Background & Aims

The endocannabinoid system has been implicated in pain, mood, appetite, cognition, inflammation and motor functioning. Fatty amide acid hydrolase (FAAH) is key enzyme expressed throughout the central and peripheral nervous system responsible for degradation of key endocannabinoid anandamide. Genetic FAAH deletion in animal models show decreased pain sensitivity, positing FAAH as a potential pharmacological target for analgesics. Case studies in humans with FAAH polymorphisms and deletions show hypoalgesic responses, and lower levels of anxiety and stress. Here, we aimed to explore whether regional brain levels of FAAH, measured using position emission tomography (PET), are associated with pain sensitivity, measured through quantitative sensory testing (QST). We hypothesized that higher FAAH levels in nociceptive and pain modulatory regions would be associated with higher pain sensitivity, as there would be greater degradation of anandamide throughout the nervous system.

Methods

Seven participants (4 with chronic non-cancer pain on opioids, and 3 control participants not on opioids; mean age ±SD= 41.4 ± 14.7 years; 2F, 5M) completed a PET scan with [11C]CURB for FAAH. All participants attended one QST session on a separate day. The QST battery included static thresholds: thermal detection and pain thresholds, mechanical pain and detection thresholds, pressure pain threshold; and dynamic thresholds conditioned pain modulation, cold pressor task, and temporal summation. [11C]CURB binding across 12 nociceptive and pain modulatory regions—left and right anterior cingulate cortex (l/r ACC), thalamus (l/r Thal), dorsolateral prefrontal cortex (l/r dlPFC), and orbitofrontal cortex (l/r OFC), as well as an average of bilateral subgenual cingulate (sgACC), amygdala (Amyg), insula (Ins), inferior parietal lobule (IPL)—were correlated to QST measures. As an exploratory study with a small sample size, we report correlations |r|>0.5 (medium effect size).

Results

Innocuous cool and warm detection thresholds were correlated with FAAH levels in most brain regions ( r>0.5). Mechanical detection thresholds were negatively associated with FAAH levels in the l/r Thal, sgACC and Ins. Cold pain threshold was only associated with Amyg FAAH levels. In contrast, the cold pressor pain threshold and tolerance measures were associated with FAAH levels in all brain regions. Heat pain thresholds were associated only with FAAH levels in the l dlPFC. Mechanical pain thresholds were associated with r ACC, l/r Thal, and Ins FAAH levels. Pressure pain thresholds were negatively associated with l ACC, IPL and r/l dlPFC FAAH levels. Temporal summation and conditioned pain modulation were associated with Amyg FAAH levels, and conditioned pain modulation was also associated with r dlPFC FAAH levels

Conclusions

We provide the first evidence of relationships between brain FAAH levels in nociceptive and pain modulatory human brain region and pain sensitivity. Although our sample sizes are small, we show that brain FAAH levels contribute to individual differences in pain sensitivity, and thus indicate a clear role for the endocannabinoid system in human pain.

References

1Dainese, E. et al. The endocannabinoid hydrolase FAAH is an allosteric enzyme. Sci Rep 10, 2292 (2020). https://doi.org/10.1038/s41598-020-59120-1
2Wilson, A. A. et al. [11C]CURB: Evaluation of a novel radiotracer for imaging fatty acid amide hydrolase by positron emission tomography. Nucl Med Biol 38, 247-253 (2011). https://doi.org/10.1016/j.nucmedbio.2010.08.001
3Cravatt, B. F. et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 98, 9371-9376 (2001). https://doi.org/10.1073/pnas.161191698
4Habib, A. M. et al. Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Br J Anaesth 123, e249-e253 (2019). https://doi.org/10.1016/j.bja.2019.02.019

Presenting Author

Matthew Mockford

Poster Authors

Matthew Mockford

BSc

University of Toronto

Lead Author

E-mail

Massieh Moayedi; PhD

Centre for Multimodal Sensorimotor and Pain Research, Faculty of Dentistry, University of Toronto

Lead Author

E-mail

Claire Shyu

Centre for Addiction and Mental Health

Lead Author

E-mail

Isabelle Boileau

PhD

Centre for Addiction and Mental Health

Lead Author

E-mail

Bernard Le Foll

PhD

Centre for Addiction and Mental Health

Lead Author

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Topics

  • Pain Imaging