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Monoacylglycerol Lipase Regulates Fever Response.

Sanchez-Alavez M, Nguyen W, Mori S, Moroncini G, Viader A, Nomura DK, Cravatt BF, Conti B - PLoS ONE (2015)

Bottom Line: Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2).We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors.Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.

ABSTRACT
Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

No MeSH data available.


Related in: MedlinePlus

Anti-pyrogenic effects of MAGL inhibitors are independent of CB1 cannabinoid receptor activity.CBT profile following i.p. injection of LPS (100 μg/kg) of Mgll+/+ mice receiving i.p. injection of rimonabant (1 mg/kg) and/ or JZL184 (40 mg/kg). Rimonabant did not affect the hypothermic effects of JZL184. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh + Veh vs. Mgll+/++ Veh + Veh + LPS; #p<0.05, Mgll+/++ Veh + Veh + LPS vs. Mgll+/++ JZL184 + Veh + LPS; &p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ Veh + Rim + Veh; $p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ JZL184 + Rim + LPS. p>0.05 (NS) Mgll+/++ Veh + Veh + Veh vs Mgll+/++ Veh + Rim + Veh, Mgll+/++ JZL184 + Rim + LPS vs Mgll+/ + JZL184 + Veh + LPS, Mgll+/++ Veh + Veh + LPS vs Mgll+/++ Veh + Rim + LPS.
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pone.0134437.g004: Anti-pyrogenic effects of MAGL inhibitors are independent of CB1 cannabinoid receptor activity.CBT profile following i.p. injection of LPS (100 μg/kg) of Mgll+/+ mice receiving i.p. injection of rimonabant (1 mg/kg) and/ or JZL184 (40 mg/kg). Rimonabant did not affect the hypothermic effects of JZL184. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh + Veh vs. Mgll+/++ Veh + Veh + LPS; #p<0.05, Mgll+/++ Veh + Veh + LPS vs. Mgll+/++ JZL184 + Veh + LPS; &p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ Veh + Rim + Veh; $p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ JZL184 + Rim + LPS. p>0.05 (NS) Mgll+/++ Veh + Veh + Veh vs Mgll+/++ Veh + Rim + Veh, Mgll+/++ JZL184 + Rim + LPS vs Mgll+/ + JZL184 + Veh + LPS, Mgll+/++ Veh + Veh + LPS vs Mgll+/++ Veh + Rim + LPS.

Mentions: Since endocannabinoids have been shown to participate to hypothermic responses via activation of CB1 receptors [35], we next tested whether the anti-pyrogenic effects of MAGL inhibitors were dependent on the central CB1 cannabinoid receptor. Pre-treatment of mice with a cannabinoid receptor type 1 (CB1) antagonist rimonabant (RIM) (1 mg/kg, i.p.) did not alter the anti-pyrogenic effects of JZL184 in LPS-treated mice (Fig 4). These data indicate that the anti-pyrogenic effects of MAGL inhibitors are likely due to reductions in brain PGE2.


Monoacylglycerol Lipase Regulates Fever Response.

Sanchez-Alavez M, Nguyen W, Mori S, Moroncini G, Viader A, Nomura DK, Cravatt BF, Conti B - PLoS ONE (2015)

Anti-pyrogenic effects of MAGL inhibitors are independent of CB1 cannabinoid receptor activity.CBT profile following i.p. injection of LPS (100 μg/kg) of Mgll+/+ mice receiving i.p. injection of rimonabant (1 mg/kg) and/ or JZL184 (40 mg/kg). Rimonabant did not affect the hypothermic effects of JZL184. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh + Veh vs. Mgll+/++ Veh + Veh + LPS; #p<0.05, Mgll+/++ Veh + Veh + LPS vs. Mgll+/++ JZL184 + Veh + LPS; &p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ Veh + Rim + Veh; $p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ JZL184 + Rim + LPS. p>0.05 (NS) Mgll+/++ Veh + Veh + Veh vs Mgll+/++ Veh + Rim + Veh, Mgll+/++ JZL184 + Rim + LPS vs Mgll+/ + JZL184 + Veh + LPS, Mgll+/++ Veh + Veh + LPS vs Mgll+/++ Veh + Rim + LPS.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543552&req=5

pone.0134437.g004: Anti-pyrogenic effects of MAGL inhibitors are independent of CB1 cannabinoid receptor activity.CBT profile following i.p. injection of LPS (100 μg/kg) of Mgll+/+ mice receiving i.p. injection of rimonabant (1 mg/kg) and/ or JZL184 (40 mg/kg). Rimonabant did not affect the hypothermic effects of JZL184. Data are shown as mean ± sem, n = 6 mice per group, *p<0.05, Mgll+/++ Veh + Veh + Veh vs. Mgll+/++ Veh + Veh + LPS; #p<0.05, Mgll+/++ Veh + Veh + LPS vs. Mgll+/++ JZL184 + Veh + LPS; &p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ Veh + Rim + Veh; $p<0.05, Mgll+/++ Veh + Rim + LPS vs. Mgll+/++ JZL184 + Rim + LPS. p>0.05 (NS) Mgll+/++ Veh + Veh + Veh vs Mgll+/++ Veh + Rim + Veh, Mgll+/++ JZL184 + Rim + LPS vs Mgll+/ + JZL184 + Veh + LPS, Mgll+/++ Veh + Veh + LPS vs Mgll+/++ Veh + Rim + LPS.
Mentions: Since endocannabinoids have been shown to participate to hypothermic responses via activation of CB1 receptors [35], we next tested whether the anti-pyrogenic effects of MAGL inhibitors were dependent on the central CB1 cannabinoid receptor. Pre-treatment of mice with a cannabinoid receptor type 1 (CB1) antagonist rimonabant (RIM) (1 mg/kg, i.p.) did not alter the anti-pyrogenic effects of JZL184 in LPS-treated mice (Fig 4). These data indicate that the anti-pyrogenic effects of MAGL inhibitors are likely due to reductions in brain PGE2.

Bottom Line: Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2).We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors.Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA, 92037, United States of America.

ABSTRACT
Cyclooxygenase inhibitors such as ibuprofen have been used for decades to control fever through reducing the levels of the pyrogenic lipid transmitter prostaglandin E2 (PGE2). Historically, phospholipases have been considered to be the primary generator of the arachidonic acid (AA) precursor pool for generating PGE2 and other eicosanoids. However, recent studies have demonstrated that monoacyglycerol lipase (MAGL), through hydrolysis of the endocannabinoid 2-arachidonoylglycerol, provides a major source of AA for PGE2 synthesis in the mammalian brain under basal and neuroinflammatory states. We show here that either genetic or pharmacological ablation of MAGL leads to significantly reduced fever responses in both centrally or peripherally-administered lipopolysaccharide or interleukin-1β-induced fever models in mice. We also show that a cannabinoid CB1 receptor antagonist does not attenuate these anti-pyrogenic effects of MAGL inhibitors. Thus, much like traditional nonsteroidal anti-inflammatory drugs, MAGL inhibitors can control fever, but appear to do so through restricted control over prostaglandin production in the nervous system.

No MeSH data available.


Related in: MedlinePlus