TNFα is involved in neuropathic pain induced by nucleoside reverse transcriptase inhibitor in rats

Abstract

In patients with HIV/AIDS, neuropathic pain is a common neurological complication. Infection with the HIV itself may lead to neuropathic pain, and painful symptoms are enhanced when patients are treated with nucleoside reverse transcriptase inhibitors (NRTI). The mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In the current studies, we tested the role of TNFα in antiretroviral drug-induced neuropathic pain. We administered 2′,3′-dideoxycytidine (ddC, one of the NRTIs) systemically to induce mechanical allodynia. We found that ddC induced overexpression of both mRNA and proteins of GFAP and TNFα in the spinal dorsal horn. TNFα was colocalized with GFAP in the spinal dorsal horn and with NeuN in the DRG. Knockdown of TNFα with siRNA blocked the mechanical allodynia induced by ddC. Intrathecal administration of glial inhibitor or recombinant TNF soluble receptor, reversed mechanical allodynia induced by ddC. These results suggest that TNFα is involved in NRTI-induced neuropathic pain.

Herpes Simplex Virus Vector Mediated Gene Therapy of Tumor Necrosis Factor-α Blockade for Bladder Overactivity and Nociception in Rats

“…26,27 In addition, the TNF␣ expression level correlates with neuropathic pain 3,28 and exogenous administration of TNF␣ causes allodynia or hyperalgesia, 3 whereas anti-TNF␣ treatment has a therapeutic effect. 7,8 Thus, it seems reasonable that systemic administration of anti-TNF␣ antibody or recombinant TNF␣sR would also effectively suppress bladder pain.…”

“…When TNF␣ activity is neutralized using anti-TNF␣ antibody or TNF␣sR, nociception is suppressed, as observed in several rat pain models. 3,[5][6][7][8] Anti-TNF␣ antibody and recombinant TNF␣sR are used clinically to treat several inflammatory diseases. 9,10 However, concern exists that systemic administration of these molecules may lead to a wide range of side effects due to the importance of TNF␣ in generating a powerful immune response to infectious agents and other insults.…”

Mechanisms of distal axonal degeneration in peripheral neuropathies

“…In addition to the inflammation from the virus, recent work hasidentifiedantiretrovirals to also increase inflammatory signaling[303] and activation of apoptotic machinery [26]. To this end, ddC increases expression of TNF- α in GFAP + cells in the dorsal horn and neurons in the DRG[303].…”

“…To this end, ddC increases expression of TNF- α in GFAP + cells in the dorsal horn and neurons in the DRG[303]. In addition to TNF- α , BDNF has also been shown to facilitate the development of mechanical and thermal hyperalgesia following treatment by a nucleoside analogue by increasing firing rates of dorsal horn neurons to stimuli [204].…”

Neurotoxicity in the Post-HAART Era: Caution for the Antiretroviral Therapeutics

“…Similar findings were observed in rat DRG, where stavudine or didanosine treatment resulted in shortening of neurite length (Cherry et al 2010). The increase in peripheral neuropathy was shown to involve upregulation of TNF-α and BDNF when assessed for allodynia associated with zalcitabine and stavudine, respectively (Renn et al 2011; Zheng et al 2011). Another study demonstrated that efavirenz (EFV) could induce ER stress in the brain endothelial cells via upregulation and activation of protein kinase-like ER kinase (PERK) and inositol-requiring kinase 1α (IRE1α) and inhibited autophagosome formation by preventing the synthesis of phosphatidylinositol 3-phosphate (Bertrand and Toborek 2015).…”