title: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Integrated Tissue Dynamics, LLC, Rensselaer, New York 12144, USA. albrecp@mail.amc.edu
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Albrecht
authors.forename: Quanzhi
authors.initials: Q
authors.lastname: Hou
authors.forename: Charles E
authors.initials: CE
authors.lastname: Argoff
authors.forename: James R
authors.initials: JR
authors.lastname: Storey
authors.forename: James P
authors.initials: JP
authors.lastname: Wymer
authors.forename: Frank L
authors.initials: FL
authors.lastname: Rice
mesh_terms: D000328:Adult; D000344:Afferent Pathways / Q000378:metabolism / Q000473:pathology; D000368:Aged; D001160:Arterioles / Q000294:innervation* / Q000378:metabolism*; D005260:Female; D005356:Fibromyalgia / Q000378:metabolism* / Q000473:pathology; D006225:Hand; D006801:Humans; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000294:innervation* / Q000378:metabolism; D014699:Venules / Q000294:innervation* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D009479:Neuropeptides