Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling

Conroy, Jennie; Fang, Cheng; Gu, Jun; Zeitlin, Scott; Yang, Weizhu; Yang, Jun; VanAlstine, Melissa A.; Nalwalk, Julia W.; Albrecht, Phillip J.; Mazurkiewicz, Joseph E.; Snyder-Keller, Abigail; Shan, Zhixing; Zhang, Shao Zhong; Wentland, Mark P.; Behr, Melissa; Knapp, Brian I.; Bidlack, Jean M.; Zuiderveld, Obbe P.; Leurs, Rob; Ding, Xinxin; Hough, Lindsay B.

doi:10.1038/nn.2497

Cited by 53 publications

(153 citation statements)

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“…For example, it was recently demonstrated that brain P450 epoxygenase activity is essential for achieving pain-relieving effects upon administration of opioids (Conroy et al, 2010), raising the possibility that this could be the case for cannabinoids as well. The unique regulation of brain CYP2B6 and CYP2D6 by drugs and genetics (Miksys and Tyndale, 2004) requires a much better understanding of their contribution to the metabolism of endogenous psychoactive substrates.…”

Section: Discussionmentioning

confidence: 99%

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

2011

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ABSTRACT:Anandamide is an arachidonic acid-derived endogenous cannabinoid that regulates normal physiological functions and pathophysiological responses within the central nervous system and in the periphery. Several cytochrome P450 (P450) isoforms metabolize anandamide to form hydroxylated and epoxygenated products. Human CYP2B6 and CYP2D6, which are expressed heterogeneously throughout the brain, exhibit clinically significant polymorphisms and are regulated by external factors, such as alcohol and smoking. Oxidative metabolism of anandamide by these two P450s may have important functional consequences for endocannabinoid system signaling. In this study, we investigated the metabolism of anandamide by wild-type CYP2B6 (2B6.1) and CYP2D6 (2D6.1) and by their common polymorphic mutants 2B6.4, 2B6.6, 2B6.9, and 2D6.34. Major differences in anandamide metabolism by the two isoforms and their mutants were found in vitro with respect to the formation of 20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 14,15-epoxyeicosatetraenoic acid ethanolamide (14,15-EET-EA). Pharmacological studies showed that both 20-HETE-EA and 14,15-EET-EA bind to the rat brain cannabinoid CB1 receptor with lower affinities relative to that of anandamide. In addition, both products are degraded more rapidly than anandamide in rat brain homogenates. Their degradation occurs via different mechanisms involving either fatty acid amide hydrolase (FAAH), the major anandamide-degrading enzyme, or epoxide hydrolase (EH). Thus, the current findings provide potential new insights into the actions of inhibitors FAAH and EH, which are being developed as novel therapeutic agents, as well as a better understanding of the interactions between the cytochrome P450 monooxygenases and the endocannabinoid system.

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Section: Discussionmentioning

confidence: 99%

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

2011

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“…In the periaqueductal gray, m receptor stimulation reduces presynaptic GABAergic activity, leading to activation of descending, pain-dampening circuits (Heinricher and Ingram, 2008); however, the relevant cellular mechanisms for this effect remain uncertain. We recently described the development of brain cytochrome P450 monooxygenasis (P450) reductase null (BCPRN) mice (which lack brain neuronal P450 activity) and showed that these mice exhibit defective analgesic responses to morphine (Conroy et al, 2010). P450s are best known as mediators of drug metabolism, but morphine is not metabolized by P450s (Kuo et al, 1991), and brain levels of morphine were identical in BCPRN and control mice (Conroy et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…We recently described the development of brain cytochrome P450 monooxygenasis (P450) reductase null (BCPRN) mice (which lack brain neuronal P450 activity) and showed that these mice exhibit defective analgesic responses to morphine (Conroy et al, 2010). P450s are best known as mediators of drug metabolism, but morphine is not metabolized by P450s (Kuo et al, 1991), and brain levels of morphine were identical in BCPRN and control mice (Conroy et al, 2010). Since P450s also catalyze the oxidation of endogenous lipids (Spector, 2009), a pharmacodynamic (versus pharmacokinetic) mechanism best explains the brain P450 requirement for opioid analgesia.…”

Section: Introductionmentioning

confidence: 99%

“…Since P450s also catalyze the oxidation of endogenous lipids (Spector, 2009), a pharmacodynamic (versus pharmacokinetic) mechanism best explains the brain P450 requirement for opioid analgesia. Conroy et al (2010) proposed that m opioids act in the central nervous system (CNS) by stimulating the release and P450-mediated epoxidation of arachidonic acid. The epoxide products may have pain-relieving properties (Terashvili et al, 2008;Wagner et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Identification of these proteins is of interest because they could be new analgesic drug targets (Hough et al, 2007). Although this idea has not been confirmed (Stadel et al, 2010), 3 HCIM-binding studies led to the discovery that the painrelieving effects of both nonopioid (Hough et al, 2011) and opioid (Conroy et al, 2010) analgesic drugs require brain P450 activity.…”

Section: Introductionmentioning

confidence: 99%

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Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms

et al. 2015

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Cytochrome P450 monooxygenases (P450s), which are well-known drug-metabolizing enzymes, are thought to play a signal transduction role in m opioid analgesia and may serve as high-affinity HCIM binding sites may also be related to opioid or nonopioid analgesia. However, of the more than 100 murine P450 enzymes, the specific isoform(s) responsible for either function have not been identified. Presently, three lines of constitutive P450 gene cluster knockout (KO) mice with full-length deletions of 14 Cyp2c, 9 Cyp2d, and 7 Cyp3a genes were studied for deficiencies in proteins. Cyp2d KO and Cyp3a KO mice showed normal antinociceptive responses to a moderate systemic dose of morphine (20 mg/kg, s.c.), thereby excluding 16 P450 isoforms as mediators of opioid analgesia. In contrast, Cyp2c KO mice showed a 41% reduction in analgesic responses following systemically (s.c.) administered morphine. However, the significance of brain Cyp2c gene products in opioid analgesia is uncertain because little or no analgesic deficits were noted in Cyp2c KO mice following intracerebroventricular or intrathecalmorphine administration, respectively. These results show that the gene products of Cyp2d and Cyp3a do not contribute to m opioid analgesia in the central nervous system. A possible role for Cyp2c gene products in opioid analgesia requires further consideration.

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Epoxy fatty acids mediate analgesia in murine diabetic neuropathy

Wagner

Lee

Yang

2016

European Journal of Pain

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Background Neuropathic pain is a debilitating condition with no adequate therapy. The health benefits of omega‐3 fatty acids are established, however, the role of docosahexaenoic acid (DHA) in limiting pain has only recently been described and the mechanisms of this action remain unknown. DHA is metabolized into epoxydocosapentanoic acids (EDPs) via cytochrome P450 (CYP450) enzymes which are substrates for the soluble epoxide hydrolase (sEH) enzyme. Here, we tested several hypotheses; first, that the antinociceptive action of DHA is mediated by the EDPs. Second, based on evidence that DHA and CYP450 metabolites elicit analgesia through opioid signalling, we investigated this as a possible mechanism of action. Third, we tested whether the analgesia mediated by epoxy fatty acids had similar rewarding effects as opioid analgesics. Methods We tested diabetic neuropathic wild‐type and sEH null mice in a conditioned place preference assay for their response to EDPs, sEHI and antagonism of these treatments with naloxone, a mu‐opioid receptor antagonist. Results The EDPs and sEH inhibitors were efficacious against chronic pain, and naloxone antagonized the action of both EDPs and sEH inhibitors. Despite this antagonism, the sEH inhibitors lacked reward side effects differing from opioids. Conclusions The EpFA are analgesic against chronic pain differing from opioids which have limited efficacy in chronic conditions. Significance EDPs and sEHI mediate analgesia in modelled chronic pain and this analgesia is blocked by naloxone. However, unlike opioids, sEHI are highly effective in neuropathic pain models and importantly lack rewarding side effects.

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Opioids activate brain analgesic circuits through cytochrome P450/epoxygenase signaling

Cited by 53 publications

References 14 publications

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6

Opioid Analgesia in P450 Gene Cluster Knockout Mice: A Search for Analgesia-Relevant Isoforms

Epoxy fatty acids mediate analgesia in murine diabetic neuropathy

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