Abstract
BackgroundTo examine the role of inflammatory mediators in neuropathic pain, we used a replication-defective genomic herpes simplex virus (HSV)-based vector containing the coding sequence for the anti-inflammatory peptide interleukin (IL)-4 under the transcriptional control of the HSV ICP4 immediate early promoter, vector S4IL4, to express IL-4 in dorsal root ganglion (DRG) neurons in vivo.ResultsSubcutaneous inoculation of S4IL4 in the foot transduced lumbar DRG to produce IL-4. Transgene-mediated expression of IL-4 did not alter thermal latency or tactile threshold in normal animals, but inoculation of S4IL4 1 week after spinal nerve ligation (SNL) reduced mechanical allodynia and reversed thermal hyperalgesia resulting from SNL. Inoculation of S4IL4 1 week before SNL delayed the development of thermal hyperalgesia and tactile allodynia, but did not prevent the ultimate development of these manifestations of neuropathic pain. S4IL4 inoculation suppressed non-noxious-induced expression of c-Fos immunoreactivity in dorsal horn of spinal cord and reversed the upregulation of spinal IL-1β, PGE2, and phosphorylated-p38 MAP kinase, characteristic of neuropathic pain.ConclusionHSV-mediated expression of IL-4 effectively reduces the behavioral manifestations of neuropathic pain, and reverses some of the biochemical and histologic correlates of neuropathic pain at the spinal level.
Highlights
To examine the role of inflammatory mediators in neuropathic pain, we used a replication-defective genomic herpes simplex virus (HSV)-based vector containing the coding sequence for the anti-inflammatory peptide interleukin (IL)-4 under the transcriptional control of the HSV ICP4 immediate early promoter, vector S4IL4, to express IL-4 in dorsal root ganglion (DRG) neurons in vivo
We found that HSV-mediated expression of IL-4 reduced mechanical allodynia and thermal hyperalgesia and reduced the induction of c-Fos-like immunoreactivity (Fos-LI) by non-noxious touch, and blocked the increase in expression of IL-1β, PGE2, and phosphorylated p38 (p-p38) in the spinal cord after spinal nerve ligation (SNL)
S4IL4 produces IL-4 in vitro and in vivo Transduction of primary DRG neurons in culture with S4IL4 (Figure 1a) at a multiplicity of infection (MOI) of 1 resulted in the production and release of substantial amounts of IL-4 into the medium as detected by ELISA (110 pg/ml over 24 hrs from cells infected with S4IL4 compared to 10 pg/ml from cells infected with control vector SHZ)
Summary
To examine the role of inflammatory mediators in neuropathic pain, we used a replication-defective genomic herpes simplex virus (HSV)-based vector containing the coding sequence for the anti-inflammatory peptide interleukin (IL)-4 under the transcriptional control of the HSV ICP4 immediate early promoter, vector S4IL4, to express IL-4 in dorsal root ganglion (DRG) neurons in vivo. Partial nerve injury results in the release of proinflammatory cytokines interleukin (IL)1β, IL-6, and tumor necrosis factor alpha from activated Schwann cells, endothelial cells, and macrophages in nerve [1] to produce direct effects on nociceptive activity [2]. Peripheral nerve damage activates microglia and astrocytes in spinal cord to release the same proinflammatory cytokines in dorsal horn [3,4,5,6], resulting in central sensitization [7,8] and an exaggerated pain response characteristic of neuropathic pain [9,10,11].
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