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Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity.

Taschler U, Eichmann TO, Radner FP, Grabner GF, Wolinski H, Storr M, Lass A, Schicho R, Zimmermann R - Br. J. Pharmacol. (2015)

Bottom Line: Conversely, genetic deletion of MGL did not affect gut transit despite increased 2-AG levels.Finally, MGL-deficient mice displayed accelerated colonic propulsion and were hypersensitive to μ receptor agonist-mediated inhibition of colonic motility.This phenotype was reproduced by chronic pharmacological inhibition of MGL.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.

No MeSH data available.


Related in: MedlinePlus

MGL deficiency causes 2-AG accumulation in the intestine and insensitivity to CB receptor agonist treatment. (A) MGL expression in different segments of the intestine. MGL expression was determined in preparations of duodenum, jejunum, ileum and colon of wild-type and MGL-KO mice using a rabbit polyclonal MGL antiserum. The membrane was stained with Coomassie blue (Co) as loading control. (B) 2-AG levels in different segments of the intestine of wild-type and MGL-KO mice. 2-AG was quantified by LC/MS measurement in tissue lipid extracts of overnight fasted mice using 1-heptadecanoyl-rac-glycerol as internal standard. Data are presented as means ± SEM (n = 6 per genotype). (C) Whole gut transit and effect of CB receptor agonists on gut transit in wild-type and MGL-KO mice. Animals were kept in single cages without bedding and fasted overnight. Subsequently, animals were injected i.p. with either carrier solution, CP 55,940 (0.1 mg·kg−1 mouse) or WIN 55,212-2 (1 mg·kg−1 mouse). After 20 min, mice were gavaged with Evans Blue and received free access to food. The time until the appearance of Evans Blue in the faeces was recorded. Data are presented as means ± SEM (n = 12 per genotype for carrier solution and CP 55,940; n = 6 per genotype for WIN 55,212-2). (D) 2-AG levels in different segments of the intestine of wild-type mice treated with JZL184. Data are presented as means ± SEM (n = 3–4 per group). (E) Whole gut transit and effect of JZL184 on gut transit in wild-type and CB1-KO mice. Animals were injected i.p. with either carrier solution or JZL184 (16 mg·kg−1 mouse). Then, Evans Blue was administered and its appearance recorded as in (C). Data are presented as means ± SEM (n = 5–6 per genotype). Statistical differences were determined using Student's unpaired t-test or two-way anova followed by Bonferroni's post hoc test, **P < 0.01 and ***P < 0.001 for comparison of genotypes; ##P < 0.01 and ###P < 0.001 for comparison of treatments.
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fig01: MGL deficiency causes 2-AG accumulation in the intestine and insensitivity to CB receptor agonist treatment. (A) MGL expression in different segments of the intestine. MGL expression was determined in preparations of duodenum, jejunum, ileum and colon of wild-type and MGL-KO mice using a rabbit polyclonal MGL antiserum. The membrane was stained with Coomassie blue (Co) as loading control. (B) 2-AG levels in different segments of the intestine of wild-type and MGL-KO mice. 2-AG was quantified by LC/MS measurement in tissue lipid extracts of overnight fasted mice using 1-heptadecanoyl-rac-glycerol as internal standard. Data are presented as means ± SEM (n = 6 per genotype). (C) Whole gut transit and effect of CB receptor agonists on gut transit in wild-type and MGL-KO mice. Animals were kept in single cages without bedding and fasted overnight. Subsequently, animals were injected i.p. with either carrier solution, CP 55,940 (0.1 mg·kg−1 mouse) or WIN 55,212-2 (1 mg·kg−1 mouse). After 20 min, mice were gavaged with Evans Blue and received free access to food. The time until the appearance of Evans Blue in the faeces was recorded. Data are presented as means ± SEM (n = 12 per genotype for carrier solution and CP 55,940; n = 6 per genotype for WIN 55,212-2). (D) 2-AG levels in different segments of the intestine of wild-type mice treated with JZL184. Data are presented as means ± SEM (n = 3–4 per group). (E) Whole gut transit and effect of JZL184 on gut transit in wild-type and CB1-KO mice. Animals were injected i.p. with either carrier solution or JZL184 (16 mg·kg−1 mouse). Then, Evans Blue was administered and its appearance recorded as in (C). Data are presented as means ± SEM (n = 5–6 per genotype). Statistical differences were determined using Student's unpaired t-test or two-way anova followed by Bonferroni's post hoc test, **P < 0.01 and ***P < 0.001 for comparison of genotypes; ##P < 0.01 and ###P < 0.001 for comparison of treatments.

Mentions: To investigate the contribution of MGL to intestinal 2-AG degradation, we first measured MGL expression in different segments of the intestinal tract and compared 2-AG levels of wild-type and MGL-KO mice. Western blotting analyses revealed that MGL was expressed in all the intestinal segments investigated, whereas no expression was detected in segments of MGL-ko mice. The highest expression of MGL was detected in the colon (Figure 1A). As shown in Figure 1B, MGL-KO mice exhibited increased 2-AG levels throughout the intestine in comparison with wild-type controls (1.6-, 1.9-, 2.3- and 2.7-fold in duodenum, jejunum, ileum and colon respectively).


Monoglyceride lipase deficiency causes desensitization of intestinal cannabinoid receptor type 1 and increased colonic μ-opioid receptor sensitivity.

Taschler U, Eichmann TO, Radner FP, Grabner GF, Wolinski H, Storr M, Lass A, Schicho R, Zimmermann R - Br. J. Pharmacol. (2015)

MGL deficiency causes 2-AG accumulation in the intestine and insensitivity to CB receptor agonist treatment. (A) MGL expression in different segments of the intestine. MGL expression was determined in preparations of duodenum, jejunum, ileum and colon of wild-type and MGL-KO mice using a rabbit polyclonal MGL antiserum. The membrane was stained with Coomassie blue (Co) as loading control. (B) 2-AG levels in different segments of the intestine of wild-type and MGL-KO mice. 2-AG was quantified by LC/MS measurement in tissue lipid extracts of overnight fasted mice using 1-heptadecanoyl-rac-glycerol as internal standard. Data are presented as means ± SEM (n = 6 per genotype). (C) Whole gut transit and effect of CB receptor agonists on gut transit in wild-type and MGL-KO mice. Animals were kept in single cages without bedding and fasted overnight. Subsequently, animals were injected i.p. with either carrier solution, CP 55,940 (0.1 mg·kg−1 mouse) or WIN 55,212-2 (1 mg·kg−1 mouse). After 20 min, mice were gavaged with Evans Blue and received free access to food. The time until the appearance of Evans Blue in the faeces was recorded. Data are presented as means ± SEM (n = 12 per genotype for carrier solution and CP 55,940; n = 6 per genotype for WIN 55,212-2). (D) 2-AG levels in different segments of the intestine of wild-type mice treated with JZL184. Data are presented as means ± SEM (n = 3–4 per group). (E) Whole gut transit and effect of JZL184 on gut transit in wild-type and CB1-KO mice. Animals were injected i.p. with either carrier solution or JZL184 (16 mg·kg−1 mouse). Then, Evans Blue was administered and its appearance recorded as in (C). Data are presented as means ± SEM (n = 5–6 per genotype). Statistical differences were determined using Student's unpaired t-test or two-way anova followed by Bonferroni's post hoc test, **P < 0.01 and ***P < 0.001 for comparison of genotypes; ##P < 0.01 and ###P < 0.001 for comparison of treatments.
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Related In: Results  -  Collection

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fig01: MGL deficiency causes 2-AG accumulation in the intestine and insensitivity to CB receptor agonist treatment. (A) MGL expression in different segments of the intestine. MGL expression was determined in preparations of duodenum, jejunum, ileum and colon of wild-type and MGL-KO mice using a rabbit polyclonal MGL antiserum. The membrane was stained with Coomassie blue (Co) as loading control. (B) 2-AG levels in different segments of the intestine of wild-type and MGL-KO mice. 2-AG was quantified by LC/MS measurement in tissue lipid extracts of overnight fasted mice using 1-heptadecanoyl-rac-glycerol as internal standard. Data are presented as means ± SEM (n = 6 per genotype). (C) Whole gut transit and effect of CB receptor agonists on gut transit in wild-type and MGL-KO mice. Animals were kept in single cages without bedding and fasted overnight. Subsequently, animals were injected i.p. with either carrier solution, CP 55,940 (0.1 mg·kg−1 mouse) or WIN 55,212-2 (1 mg·kg−1 mouse). After 20 min, mice were gavaged with Evans Blue and received free access to food. The time until the appearance of Evans Blue in the faeces was recorded. Data are presented as means ± SEM (n = 12 per genotype for carrier solution and CP 55,940; n = 6 per genotype for WIN 55,212-2). (D) 2-AG levels in different segments of the intestine of wild-type mice treated with JZL184. Data are presented as means ± SEM (n = 3–4 per group). (E) Whole gut transit and effect of JZL184 on gut transit in wild-type and CB1-KO mice. Animals were injected i.p. with either carrier solution or JZL184 (16 mg·kg−1 mouse). Then, Evans Blue was administered and its appearance recorded as in (C). Data are presented as means ± SEM (n = 5–6 per genotype). Statistical differences were determined using Student's unpaired t-test or two-way anova followed by Bonferroni's post hoc test, **P < 0.01 and ***P < 0.001 for comparison of genotypes; ##P < 0.01 and ###P < 0.001 for comparison of treatments.
Mentions: To investigate the contribution of MGL to intestinal 2-AG degradation, we first measured MGL expression in different segments of the intestinal tract and compared 2-AG levels of wild-type and MGL-KO mice. Western blotting analyses revealed that MGL was expressed in all the intestinal segments investigated, whereas no expression was detected in segments of MGL-ko mice. The highest expression of MGL was detected in the colon (Figure 1A). As shown in Figure 1B, MGL-KO mice exhibited increased 2-AG levels throughout the intestine in comparison with wild-type controls (1.6-, 1.9-, 2.3- and 2.7-fold in duodenum, jejunum, ileum and colon respectively).

Bottom Line: Conversely, genetic deletion of MGL did not affect gut transit despite increased 2-AG levels.Finally, MGL-deficient mice displayed accelerated colonic propulsion and were hypersensitive to μ receptor agonist-mediated inhibition of colonic motility.This phenotype was reproduced by chronic pharmacological inhibition of MGL.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.

No MeSH data available.


Related in: MedlinePlus