Effects of transgene-mediated endomorphin-2 in inflammatory pain.
We examined the analgesic properties of endomorphin-2 expressed in DRG neurons transduced with a non-replicating herpes simplex virus (HSV)-based vector containing a synthetic endomorphin-2 gene construct. HSV-mediated endomorphin-2 expression reduced nocisponsive behaviors in response to mechanical and thermal stimuli after injection of complete Freund's adjuvant (CFA) into the paw, and reduced peripheral inflammation measured by paw swelling after injection of CFA. The analgesic effect of the vector was blocked by either intraperitoneal or intrathecal administration of naloxone methiodide, blocking peripheral and central mu opioid receptors, respectively. Endomorphin-2 vector injection also reduced spontaneous pain-related behaviors in the delayed phase of the formalin test and in both CFA and formalin models suppressed spinal c-fos expression. The magnitude of the vector-mediated analgesic effect on the delayed phase of the formalin test was similar in naïve animals and in animals with opiate tolerance induced by twice daily treatment with morphine, suggesting that there was no cross-tolerance between vector-mediated endomorphin-2 and morphine. These results suggest that transgene-mediated expression of endomorphin-2 in transduced DRG neurons in vivo acts both peripherally and centrally through mu opioid receptors to reduce pain perception.
Department of Neurology and VA Ann Arbor Healthcare System, Ann Arbor, MI, USA.
Shuanglin
S
Hao
Darren
D
Wolfe
Joseph C
JC
Glorioso
Marina
M
Mata
David J
DJ
Fink
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000502:physiology; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000494:pharmacology; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology; D009619:Nociceptors / Q000166:cytology / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics*; D010146:Pain / Q000235:genetics* / Q000378:metabolism; D059408:Pain Management; D010147:Pain Measurement; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics*
D000701:Analgesics, Opioid; D018836:Inflammation Mediators; D009292:Narcotic Antagonists; D009842:Oligopeptides; D016760:Proto-Oncogene Proteins c-fos; D017450:Receptors, Opioid, mu; C105294:endomorphin 2