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Paul R. Kinchington, Michael B. Yee, Mingdi Zhang, William F. Goins; Treatment of VZV-induced Chronic Pain in a Rat Model of Post-Herpetic Neuralgia Using Replication Defective HSV-1 Expressing the Tonal Modulator Proenkephalin. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6159.
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© ARVO (1962-2015); The Authors (2016-present)
Herpes zoster ophthalmicus, caused by reactivation of the human herpesvirus VZV from latency at the trigeminal ganglia, leads to complex ocular diseases and problems, with ocular pain and post herpetic neuralgia (PHN) being the most common. The chronic intractable neuropathic pain state of PHN, which can last months to years, has unmet needs for better treatment strategies. We have developed a rat model of VZV induced pain to evaluate pain treatment using replication defective HSV-1 vectors to express modulators of nociceptive signal transmission in the ganglia.
Sprague Dawley rats inoculated in the hindpaw with 105 infectious doses of cell associated VZV (or uninfected cell equivalents as control) were monitored for development of mechanical allodynia (MA) using Von Frey hair filament stimulation: and thermal hyperalgesia (TH) from heat applied to the paw using Hargreaves apparatus. Following induction of behavioral indices of pain, rat groups were left untreated, inoculated at the same footpad with replication defective HSV-1 control or received HSV-1 expressing proenkephalin, a tonal opioid modulator of nociception, from the latency active promoter.
Rats develop chronic (lasting 8-12 weeks) pain indices by day 6 post VZV infection, indicated by increased MA sensitivity (at levels 12-17% of weight applied to control footpads) and increased TH (68-74% withdrawal latency from heat as compared to controls). MA and TH did not develop in rats receiving uninfected cells; in the contralateral paw; or in animals receiving replication defective HSV alone. Rats showing MA and TH and treated with HSV expressing proenkephalin initated decreased MA and TH within 3 days and reached baseline control levels by 11 days. Animals remained pain free for longer than 4 weeks. HSV-1 vector controls did not signficantly attenuate VZV induced pain indices.
This work establishes a new model of VZV induced pain and its use to evaluate ganglionic gene delivery treatment strategies using HSV-1 vector latency driven long term expression of the opioid receptor binding protein enkephalin at the ganglia. This model system allows evaluation of novel treatment approaches that can be futher developed to treat ocular pain and PHN that follows zoster.
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