Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects

Lindsay B. Hough, Julia W. Nalwalk, Rachel A. Cleary, James G. Phillips, Cheng Fang, Weizhu Yang, Xinxin Ding

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)255-262
Number of pages8
JournalEuropean Journal of Pharmacology
Volume740
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Analgesia
Cytochrome P-450 Enzyme System
Morphine
Opioid Analgesics
Analgesics
Brain
Opioid Receptors
Respiratory Insufficiency
Gastrointestinal Motility
Constipation
Transgenic Mice
Neurons
Pain
Therapeutics

Keywords

  • Analgesia
  • Brain
  • Cytochrome P450
  • Locomotor activity
  • Opioid
  • Respiration

ASJC Scopus subject areas

  • Pharmacology

Cite this

Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects. / Hough, Lindsay B.; Nalwalk, Julia W.; Cleary, Rachel A.; Phillips, James G.; Fang, Cheng; Yang, Weizhu; Ding, Xinxin.

In: European Journal of Pharmacology, Vol. 740, 01.01.2014, p. 255-262.

Research output: Contribution to journalArticle

Hough, Lindsay B. ; Nalwalk, Julia W. ; Cleary, Rachel A. ; Phillips, James G. ; Fang, Cheng ; Yang, Weizhu ; Ding, Xinxin. / Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects. In: European Journal of Pharmacology. 2014 ; Vol. 740. pp. 255-262.
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