. A revised view of pain coding within SI cortex is discussed, and potentially significant clinical implications are emphasized