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

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Copyright © 2021 Tuckey, Srbely, Rigney, Vythilingam and Shah.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Nociceptive bombardment (various sources) produces PCs including IL-1β, IL-6, TNF-α etc. PANs of multiple tissues embedded in the ECM are stimulated, transporting these substances to the DRG, causing antidromic release of neuropeptides from the DRG into the injured and neurosegmentally linked tissues, exacerbating the response beyond the region of primary hyperalgesia. Glial cells in the DH are stimulated leading to central and peripheral neuroinflammation/sensitization. PAN entry into the DH at multiple levels alters the activity of alpha and gamma motor neurons, creating multi-segmental muscle guarding reflexes, and myofascial compression of pre-lymphatic pathways. Simultaneously, somato/visceral-sympathetic reflexes are stimulated, causing the release of NE, resulting in peripheral vasoconstriction (including fascial vasculature) while cytokines IL-1β, IL-6, TNF-α deactivate local lymphatic propulsion and stimulate fibroblasts to differentiate into myofibroblasts. TGF-b1 released by fibroblasts & myofibroblasts, creates local fascial contraction, perimysial stiffness (gamma motor activation) and compression of pre-lymphatic pathways. Due to the combined mechanisms, areas of hypoxia and inflammatory stasis develop which continuously stimulate local PANs. A pathophysiological feed-forward loop of lymphatic stasis, nociceptor stimulation and SNA manifests in chronic pain, sub-threshold action potentials and idiopathic visceral/vascular dysfunction.