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Molecular Machinery of Pain Insensitivity Uncovered

The biology underpinning a rare genetic mutation that allows its carrier to live virtually pain-free, heal more rapidly, and experience reduced anxiety and fear, has been uncovered by researchers.

In the UK, chronic pain affects up to 50% of adults and about 12% of those have moderate-to-severe disabling pain. When inadequately treated, it makes life "intolerable", said the authors of a new observational study published in Brain. "New pain-killing medications are urgently needed," they added.

Heather Wallace, chief executive of the charity Pain Concern, told Medscape News UK that "worldwide, persistent pain is one of the biggest causes of disability, reducing quality of life more than almost any other condition". She said the "exciting and important" new research provided "hope" for future treatments.

Coherent Explanation for Pain Insensitivity

In 2019, researchers from University College London (UCL) discovered the novel FAAH-OUT gene, and the associated rare mutations that caused a female patient to feel virtually no pain, and never to feel anxious or afraid.

The area of the genome containing FAAH-OUT had previously been assumed to be 'junk' DNA that had no function, the authors explained. However, it was found to "mediate the expression of FAAH" (fatty acid amide hydrolase), a gene that was part of the endocannabinoid (eCB system or eCBS system), well-known for its involvement in pain, mood, and memory. Components of the eCBS were potential therapeutic targets for a wide range of neurological conditions – including chronic pain, anxiety and depression, Alzheimer’s disease and Parkinson’s disease – the authors pointed out.

The researchers investigated how the FAAH-OUT gene worked at a molecular level, and used a range of approaches, such as CRISPR-Cas9 experiments on cell lines, to mimic the effect of the mutation on other genes, as well as analysing the expression of genes to see which were active in molecular pathways involved with pain, mood, and healing.

This, the authors postulated, was the first step towards being able to take advantage of this unique biology for applications like drug discovery.

The researchers looked at fibroblasts taken from other patients to study the effects of the FAAH-OUT-FAAH axis on other molecular pathways, and discovered that FAAH-OUT regulated the expression of FAAH. Whilst mutations that the index patient carried 'turn down' FAAH, the researchers also found a further 797 genes that were turned up and 348 that were turned down. This included alterations in pathways associated with wound healing. In addition, two other genes linked to mood regulation and to opioid level regulation were also found to be altered. These microdeletions may contribute to the patient’s low anxiety, fear, and pain, the authors suggested.

They underlined that the data provided a "coherent" explanation for the pain insensitivity, lack of anxiety, faster wound-healing and other syndromic symptoms observed in the patient.

Potential Target for Pain Treatment

"As well as the molecular basis for painlessness, these explorations have identified molecular pathways affecting wound healing and mood, all influenced by the FAAH-OUT mutation," highlighted Dr Andrei Okorokov, UCL Medicine, and a senior author. However, the FAAH-OUT gene was just "one small corner of a vast continent", which the study had begun to map, he stressed.

"Given that FAAH is a potential target for the treatment of pain, anxiety, depression and other neurological disorders, this new understanding of the regulatory role of the FAAH-OUT gene provides a platform for the development of future gene and small molecule therapies," the authors said.

Professor James Cox, UCL Medicine, and a senior author, described the initial discovery of the genetic root of the patient's unique phenotype as a "eureka moment", and "hugely exciting". He explained that, by understanding precisely what is happening at a molecular level, "we can start to understand the biology involved, and that opens up possibilities for drug discovery that could one day have far-reaching positive impacts for patients".

Commenting to Medscape News UK, Dr Rajesh Munglani , pain medicine consultant, Royal Papworth Hospital Cambridge, and vice president of the British Pain Society, had a more sobered view, and said that whilst the scientific discovery was "very interesting", he cautioned, "we are a very long way for any practical clinical application to patients who are either in pain or anxious".

The study was funded by a Medical Research Council grant. The authors declared no conflicts of interest.