• Abdella M Habib, Andrei L Okorokov, Matthew N Hill, Jose T Bras, Man-Cheung Lee, Shengnan Li, Samuel J Gossage, Marie van Drimmelen, Maria Morena, Henry Houlden, Juan D Ramirez, BennettDavid L HDLHNuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK., Devjit Srivastava, and James J Cox.
• Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK; College of Medicine, Member of Qatar Health Cluster, Qatar University, Doha, Qatar.
• Br J Anaesth. 2019 Aug 1; 123 (2): e249-e253.

AbstractThe 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.Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.

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