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Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge

Abstract

Cannabinoid receptor agonists, such as Δ9-THC, the primary active constituent of Cannabis sativa, have anti-pyrogenic effects in a variety of assays. Recently, attention has turned to the endogenous cannabinoid system and how endocannabinoids, including 2-arachidonoylglycerol (2-AG) and anandamide, regulate multiple homeostatic processes, including thermoregulation. Inhibiting endocannabinoid catabolic enzymes, monoacylglycerol lipase (MAGL) or fatty acid amide hydrolase (FAAH), elevates levels of 2-AG or anandamide in vivo, respectively. The purpose of this experiment was to test the hypothesis that endocannabinoid catabolic enzymes function to maintain thermal homeostasis in response to hypothermic challenge. In separate experiments, male C57BL/6J mice were administered a MAGL or FAAH inhibitor, and then challenged with the bacterial endotoxin lipopolysaccharide (LPS; 2 mg/kg ip) or a cold (4 °C) ambient environment. Systemic LPS administration caused a significant decrease in core body temperature after 6 h, and this hypothermia persisted for at least 12 h. Similarly, cold environment induced mild hypothermia that resolved within 30 min. JZL184 exacerbated hypothermia induced by either LPS or cold challenge, both of which effects were blocked by rimonabant, but not SR144528, indicating a CB1 cannabinoid receptor mechanism of action. In contrast, the FAAH inhibitor, PF-3845, had no effect on either LPS-induced or cold-induced hypothermia. These data indicate that unlike direct acting cannabinoid receptor agonists, which elicit profound hypothermic responses on their own, neither MAGL nor FAAH inhibitors affect normal body temperature. However, these endocannabinoid catabolic enzymes play distinct roles in thermoregulation following hypothermic challenges.

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Abbreviations

2-AG:

2-arachidonoylglycerol

AA:

Arachidonic acid

Anandamide:

N-arachidonoylethanolamine

CB1 :

Cannabinoid receptor type 1

CB2 :

Cannabinoid receptor type 2

FAAH:

Fatty acid amide hydrolase

JZL184:

4-nitrophenyl 4-(dibenzo[d][1,3]dioxol-5-yl(hydroxy)methyl)piperidine-1-carboxylate

MAGL:

Monoacylglycerol lipase

Tb :

Body temperature

THC:

Δ9-tetrahydrocannabinol

TNFα:

Tumor necrosis factor α

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Acknowledgments

We thank Scott O’Neal and Molly Crowe for technical assistance. Financial support was provided by the National Institutes of Health, grants [T32DA007027, P01DA009789, P01DA017259, P50DA005274, R01DA030404, and R01DA015197].

Author Contributions

Participated in research design: Nass, Long, Schlosburg, Cravatt, Lichtman, Kinsey

Conducted experiments: Nass, Kinsey

Performed data analysis: Nass, Kinsey

Wrote or contributed to the writing of the manuscript: Nass, Lichtman, Kinsey

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Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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Correspondence to Steven G. Kinsey.

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Nass, S.R., Long, J.Z., Schlosburg, J.E. et al. Endocannabinoid Catabolic Enzymes Play Differential Roles in Thermal Homeostasis in Response to Environmental or Immune Challenge. J Neuroimmune Pharmacol 10, 364–370 (2015). https://doi.org/10.1007/s11481-015-9593-1

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  • DOI: https://doi.org/10.1007/s11481-015-9593-1

Keywords

  • Cannabinoid
  • Hypothermia
  • Environmental stress
  • FAAH
  • MAGL
  • MGL