Intrathecal herpes simplex virus type 1 amplicon vector-mediated human proenkephalin reduces chronic constriction injury-induced neuropathic pain in rats

Zou, Wangyuan; Guo, Qulian; Chen, Chan; Yang, Yong; Wang, E

doi:10.3892/mmr.2011.445

Cited by 10 publications

(9 citation statements)

References 26 publications

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“…To evaluate this experimentally, animals were first inoculated with PBS or 10 8 PFU of control vHG or vHPPE, followed by VZV inoculation at the same site. Nocifensive behaviors were not induced by the HSV vectors alone (data not shown), mirroring previously reported absence of pain from replication-competent HSV 23–30 or replication-defective HSV, 20,31–38 even when expressing reporter genes or other proteins. However, VZV-induced MA nocifensive behaviors only developed in animals pre-inoculated with PBS or vHG vector, and did not develop in vHPPE-treated animals (Figure 4).…”

Section: Resultssupporting

confidence: 88%

“…Indeed, Wistar rats inoculated with high titers of replicating HSV-1 show only momentary behavioral pain responses. 14 Consistent with this, we found no pain indicators developing in Sprague–Dawley rats inoculated with either vHG control vector or vHPPE vector (data not shown) as has been previously described in replication-competent HSV 23–30 or replication-defective HSV 20,31–38 vectors expressing genes other than enkephalin in various pain models. This supports the fact that while HSV and VZV are genetically related, they have very different consequences on pain induction.…”

Section: Discussionsupporting

confidence: 89%

“…Our study extends the application of this vector–gene delivery combination to a model of a common and significant clinical problem, PHN. HSV-1 vectors expressing HPPE have been used as a treatment approach in various other pain animal models, including pain associated with pancreatitis, 25,36 formalin injection, 32 spinal nerve ligation, 35 complete Freund’s adjuvant-induced arthritis, 24,28,30 chronic constriction injury (CCI), 29,38 bone cancer pain, 31 pertussis toxin-induced pain 26 and in a bladder nociception model. 20,33,34 In these studies, HSV vector-mediated enkephalin produced abrogation of nocifensive behaviors to varying extents.…”

Section: Discussionmentioning

confidence: 99%

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Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

et al. 2014

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Acute and chronic pain (post-herpetic neuralgia or PHN) are encountered in patients with herpes zoster that is caused by reactivation of varicella-zoster virus (VZV) from a state of neuronal latency. PHN is often refractory to current treatments, and additional strategies for pain relief are needed. Here we exploited a rat footpad model of PHN to show that herpes simplex virus (HSV) vector-mediated gene delivery of human preproenkephalin (vHPPE) effectively reduced chronic VZV-induced nocifensive indicators of pain. VZV inoculated at the footpad induced prolonged mechanical allodynia and thermal hyperalgesia that did not develop in controls or with ultraviolet light-inactivated VZV. Subsequent footpad administration of vHPPE relieved VZV-induced pain behaviors in a dose-dependent manner for extended periods, and prophylactic vector administration prevented VZV-induced pain from developing. Short-term pain relief following low-dose vHPPE administration could be effectively prolonged by vector re-administration. HPPE transcripts were increased three- to fivefold in ipsilateral ganglia, but not in the contralateral dorsal root ganglia. VZV hypersensitivity and its relief by vHPPE were not affected by peripheral delivery of opioid receptor agonist or antagonist, suggesting that the efficacy was mediated at the ganglion and/or spinal cord level. These results support further development of ganglionic expression of enkephalin as a novel treatment for the pain associated with Zoster.

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

et al. 2014

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“…48). More recently, spinal delivery of vectors encoding POMC or PENK improved both mechanical and heat hypersensitivity following CCI4950; yet, it is unclear whether actions of such genetically delivered and native opioid peptides are mechanistically identical. Together, the relative contribution of the CNS endogenous opioids to mechanical vs. heat hypersensitivity in neuropathic conditions has not been systematically examined.…”

Section: Discussionmentioning

confidence: 99%

Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain

Łabuz

Celik

Zimmer

et al. 2016

Sci Rep

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Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment.

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“…Many of the previous studies have utilized herpes simplex viruses (HSVs) as a delivery vector in pain treatment. In the rodent CCI neuropathic pain model, an increase in paw withdrawal latencies to mechanical and thermal stimulus following application of recombinant defective herpes simplex viral vector encoding proenkephalin has been reported [45]. Also subcutaneous injection of HSV encoding preproenkephalin to the plantar surface of the paw increased the nociceptive threshold in phase II of the formalin test [46].…”

Section: Discussionmentioning

confidence: 99%

Viral Vectors Encoding Endomorphins and Serine Histogranin Attenuate Neuropathic Pain Symptoms after Spinal Cord Injury in Rats

et al. 2015

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BackgroundThe treatment of spinal cord injury (SCI)-induced neuropathic pain presents a challenging healthcare problem. The lack of available robust pharmacological treatments underscores the need for novel therapeutic methods and approaches. Due to the complex character of neuropathic pain following SCI, therapies targeting multiple mechanisms may be a better choice for obtaining sufficient long-term pain relief. Previous studies in our lab showed analgesic effects using combinations of an NMDA antagonist peptide [Ser1]histogranin (SHG), and the mu-opioid peptides endomorphins (EMs), in several pain models. As an alternative to drug therapy, this study evaluated the analgesic potential of these peptides when delivered via gene therapy.ResultsLentiviruses encoding SHG and EM-1 and EM-2 were intraspinally injected, either singly or in combination, into rats with clip compression SCI 2 weeks following injury. Treated animals showed significant reduction in mechanical and thermal hypersensitivity, compared to control groups injected with GFP vector only. The antinociceptive effects of individually injected components were modest, but the combination of EMs and SHG produced robust and sustained antinociception. The onset of the analgesic effects was observed between 1–5 weeks post-injection and sustained without decrement for at least 7 weeks. No adverse effects on locomotor function were observed. The involvement of SHG and EMs in the observed antinociception was confirmed by pharmacologic inhibition using intrathecal injection of either the opioid antagonist naloxone or an anti-SHG antibody. Immunohistochemical analysis showed the presence of SHG and EMs in the spinal cord of treated animals, and immunodot-blot analysis of CSF confirmed the presence of these peptides in injected animals. In a separate group of rats, delayed injection of viral vectors was performed in order to mimic a more likely clinical scenario. Comparable and sustained antinociceptive effects were observed in these animals using the SHG-EMs combination vectors compared to the group with early intervention.ConclusionsFindings from this study support the potential for direct gene therapy to provide a robust and sustained alleviation of chronic neuropathic pain following SCI. The combination strategy utilizing potent mu-opioid peptides with a naturally-derived NMDA antagonist may produce additive or synergistic analgesic effects without the tolerance development for long-term management of persistent pain.

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Intrathecal herpes simplex virus type 1 amplicon vector-mediated human proenkephalin reduces chronic constriction injury-induced neuropathic pain in rats

Cited by 10 publications

References 26 publications

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin

Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain

Viral Vectors Encoding Endomorphins and Serine Histogranin Attenuate Neuropathic Pain Symptoms after Spinal Cord Injury in Rats

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