title: Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects.
abstract: Morphine-like analgesics act on µ opioid receptors in the CNS to produce highly effective pain relief, but the same class of receptors also mediates non-therapeutic side effects. The analgesic properties of morphine were recently shown to require the activity of a brain neuronal cytochrome P450 epoxygenase, but the significance of this pathway for opioid side effects is unknown. Here we show that brain P450 activity is not required for three of morphine׳s major side effects (respiratory depression, constipation, and locomotor stimulation). Following systemic or intracerebroventricular administration of morphine, transgenic mice with brain neuron - specific reductions in P450 activity showed highly attenuated analgesic responses as compared with wild-type (control) mice. However, brain P450-deficient mice showed normal morphine-induced side effects (respiratory depression, locomotor stimulation, and inhibition of intestinal motility). Pretreatment of control mice with the P450 inhibitor CC12 similarly reduced the analgesia, but not these side effects of morphine. Because activation of brain µ opioid receptors produces both opioid analgesia and opioid side effects, dissociation of the mechanisms for the therapeutic and therapy-limiting effects of opioids has important consequences for the development of analgesics with reduced side effects and/or limited addiction liability.
authors: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA. Electronic address: HoughL@mail.amc.edu.
authors: Lindsay B
authors: LB
authors: Hough
authors: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA.
authors: Julia W
authors: JW
authors: Nalwalk
authors: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA.
authors: Rachel A
authors: RA
authors: Cleary
authors: Curragh Chemistries, Valley View, OH, USA.
authors: James G
authors: JG
authors: Phillips
authors: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, NY, USA.
authors: Cheng
authors: C
authors: Fang
authors: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, NY, USA.
authors: Weizhu
authors: W
authors: Yang
authors: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, NY, USA.
authors: Xinxin
authors: X
authors: Ding
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000201:enzymology*; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D008297:Male; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency* / Q000235:genetics; D009474:Neurons / Q000201:enzymology*; D017288:Pain Threshold / Q000187:drug effects; D056152:Respiratory Rate / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine; D009251:NADPH-Ferrihemoprotein Reductase
keywords: Analgesia; Brain; Cytochrome P450; Locomotor activity; Opioid; Respiration