Effect of endocannabinoid degradation on pain

Abstract

Fatty acid amide hydrolase (FAAH) metabolizes the endocannabinoid anandamide, which has an important role in nociception. We investigated the role of common FAAH single-nucleotide polymorphisms (SNPs) in experimentally induced and postoperative pain. One thousand women undergoing surgery for breast cancer participated in the study. They were tested for cold (n = 900) and heat pain (n = 1000) sensitivity. After surgery, their pain intensities and analgesic consumption were carefully registered. FAAH genotyping was performed using MassARRAY platform and genome-wide chip (n = 926). Association between 8 FAAH SNPs and 9 pain phenotypes was analyzed using linear regression models. The results showed that carrying 2 copies of a missense variant converting proline at position 129 to threonine (rs324420) resulted in significantly lower cold pain sensitivity and less need for postoperative analgesia. More specifically, rs324420 and another highly correlated SNP, rs1571138, associated significantly with cold pain intensity (corrected P value, 0.0014; recessive model). Patients homozygous for the minor allele (AA genotype) were less sensitive to cold pain (β = -1.48; 95% CI, -2.14 to -0.8). Two other SNPs (rs3766246 and rs4660928) showed nominal association with cold pain, and SNPs rs4141964, rs3766246, rs324420, and rs1571138 nominal association with oxycodone consumption. In conclusion, FAAH gene variation was shown to associate with cold pain sensitivity with P129T/rs324420 being the most likely causal variant as it is known to reduce the FAAH enzyme activity. The same variant showed nominal association with postoperative oxycodone consumption. Our conclusions are, however, limited by the lack of replication and the results should be replicated in an independent cohort.

Breaking barriers to novel analgesic drug development

“…An irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, failed to reduce pain from osteoarthritis of the knee, in spite of decreasing FAAH activity by >96% and substantially increasing fatty acid amide endogenous substrates, and many preclinical studies showing efficacy in models of inflammatory pain 254 . In spite of this FAAH failure, others are entering clinical trials 255,256 and there is preliminary human genetic support for FAAH involvement in cold pain sensitivity 257 . Was the failure of the Pfizer compound a failure to access FAAH in the CNS?…”

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

“…For example, genetic variants in the gene of fatty acid amide hydrolase ( FAAH ) enzyme, which metabolizes AEA, have been associated not only with pain sensitivity (Cajanus et al 2016) but with mood symptoms elicited by early life stress (Lazary et al 2016), probably through neurodevelopmental effects. Indeed, the endocannabinoid system is responsible to regulate divergent physiological processes from metabolic routes through regulation of emotional behaviour to pain modulation, reflected by its broad expression throughout the brain and other parts of the body, making it challenging to specifically target it by therapeutic interventions.…”

Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity

“…The human FAAH gene contains a commonly carried hypomorphic single-nucleotide polymorphism (SNP) (C385A; rs324420; C allele frequency 74%, A 26%) that significantly reduces the activity of the FAAH enzyme 9 . Genetic association studies have investigated the link between this and other FAAH SNPs and pain sensitivity 10, 11, 12. Notably, homozygous carriers of the hypomorphic SNP (A allele) in a cohort of women undergoing breast cancer surgery were less sensitive to cold pain and had a reduced need for postoperative analgesia 10 .…”