Nuclear Factor κB-COX2 Pathway Activation in Non-myelinating Schwann Cells Is Necessary for the Maintenance of Neuropathic Pain in vivo

Chronic neuropathic pain leads to long-term changes in the sensitivity of both peripheral and central nociceptive neurons. Glial fibrillary acidic protein (GFAP)-positive glial cells are closely associated with the nociceptive neurons including astrocytes in the central nervous system (CNS), satellite glial cells (SGCs) in the sensory ganglia, and non-myelinating Schwann cells (NMSCs) in the peripheral nerves. Central and peripheral GFAP-positive cells are involved in the maintenance of chronic pain through a host of inflammatory cytokines, many of which are under control of the transcription factor nuclear factor kappa B (NF kappa B) and the enzyme cyclooxygenase 2 (COX2). To test the hypothesis that inhibiting GFAP-positive glial signaling alleviates chronic pain, we used (1) a conditional knockout (cKO) mouse expressing Cre recombinase under the hGFAP promoter and a floxed COX2 gene to inactivate the COX2 gene specifically in GFAP-positive cells; and (2) a tet-Off tetracycline transactivator system to suppress NF kappa B activation in GFAP-positive cells. We found that neuropathic pain behavior following spared nerve injury (SNI) significantly decreased in COX2 cKO mice as well as in mice with decreased glial NF kappa B signaling. Additionally, experiments were performed to determine whether central or peripheral glial NF kappa B signaling contributes to the maintenance of chronic pain behavior following nerve injury. Oxytetracycline (Oxy), a blood-brain barrier impermeable analog of doxycycline was employed to restrict transgene expression to CNS glia only, leaving peripheral glial signaling intact. Signaling inactivation in central GFAP-positive glia alone failed to exhibit the same analgesic effects as previously observed in animals with both central and peripheral glial signaling inhibition. These data suggest that the NF kappa B-COX2 signaling pathway in NMSCs is necessary for the maintenance of neuropathic pain in vivo.

Automated summary

Chronic neuropathic pain causes long-term changes in sensitivity of peripheral and central nociceptive neurons. Glial fibrillary acidic protein (GFAP)-positive glial cells, such as astrocytes in the central nervous system (CNS), satellite glial cells (SGCs) in the sensory ganglia, and non-myelinating Schwann cells (NMSCs) in the peripheral nerves, are closely associated with nociceptive neurons and play a role in the maintenance of chronic pain through inflammatory cytokines regulated by NF kappa B and COX2. Inhibiting GFAP-positive glial signaling can alleviate chronic pain. Both central and peripheral GFAP-positive cells contribute to the maintenance of chronic pain, with NF kappa B-COX2 signaling pathway in NMSCs being necessary for neuropathic pain.