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The symptoms of HIV-sensory neuropathy are dominated by neuropathic pain. Recent data show that repeated use of opiates enhances the chronic pain states in HIV patients. Limited attention has so far been devoted to exploring the exact pathogenesis of HIV painful disorder and opiate abuse in vivo, for which there is no effective treatment. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal domain protein (BET) family and functions as a chromatin ‘reader’ that binds acetylated lysines in histones in brain neurons to mediate the transcriptional regulation underlying learning and memory. Here, we established a neuropathic pain model of interaction of intrathecal HIV envelope glycoprotein 120 (gp120) and chronic morphine in rats. The combination of gp120 and morphine (gp120/M, for 5 days) induced persistent mechanical allodynia compared with either gp120 or morphine alone. Mechanical allodynia reached the lowest values at day 10 from gp120/M application, beginning to recover from day 21. In the model, gp120/M induced overexpression of Brd4 mRNA and protein at day 10 using RT-qPCR and western blots, respectively. Immunohistochemical studies showed that Brd4 at day 10 was expressed in the neurons of spinal cord dorsal horn. BET inhibitor I-BET762 dose-dependently increased the mechanical threshold in the gp120/M pain state. The present study provides preclinical evidence for treating HIV neuropathic pain with opioids using the BET inhibitor.

Published ahead of print September 28, 2015

Published ahead of print April 6, 2015

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.

Infection of the nervous system with the human immunodeficiency virus (HIV-1) can lead to cognitive, motor and sensory disorders. HIV-related sensory neuropathy (HIV-SN) mainly contains the HIV infection-related distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathies (ATN). The main pathological features that characterize DSP and ATN include retrograde (“dying back”) axonal degeneration of long axons in distal regions of legs or arms, loss of unmyelinated fibers, and variable degree of macrophage infiltration in peripheral nerves and dorsal root ganglia (DRG). One of the most common complaints of HIV-DSP is pain. Unfortunately, many conventional agents utilized as pharmacologic therapy for neuropathic pain are not effective for providing satisfactory analgesia in painful HIV-related distal sensory polyneuropathy, because the molecular mechanisms of the painful HIV-SDP are not clear in detail. The HIV envelope glycoprotein, gp120, appears to contribute to this painful neuropathy. Recently, preclinical studies have shown that glia activation in the spinal cord and DRG has become an attractive target for attenuating chronic pain. Cytokines/chemokines have been implicated in a variety of painful neurological diseases and in animal models of HIVrelated neuropathic pain. Mitochondria injured by ATN and/or gp120 may be also involved in the development of HIVneuropathic pain. This review discusses the neurochemical and pharmacological mechanisms of HIV-related neuropathic pain based on the recent advance in the preclinical studies, providing insights into novel pharmacological targets for future therapy.

Chronic pain is a highly prevalent condition that impacts adversely on individual quality of life, imposes substantial costs on the healthcare system and a considerable burden on society. Advances in the understanding of pain mechanisms have opened the way for the development of new treatment strategies. The continuous delivery of short-lived potent bioactive molecules to sensory nerves, spinal cord or meninges - achieved by directed gene transfer - offers the possibility to selectively interrupt nociceptive neurotransmission or to interfere with the plastic changes in the nervous system underlying the development or persistence of chronic pain. In this review we describe advances in the use of nonviral and viral vector-based gene transfer for the treatment of pain, with a special focus on the use of recombinant nonreplicating herpes simplex virus-based vectors and the prospects for clinical trials.

We tested whether transfer of the gene coding for glutamic acid decarboxylase to dorsal root ganglion using a herpes simplex virus vector to achieve release of GABA in dorsal horn would attenuate nociception in this condition. Subcutaneous inoculation of a replication‐defective herpes simplex virus vector expressing glutamic acid decarboxylase (vector QHGAD67) 7 days after selective L5 spinal nerve ligation reversed mechanical allodynia and thermal hyperalgesia; the antiallodynic effect lasted 6 weeks and was reestablished by reinoculation. QHGAD67 inoculation also suppressed induction of c‐Fos and phosphorylated extracellular signal–regulated kinase 1 and 2 in the spinal cord. Ann Neurol 2005;57:914–918