TNF signal, ROS, and caspase-11 play important role in HIV gp120 with morphine-Induced Neuropathic Pain.

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      Recent clinical evidence suggests that repeated use of opioid medications increases chronic pain in individuals living with HIV. It is important to elucidate the exact molecular mechanisms of neuropathic pain (NP) in opioid users living with HIV. HIV-related neuron damage is induced by activating glial cells releasing neurotoxic factors (such as, TNFα). Chronic morphine use also induces TNFα product. Spinal mitochondrial superoxide (mtO2●-) plays important role in neuropathic pain. Non-canonical inflammasome, caspase-11 signal pathway is involved in methamphetamine-induced neuron apoptosis. Increased ROS enhances caspase-11 expression during enteric pathogen infection. In the present study, we investigated the role of TNFRI, mtO2●- and caspase-11 in a HIV coat glycoprotein gp120 with morphine (gp120/M)-induced neuropathic pain state. HIV-gp120 with morphine induced mechanical allodynia lasting for 3 weeks. HIV-gp120/M upregulated the expression of TNFRI, mitochondrial superoxide, with caspase-11, and down-regulated Sirt3 in the spinal dorsal horn. TNFRI-/- knockout mice were higher mechanical threshold and longer thermal latency than that in wildtype mice. Intrathecal administration of antisense oligonucleotides against TNFRI, Mito-Temple (mitochondrial scavenger of mtO2●-), or siRNA agonist caspase-11 mRNA reduced mechanical allodynia in the gp120/M neuropathic pain model. Antisense oligonucleotides against TNFRI reduced the number of MitoSox (a marker of mtO2●-) positive cells in the SCDH in gp120/M group. The rat neuronal neuroblast (B35) cell line (ATCC) were treated with rTNFα (10 ng/mL, Peprotech) increased expression of mtO2●- and caspase-11, and caspase-11 related inflammatory factors such as, caspase-1, and IL-1β. In conclusions, spinal TNFRI signal plays a significant role in the HIV gp120-related neuropathic pain state, and provide evidence for a novel approach to treating chronic pain in opioid users living with HIV. NIH R01DA34749, R01DA047089, and R01DA047157, and R01DA047157-03S1.
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