Association of polymorphisms of the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes with heroin addiction: impact of long repeats of CNR1

Proudnikov, Dmitri; Kroslak, Thomas; Sipe, Jack C.; Randesi, Matthew; Li, D; Hamon, Sara; Ho, Ann; Ott, Jürg; Kreek, Mary Jeanne

doi:10.1038/tpj.2009.59

Cited by 44 publications

(41 citation statements)

References 45 publications

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“…In particular, no association between FAAH 385 genotype and alcoholism (Iwasaki et al, 2007) or methamphetamine dependence (Morita et al, 2005) were found in a study of Japanese. No association of FAAH 385 genotype with heroin addiction was found in an ethnically mixed sample (Proudnikov et al, 2010). Therefore, drug-specific studies have not replicated the observations made in polydrug abusers.…”

Section: 0 Associations Between Heterogeneity In Endocannabinoid Cmentioning

confidence: 87%

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Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence

Hillard¹,

Weinlander²,

Stuhr³

2012

Neuroscience

157

135

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The endocannabinoid signaling system is a widespread, neuromodulatory system in brain and is also widely utilized in the periphery to modulate metabolic functions and the immune system. Preclinical data demonstrate that endocannabinoid signaling is an important stress buffer and modulates emotional and cognitive functions. These data suggest the hypothesis that endocannabinoid signaling could be dysfunctional in a number of mental disorders. Genetic polymorphisms in the human genes for two important proteins of the endocannabinoid signaling system, the CB1 cannabinoid receptor (CB1R) and fatty acid amide hydrolase (FAAH), have been explored in the context of normal and pathological conditions. In the case the gene for FAAH, the mechanistic relationships among the common genetic polymorphism, the expression of the FAAH protein and its likely impact on endocannabinoid signaling are understood. However, multiple polymorphisms in the gene for the CB1R occur and are associated with human phenotypic differences without an understanding of the functional relationships among the gene, mRNA, protein and protein function. The endocannabinoid ligands are found in the circulation and several studies have identified changes in their concentrations under various conditions. These data are reviewed for the purpose of generating hypotheses and to encourage further studies in this very interesting and important area.

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Section: 0 Associations Between Heterogeneity In Endocannabinoid Cmentioning

confidence: 87%

“…Risk was associated with having at least 16 repeats and the effect size was small (odds ratio 1.55). In a study not included in the meta-analysis, AAT repeats of 14 or greater were significantly associated with heroin abuse in Caucasians as was the SNP at rs1049353 (Proudnikov et al, 2010). …”

Section: 0 Associations Between Heterogeneity In Endocannabinoid Cmentioning

confidence: 99%

Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence

Hillard¹,

Weinlander²,

Stuhr³

2012

Neuroscience

157

135

View full text Add to dashboard Cite

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“…This discovery may have important therapeutic implications. Indeed, even though globally active FAAH inhibitors exert few side effects in animals, human genetic studies suggest that long-term impairment of brain FAAH activity may result in increased vulnerability to substance abuse [35, 36]. Peripherally restricted FAAH inhibitors such as URB937 would not be subject to this potential risk.…”

Section: Discussionmentioning

confidence: 99%

Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions

Sasso

Bertorelli

Bandiera

et al. 2012

Pharmacological Research

110

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Fatty-acid amide hydrolase (FAAH) catalyzes the intracellular hydrolysis of the endocannabinoid anandamide and other bioactive lipid amides. In the present study, we conducted a comparative characterization of the effects of the newly identified brain-impermeant FAAH inhibitor, URB937 ([3-(3-carbamoylphenyl)-4-hydroxy-phenyl] N-cyclohexylcarbamate), in various rodent models of acute and persistent pain. When administered by the oral route in mice, URB937 was highly active (median effective dose, ED50, to inhibit liver FAAH activity: 0.3 mg-kg−1) and had a bioavailability of 5.3%. The antinociceptive effects of oral URB937 were investigated in mouse models of acute inflammation (carrageenan), peripheral nerve injury (chronic sciatic nerve ligation) and arthritis (complete Freund’s adjuvant). In all models, URB937 was as effective or more effective than standard analgesic and anti-inflammatory drugs (indomethacin, gabapentin, dexamethasone) and reversed pain-related responses (mechanical hyperalgesia, thermal hyperalgesia, and mechanical allodynia) in a dose-dependent manner. ED50 values ranged from 0.2 to 10 mg-kg−1, depending on model and readout. Importantly, URB937 was significantly more effective than two global FAAH inhibitors, URB597 and PF-04457845, in the complete Freund’s adjuvant model. The effects of a combination of URB937 with the non-steroidal anti-inflammatory agent, indomethacin, were examined in the carrageenan and chronic sciatic nerve ligation models. Isobolographic analyses showed that the two compounds interacted synergistically to attenuate pain-related behaviors. Furthermore, URB937 reduced the number and severity of gastric lesions produced by indomethacin, while exerting no ulcerogenic effect when administered alone. The results indicate that the peripheral FAAH inhibitor URB937 is more effective than globally active FAAH inhibitors at inhibiting inflammatory pain. Our findings further suggest that FAAH and cyclooxygenase inhibitors interact functionally in peripheral tissues, to either enhance or hinder each other’s actions.

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“…Although some studies have not detected an association between rs324420 and SU (Haughey et al, 2008; Proudnikov et al, 2010; Verweij et al, 2012), particularly in Asian populations (Iwasaki et al, 2007; Morita et al, 2005), the literature overwhelmingly supports a role for rs324420 in SU (Buhler et al, 2014; Flanagan et al, 2006). While one study found that subjects homozygous for the minor allele were 0.25 times less likely to be cannabis dependent (Tyndale et al, 2007), our results suggesting the A allele increases risk for CUDs are in line with previous findings (Li et al, 2011; Sipe et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans

Melroy-Greif

Wilhelmsen

Ehlers

2016

Drug and Alcohol Dependence

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Background Cannabis is a commonly used drug and studies have shown that a significant portion of the variation in cannabis use disorders (CUDs) is heritable. Five genes known to play a role in the endocannabinoid system and CUDs were examined in a community sample of young adult Mexican Americans (MAs): CNR1, MGLL, FAAH, DAGLA, and DAGLB. Methods Gene-based tests were run to test for association between each gene and two DSM-5 cannabis phenotypes. Subsequent linear regressions were run in PLINK using an additive model to determine which single nucleotide polymorphisms (SNPs) were driving the association. Results FAAH was significantly associated with DSM-5 cannabis use disorder group count (DSM-5 CUD) using a gene-based test (p = 0.0035). This association survived Bonferroni correction for multiple testing at p < 0.004. Post hoc analyses suggested this association was driven by two common (minor allele frequency > 5%) SNPs in moderate linkage disequilibrium, rs324420 and rs4141964, at p = 0.0014 and p = 0.0023, respectively. In both cases the minor allele increased risk for DSM-5 CUD. Conclusions Genetic variation in FAAH was associated with DSM-5 CUD in MAs. This association was primarily driven by the missense SNP rs324420. In vitro work has provided evidence that the risk allele generates an enzyme with decreased expression and cellular stability. Although this SNP has been previously associated with substance use in the literature, this is the first association in a young adult MA sample.

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Association of polymorphisms of the cannabinoid receptor (CNR1) and fatty acid amide hydrolase (FAAH) genes with heroin addiction: impact of long repeats of CNR1

Cited by 44 publications

References 45 publications

Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence

Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence

Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions

Genetic variation in FAAH is associated with cannabis use disorders in a young adult sample of Mexican Americans

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