Virally mediated delivery of enkephalin and other neuropeptide transgenes in experimental pain models

We have constructed recombinant herpes simplex virus type 1 vectors for delivery of genes to sensory neurons in an attempt to modulate nociception. Delivery of recombinant viruses to the skin of mice results in expression of encoded complementary DNA (cDNA) genes in DRG neurons within three to four days. Expression of marker genes persists for at least 10 weeks. Testing of baseline thermal nociceptive latencies at the site of virus application revealed no differences between a control virus and a virus encoding human preproenkephalin (hPPE) when performed at either low stimulus intensities (C-fiber activation) or high stimulus intensities (Adelta neurons). By contrast, sensitization of nociceptors by capsaicin or dimethylsulfoxide was reduced or abolished by infection with the virus encoding hPPE, but not by a control virus. These antihyperalgesic responses are mediated by opioids released at the central terminals of the primary afferents because they are blocked by intrathecal administration of the opioid antagonist naloxone. Similar experiments performed in macaques demonstrated an antihyperalgesic effect of the herpes virus vector encoding hPPE. This hPPE-encoding virus was also tested in a model of neuropathic pain in mice, with similar effect. A virus containing an antisense cDNA for calcitonin gene-related peptide precursor (ACGRP) has also been constructed and found to reverse C-fiber hyperalgesia caused by application of capsaicin to the skin for up to 14 weeks postinfection. These results raise the possibility that herpes-mediated, gene-based approaches to treat chronic pain states may be useful in therapy of chronic pain in humans.