title: Contribution of acid sphingomyelinase in the periaqueductal gray region to morphine-induced analgesia in mice.
abstract: Opioids are the most widely used drugs for long-term pain management, but their use is limited by the development of antinociceptive tolerance. The present study investigated the role of ceramide production through acid sphingomyelinase (ASM) activation in the periaqueductal gray region, a brain region implicated in opioid analgesia and tolerance. Morphine treatment was found, using immunohistochemistry, to increase ASM expression and intracellular ceramide in the periaqueductal gray 30 min after an acute injection (10 mg/kg). The effects of acute morphine treatment on ASM expression and ceramide generation in the periaqueductal gray region were completely blocked by pretreatment with naloxone and by silencing the ASM gene by plasmid-mediated transfection of ASM shRNA. In chronic morphine pellet-implanted mice, ASM expression and ceramide generation in the periaqueductal gray region were also significantly increased. Functionally, selective silencing of the ASM gene by local ASM shRNA transfection reduced the analgesic response to acute morphine, but the data on the effect of ASM shRNA on the development of antinociceptive tolerance were inconclusive. These data provide evidence that ASM activation and ceramide generation in the periaqueductal gray region play a major role in the antinociceptive mechanism of morphine.
authors: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0613, USA. jkritter@vcu.edu
authors: Joseph K
authors: JK
authors: Ritter
authors: Youwen
authors: Y
authors: Fang
authors: Min
authors: M
authors: Xia
authors: Pin-Lan
authors: PL
authors: Li
authors: William L
authors: WL
authors: Dewey
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D004361:Drug Tolerance / Q000502:physiology; D008297:Male; D051379:Mice; D009020:Morphine / Q000633:toxicity*; D010146:Pain / Q000201:enzymology* / Q000503:physiopathology*; D059408:Pain Management; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects / Q000201:enzymology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D013108:Sphingomyelin Phosphodiesterase