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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

Genetic or pharmacological ablation of MAGL reduces fever response in central IL-1β-induced fever model.(A) CBT profile following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/+ + Veh vs. Mgll+/+ + IL-1β; #p<0.05 Mgll+/ + IL-1β vs. Mgll-/-+ IL-1β. (B) CBT profile of Mgll-/- and Mgll+/+ mice following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group. *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/++ Veh + IL-1β; #p<0.05 Mgll+/++ Veh+ IL-1β vs. Mgll+/++ JZL184 + IL-1β.
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pone.0134437.g003: Genetic or pharmacological ablation of MAGL reduces fever response in central IL-1β-induced fever model.(A) CBT profile following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/+ + Veh vs. Mgll+/+ + IL-1β; #p<0.05 Mgll+/ + IL-1β vs. Mgll-/-+ IL-1β. (B) CBT profile of Mgll-/- and Mgll+/+ mice following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group. *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/++ Veh + IL-1β; #p<0.05 Mgll+/++ Veh+ IL-1β vs. Mgll+/++ JZL184 + IL-1β.

Mentions: To examine whether the observed fever-reducing effects were due to modulation of central pyrogens, we next examined whether genetic or pharmacological ablation of MAGL was capable of attenuating centrally-induced fever in mice through POA administration of the endogenous pyrogen interleukin-1β (IL-1β) (500 pg/0.5 μl). We show that either Mgll–/–(Fig 3A) mice or mice treated with JZL184 (40 mg/kg, i.p., 1 hr before IL-1βadministration) (Fig 3B) display significantly reduced IL-1β-mediated CBT compared to vehicle-treated or Mgll+/+ control mice.


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)

Genetic or pharmacological ablation of MAGL reduces fever response in central IL-1β-induced fever model.(A) CBT profile following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/+ + Veh vs. Mgll+/+ + IL-1β; #p<0.05 Mgll+/ + IL-1β vs. Mgll-/-+ IL-1β. (B) CBT profile of Mgll-/- and Mgll+/+ mice following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group. *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/++ Veh + IL-1β; #p<0.05 Mgll+/++ Veh+ IL-1β vs. Mgll+/++ JZL184 + IL-1β.
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pone.0134437.g003: Genetic or pharmacological ablation of MAGL reduces fever response in central IL-1β-induced fever model.(A) CBT profile following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF of Mgll+/+ mice treated i.p. with JZL184 (40 mg/kg). *p<0.05, Mgll+/+ + Veh vs. Mgll+/+ + IL-1β; #p<0.05 Mgll+/ + IL-1β vs. Mgll-/-+ IL-1β. (B) CBT profile of Mgll-/- and Mgll+/+ mice following icv injection into POA of IL-1β (500 pg/0.5 μl) or aCSF as indicated. Injection was performed at time 0. Data are shown as mean ± sem, n = 6 mice per group. *p<0.05, Mgll+/++ Veh + Veh vs. Mgll+/++ Veh + IL-1β; #p<0.05 Mgll+/++ Veh+ IL-1β vs. Mgll+/++ JZL184 + IL-1β.
Mentions: To examine whether the observed fever-reducing effects were due to modulation of central pyrogens, we next examined whether genetic or pharmacological ablation of MAGL was capable of attenuating centrally-induced fever in mice through POA administration of the endogenous pyrogen interleukin-1β (IL-1β) (500 pg/0.5 μl). We show that either Mgll–/–(Fig 3A) mice or mice treated with JZL184 (40 mg/kg, i.p., 1 hr before IL-1βadministration) (Fig 3B) display significantly reduced IL-1β-mediated CBT compared to vehicle-treated or Mgll+/+ control mice.

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