Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. (August 2019)

• Record Type: Journal Article
• Authors: Habib, Abdella M.; Okorokov, Andrei L.; Hill, Matthew N.; Bras, Jose T.; Lee, Man-Cheung; Li, Shengnan; Gossage, Samuel J.; van Drimmelen, Marie; Morena, Maria; Houlden, Henry; Ramirez, Juan D.; Bennett, David L.H.; Srivastava, Devjit; Cox, James J.
• Is Part Of: British journal of anaesthesia. Volume 123:Number 2(2019)
• Page Start: e249
• Page End: e253
• Publication Date: 2019-08
• Subjects: anandamide -- anxiolytic -- endocannabinoids -- pain insensitivity -- postoperative analgesia; Anesthesiology -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1016/j.bja.2019.02.019
• Languages: English
• ISSNs: 0007-0912

Abstract

Summary: The study of rare families with inherited pain insensitivity can identify new human-validated analgesic drug targets. Here, a 66-yr-old female presented with nil requirement for postoperative analgesia after a normally painful orthopaedic hand surgery (trapeziectomy). Further investigations revealed a lifelong history of painless injuries, such as frequent cuts and burns, which were observed to heal quickly. We report the causative mutations for this new pain insensitivity disorder: the co-inheritance of (i) a microdeletion in dorsal root ganglia and brain-expressed pseudogene, FAAH-OUT, which we cloned from the fatty-acid amide hydrolase ( FAAH ) chromosomal region; and (ii) a common functional single-nucleotide polymorphism in FAAH conferring reduced expression and activity. Circulating concentrations of anandamide and related fatty-acid amides (palmitoylethanolamide and oleoylethanolamine) that are all normally degraded by FAAH were significantly elevated in peripheral blood compared with normal control carriers of the hypomorphic single-nucleotide polymorphism. The genetic findings and elevated circulating fatty-acid amides are consistent with a phenotype resulting from enhanced endocannabinoid signalling and a loss of function of FAAH. Our results highlight previously unknown complexity at the FAAH genomic locus involving the expression of FAAH-OUT, a novel pseudogene and long non-coding RNA. These data suggest new routes to develop FAAH -based analgesia by targeting of FAAH-OUT, which could significantly improve the treatment of postoperative pain and potentially chronic pain and anxiety disorders.