Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling.
To assess the importance of brain cytochrome P450 (P450) activity in mu opioid analgesic action, we generated a mutant mouse with brain neuron-specific reductions in P450 activity; these mice showed highly attenuated morphine antinociception compared with controls. Pharmacological inhibition of brain P450 arachidonate epoxygenases also blocked morphine antinociception in mice and rats. Our findings indicate that a neuronal P450 epoxygenase mediates the pain-relieving properties of morphine.
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, USA.
Jennie L
JL
Conroy
Cheng
C
Fang
Jun
J
Gu
Scott O
SO
Zeitlin
Weizhu
W
Yang
Jun
J
Yang
Melissa A
MA
VanAlstine
Julia W
JW
Nalwalk
Phillip J
PJ
Albrecht
Joseph E
JE
Mazurkiewicz
Abigail
A
Snyder-Keller
Zhixing
Z
Shan
Shao-Zhong
SZ
Zhang
Mark P
MP
Wentland
Melissa
M
Behr
Brian I
BI
Knapp
Jean M
JM
Bidlack
Obbe P
OP
Zuiderveld
Rob
R
Leurs
Xinxin
X
Ding
Lindsay B
LB
Hough
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors
D000701:Analgesics, Opioid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017450:Receptors, Opioid, mu; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2