Relief of pain induced by varicella-zoster virus in a rat model of post-herpetic neuralgia using a herpes simplex virus vector expressing enkephalin.
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.
1] Graduate Program in Molecular Virology and Microbiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
J-M G
JM
Guedon
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
M
M
Zhang
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
J C
JC
Glorioso
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
W F
WF
Goins
1] Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA [2] Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
P R
PR
Kinchington
D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005528:Foot / Q000821:virology; D045888:Ganglion Cysts / Q000378:metabolism*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D051474:Neuralgia, Postherpetic / Q000517:prevention & control* / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018139:Simplexvirus / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism
D004745:Enkephalins