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Br J Anaesth. 2019 Mar 28. pii: S0007-0912(19)30138-2. doi: 10.1016/j.bja.2019.02.019. [Epub ahead of print]

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

Author information

1
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.
2
Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK.
3
Hotchkiss Brain Institute, Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, AB, Canada.
4
UK Dementia Research Institute at UCL, London, UK; Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
5
Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK; University Division of Anaesthesia, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, UK; Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA.
6
Department of Pathology, Raigmore Hospital, Inverness, UK.
7
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
8
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
9
Department of Anaesthesia, Raigmore Hospital, Inverness, UK. Electronic address: dev.srivastava@nhs.net.
10
Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK. Electronic address: j.j.cox@ucl.ac.uk.

Abstract

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.

KEYWORDS:

anandamide; anxiolytic; endocannabinoids; pain insensitivity; postoperative analgesia

PMID:
30929760
DOI:
10.1016/j.bja.2019.02.019
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