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. 2021 Aug 23;2:691740. doi: 10.3389/fpain.2021.691740

Figure 1.

Figure 1

Trauma and/ or immune responses lead to PC production, most notably IL-1β, IL-6 and TNF-α. PANs of multiple tissues embedded in the ECM are stimulated, transporting these substances to the DRG and DH where glial cells are stimulated leading to central and peripheral neuroinflammation/sensitization. Nociceptive bombardment stimulates somato/visceral-sympathetic reflexes causing the release of NE, resulting in peripheral vasoconstriction (including fascial vasculature) while the cytokines IL-1β, IL-6, TNF-α which deactivate the local lymphatic pump mechanism and simultaneously stimulate fibroblasts to differentiate into myofibroblasts. TGF-b1 released by fibroblasts & myofibroblasts, causes contraction of fascial tissues compressing pre-lymphatic pathways. Impaired hemodynamics from vasoconstriction, deactivation of the lymphatic pump mechanism and compression of pre-lymphatic pathways create areas of hypoxia and IIS. Continued PAN stimulation results in a pathophysiological feed-forward loop of lymphatic stasis, nociceptor stimulation and sympathetic activation which manifests in chronic pain, sub-threshold action potentials and idiopathic visceral/vascular dysfunction.