Excessive Peptidergic Sensory Innervation of Cutaneous Arteriole-Venule Shunts (AVS) in the Palmar Glabrous Skin of Fibromyalgia Patients: Implications for Widespread Deep Tissue Pain and Fatigue.
ABSTRACT OBJECTIVE: To determine if peripheral neuropathology exists among the innervation of cutaneous arterioles and arteriole-venule shunts (AVS) in fibromyalgia (FM) patients. SETTING: Cutaneous arterioles and AVS receive a convergence of vasoconstrictive sympathetic innervation, and vasodilatory small-fiber sensory innervation. Given our previous findings of peripheral pathologies in chronic pain conditions, we hypothesized that this vascular location may be a potential site of pathology and/or serotonergic and norepinephrine reuptake inhibitors (SNRI) drug action. SUBJECTS: Twenty-four female FM patients and nine female healthy control subjects were enrolled for study, with 14 additional female control subjects included from previous studies. AVS were identified in hypothenar skin biopsies from 18/24 FM patient and 14/23 control subjects. METHODS: Multimolecular immunocytochemistry to assess different types of cutaneous innervation in 3 mm skin biopsies from glabrous hypothenar and trapezius regions. RESULTS: AVS had significantly increased innervation among FM patients. The excessive innervation consisted of a greater proportion of vasodilatory sensory fibers, compared with vasoconstrictive sympathetic fibers. In contrast, sensory and sympathetic innervation to arterioles remained normal. Importantly, the sensory fibers express α2C receptors, indicating that the sympathetic innervation exerts an inhibitory modulation of sensory activity. CONCLUSIONS: The excessive sensory innervation to the glabrous skin AVS is a likely source of severe pain and tenderness in the hands of FM patients. Importantly, glabrous AVS regulate blood flow to the skin in humans for thermoregulation and to other tissues such as skeletal muscle during periods of increased metabolic demand. Therefore, blood flow dysregulation as a result of excessive innervation to AVS would likely contribute to the widespread deep pain and fatigue of FM. SNRI compounds may provide partial therapeutic benefit by enhancing the impact of sympathetically mediated inhibitory modulation of the excess sensory innervation.
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ABSTRACT: PURPOSE: The present study aimed: (1) to test the associations of overall physical fitness and subjective well-being with fibromyalgia severity and (2) to determine whether the combination of overall physical fitness and subjective well-being is associated with fibromyalgia severity among adult women patients. METHODS: This cross-sectional study included 424 participants from Andalusia, southern Spain. Overall physical fitness and the components of subjective well-being (positive affect, negative affect and cognitive well-being), and fibromyalgia severity were assessed using the Functional Senior Physical Fitness Test Battery, the Positive and Negative Affect Schedule, the Satisfaction With Life Scale, and the Fibromyalgia Impact Questionnaire, respectively. RESULTS: Overall physical fitness (beta = -.23), positive affect (beta = -.18), negative affect (beta = .26), and cognitive well-being (beta = -.18) were all associated with fibromyalgia severity. The patients with the highest overall physical fitness and increased subjective well-being reported ~15 % lower fibromyalgia severity than those with the lowest fitness and poorest subjective well-being (Cohen's d > 1.0). CONCLUSION: Our results suggest that higher levels of overall physical fitness and subjective well-being are independently associated with lower fibromyalgia severity. Moreover, patients with higher overall physical fitness and increased subjective well-being (high positive affect, low negative affect, or high cognitive well-being) reported lower fibromyalgia severity than those with low levels of overall physical fitness and subjective well-being.Quality of Life Research 01/2015; DOI:10.1007/s11136-015-0917-7 · 2.86 Impact Factor
Article: Reply to Quintner and CohenPain Medicine 04/2014; 15(4). DOI:10.1111/pme.12393 · 2.24 Impact Factor
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ABSTRACT: The skin is a morphologically complex organ that serves multiple complementary functions, including an important role in thermoregulation, which is mediated by a rich vasculature that is innervated by sympathetic and sensory endings. Two autosomal dominant disorders characterized by episodes of severe pain, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) have been directly linked to mutations that enhance the function of sodium channel NaV1.7. Pain attacks are accompanied by reddening of the skin in both disorders. NaV1.7 is known to be expressed at relatively high levels within both dorsal root ganglion (DRG) and sympathetic ganglion neurons, and mutations that enhance the activity of NaV1.7 have been shown to have profound effects on the excitability of both cell-types, suggesting that dysfunction of sympathetic and/or sensory fibers, which release vasoactive peptides at skin vasculature, may contribute to skin reddening in IEM and PEPD. In the present study, we demonstrate that smooth muscle cells of cutaneous arterioles and arteriole-venule shunts (AVS) in the skin express sodium channel Nav1.7. Moreover, Nav1.7 is expressed by endothelial cells lining the arterioles and AVS and by sensory and sympathetic fibers innervating these vascular elements. These observations suggest that the activity of mutant Nav1.7 channels in smooth muscle cells of skin vasculature and innervating sensory and sympathetic fibers contribute to the skin reddening and/or pain in IEM and PEPD.Molecular Pain 05/2015; 11(1):26. DOI:10.1186/s12990-015-0024-3 · 3.53 Impact Factor