Abstract
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 κB (NFκB) 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 NFκB 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 NFκB signaling. Additionally, experiments were performed to determine whether central or peripheral glial NFκB 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 NFκB-COX2 signaling pathway in NMSCs is necessary for the maintenance of neuropathic pain in vivo.
Highlights
Neuropathic pain resulting from peripheral nerve insult is the result of both peripheral and central sensitization of nociceptive neurons
These data suggested that COX2 in Glial fibrillary acidic protein (GFAP)-positive glia contributes to the maintenance of neuropathic pain following peripheral nerve injury
We found that the inhibition of nuclear factor κB (NFκB) in GFAP-positive cells temporarily alleviates pain beginning at 1 week and lasts through 3 weeks post-spared nerve injury (SNI) injury in both male and female mice
Summary
Neuropathic pain resulting from peripheral nerve insult is the result of both peripheral and central sensitization of nociceptive neurons. Both central and peripheral GFAP-positive glia have been implied in neuropathic pain through the release of inflammatory molecules (Ma and Bisby, 1998; Milligan and Watkins, 2009; Fu et al, 2010). NFκB positively regulates the expression of several proinflammatory cytokines, including nitric oxide and dynorphin as well as increasing the expression of the enzyme cyclooxygenase-2 (COX2; Adcock et al, 1997; Neill and Kaltschmidt, 1997). While COX2 seems to be involved in the generation of persistent pain, the cellular source of the COX2 upregulation remains unidentified
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