Reversal of Ongoing Thermal Hyperalgesia in Mice by a Recombinant Herpesvirus that Encodes Human Preproenkephalin

doi:doi:10.1016/j.ymthe.2003.10.008

Molecular Therapy (2004) 9, 24–29; doi: 10.1016/j.ymthe.2003.10.008

Reversal of Ongoing Thermal Hyperalgesia in Mice by a Recombinant Herpesvirus that Encodes Human Preproenkephalin

David C. Yeomans¹, Toni Jones¹, Charles E. Laurito², Ying Lu² and Steven P. Wilson³

¹Department of Anesthesia, Stanford University, 300 Pasture Drive, Stanford, California 94305, USA
²Department of Anesthesiology, University of Illinois at Chicago, 3200W UICH, Chicago, Illinois 60612, USA
³Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA

Correspondence: David C Yeomans, Department of Anesthesia, Stanford University, 300 Pasteur Drive, Stanford, California 94305. Fax: (650)725-8052. E-mail: dcyeomans@stanford.edu

Received 9 September 2003; Accepted 28 October 2003.

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Abstract

Herpesvirus-mediated transfer of the human preproenkephalin gene to primary afferent nociceptors prevents phasic thermal allodynia/hyperalgesia in mice. It is not known, however, whether similar viral treatments would reverse ongoing or chronic pain and allodynia/hyperalgesia. To this end, mice were given intrathecal injections of pertussis toxin (PTX), which produces a weeks-long thermal hyperalgesia apparently by uncoupling certain G proteins from inhibitory neurotransmitter receptors. This treatment produced profound thermal hyperalgesia in both A delta and C-fiber thermonociceptive tests lasting at least 6 weeks. However, treatment of skin surfaces with an enkephalin-encoding herpesvirus, but not control virus or vehicle, completely reversed this hyperalgesia. This profound antihyperalgesia was observed for both A delta - and C-fiber-mediated responses. Interestingly, however, while the antihyperalgesic effect of the enkephalin-encoding virus on C-fiber-mediated responses was reversed by intrathecal application of or delta opioid antagonists, only delta antagonists reversed the effect of this virus on A delta hyperalgesia. Thus, virus-mediated delivery of the proenkephalin cDNA reverses thermal hyperalgesia produced by PTX-induced ribosylation of inhibitory G proteins by an opioid-mediated mechanism. These results suggest that herpesvirus vectors encoding analgesic peptides may be useful in attenuating centrally mediated, ongoing neuropathic pain and/or hyperalgesia.