Objectives. Franks, William F. The symptoms of HIV-SN are dominated by distal neuropathic pain. Patients received relief when they took medications addressing the herpes infection. When combined or compared with transgenic approaches, this vector may provide valuable information in the mechanistic study of pain. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. To elucidate the role of spinal TNF in the pathogenesis of neuropathic pain, we used viral vector-mediated transfer of the gene coding for the p55 sTNFR antagonist of TNF to the dorsal root ganglion (DRG) to release p55 sTNFR into the dorsal horn of spinal cord in rats with neuropathic pain created by selective SNL.
24). In previous studies we have shown that vectors constructed from nonreplicating herpes simplex virus (HSV) recombinants can be used effectively to transfer genes into DRG neurons from subcutaneous inoculation, and that release of inhibitory neurotransmitters or antiinflammatory proteins from the central afferent terminals of transduced DRG neurons in vivo can be used to modulate pain-related behaviors.11,12,17,18 In this study, we used a nonreplicating HSV vector constructed to express and release IL-10 in the formalin model of inflammatory pain. Cytokines have pleiotropic activities that can trigger several cellular responses depending on cell type, timing, and molecular environment. Curiously, transduction of the DRG following subcutaneous delivery has not been observed previously for rAAV, with rAAV serotype 2 (rAAV serotype 2 genome packaged in the serotype 2 capsid, rAAV2/2) failing to transduce DRG cells following subcutaneous injection into the hindpaw of rats . This is not surprising as rAAV2/2 is inefficient at retrograde transport in comparison to rAAV2/6 . Specifically, we will discuss the use of herpes simplex virus (HSV) vectors in both the treatment of chronic pain and the identification and delivery of novel therapeutic interventions. codeine) to strong opioids such as morphine.
This is in part due to the use of secreted transgenic peptides that have had the capacity to exert paracrine functions on non-transduced cells. But infection of DRG neurons by serotype 8 AAV is apparently unique; serotype 2 AAV, for example, does not infect DRG neurons when administered by the same route. A double-blind, randomized, controlled trial has demonstrated that methadone 10 to 20 mg per day has an analgesic effect in neuropathic pain (Watson et al 2003). For conditions in which the primary cause of the chronic pain is either not readily reversible or not identifiable the search for treatment has focused primarily on components of the ascending pain pathway. At a minimum, serotype 8 AAV should provide an interesting tool for animal studies investigating DRG mechanisms in chronic pain, but important issues are also raised that need to be explored further: (1) what is the rostro-caudal extent of transgene expression in the DRG following intrathecal injection? Thus, in the present study, we investigated the feasibility of HSV vector mediated GAD67 gene therapy for the treatment of DO following SCI. However, recent literature consistently reports that activation of astrocytes and microglia contributes significantly to CNP following SCI (Gwak et al., 2008, Gwak and Hulsebosch, 2009; Hains and Waxman, 2006).
With the goal of increasing the number of transduced nociceptive neurons that would be required for exploring the mechanisms of pain, we examined sciatic nerve and intrathecal routes administration of rAAV that have recently reported success in the transduction of rat DRG. Clatworthy et al. For example, the anti-allodynic effect of systemic loperamide was blocked by systemic pretreatment with naloxone hydrochloride or the peripherally acting MOR-preferring antagonist, methylnaltrexone. Among them, the ionotropic NMDA receptor is most involved in the events correlated with nociception , and with the maintenance of central sensitization and hyperexcitability of dorsal horn neurons. Interestingly, the efficiency and profile of transduction was similar for the three mouse strains examined, suggesting that rAAV2/6 transduction of DRG neurons can be applied to the mouse regardless of the model being used. Several lines of evidence indicate that tumor necrosis factor-alpha (TNFα) plays an key role in the development of chronic pain. With the exception of ICP47, these IE gene products trigger the expression of early (E) genes that code for proteins involved in DNA replication and late (L) genes coding for structural HSV proteins.18 As the viral thymidine kinase (tk) is required for replication in neurons, recombinants defective in tk can be propagated in culture and can replicate in skin, but not in the DRG.
Between 6 h and 3 days following injection of DNA, but not vehicle, cell counts in cerebrospinal fluid (CSF) at the site of injection are significantly elevated. Although surgical resection alleviates cancer pain, more effective analgesics are still needed; pre-surgical patients often experience extended periods of severe pain, some cancers cannot be excised, some patients are too sick to have surgery, and many patients develop an untreatable recurrence of the cancer or a second primary cancer. All the tissue culture experiments were repeated 3 times.