Reversal of ongoing thermal hyperalgesia in mice by a recombinant herpesvirus that encodes human preproenkephalin.
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 Adelta 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 anti-hyperalgesia was observed for both Adelta- and C-fiber-mediated responses. Interestingly, however, while the anti-hyperalgesic effect of the enkephalin-encoding virus on C-fiber-mediated responses was reversed by intrathecal application of micro or delta opioid antagonists, only delta antagonists reversed the effect of this virus on Adelta 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.
Yeomans
David C
DC
Department of Anesthesia, Stanford University, Stanford, CA 94305, USA. dcyeomans@stanford.edu
Jones
Toni
T
Laurito
Charles E
CE
Lu
Ying
Y
Wilson
Steven P
SP
D000279:Administration, Cutaneous; D000818:Animals; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D006564:Herpesviridae / Q000235:genetics*; D006930:Hyperalgesia / Q000139:chemically induced / Q000628:therapy*; D007150:Immunohistochemistry; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments; D037342:Pertussis Toxin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D017480:Receptors, sigma / Q000037:antagonists & inhibitors; D013004:Somatostatin
C529311:CTAP octapeptide; D004745:Enkephalins; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010446:Peptide Fragments; D011498:Protein Precursors; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; D013004:Somatostatin; D009271:Naltrexone; C033660:preproenkephalin; D037342:Pertussis Toxin; C055382:naltrindole