It is the story of a Scottish woman who has almost always ignored what it means to be in pain. This is reported in an article in the British Journal of Anesthesia published online on March 27, 2019.

Five years ago, Jo Cameron, who lives on the shores of Loch Ness in Scotland, went to the Raigmore Hospiral in Inverness for surgery. This patient, then aged 66, presented with rhizarthrosis, in other words osteoarthritis of the base of the thumb. This reaches the joint between the trapezius (a small bone of the wrist) and the first metacarpal (long bone of the hand, itself connected to the index). Although deformed the right thumb is not painful. The sexagenarian must undergo a trapezectomy, an intervention consisting in removing the diseased bone (trapezius), with ligament reconstruction, interposition of a tendon and realignment of a thumb extensor muscle.

In the past, this patient had also undergone an operation for varicose veins and dental procedures, surgical procedures that did not require the use of any analgesic medication. Likewise, she did not need to take painkillers every time she had wounds, such as when she had stitches and a fractured left wrist.

He also happened to burn or cut himself without feeling pain. On several occasions, she did not realize that she had burned herself until she had smelled the smell of grilled skin. Moreover, these wounds healed quickly, resulting in little or no scarring. She indicated that she could easily swallow very hot peppers (Scotch Bonnets, more than six times more powerful than cayenne peppers) and then feel a brief and pleasant sensation in the mouth.

The patient’s son also has some degree of insensitivity to pain, but much less than his mother. The patient’s father, who died, himself had little recourse to painkillers in his life.

• • • No pain, no anxiety
    • Endocannabinoid system
    • Double genetic abnormality
    • A newly identified gene
    • High blood levels of anandamide
    • A frequency may be underestimated
    • An innovative line of research

No pain, no anxiety

Now 71, Jo Cameron has worked as a primary school teacher. She expresses herself easily, says she is very happy and is optimistic. She feels no anxiety. Thus, his score is 0 out of 21 on the Generalized Anxiety Disorder Screening Scale (GAD-7). Similarly, she is in no way depressed, with a score of 0 out of 29 on the Patient Health Questionnaire-9 (PHQ-9), a tool for assessing the presence and severity of depression. However, he sometimes has memory lapses. She frequently forgets words in mid-sentences and can’t always remember where her keys are.

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Finally, she says she never gives in to panic, even in the event of dangerous or frightening situations, such as when she was the victim of a road accident. She said when her car overturned in a ditch because a van cut her off, she went to comfort the trembling young driver. Not feeling the pain despite the violence of the shock, it was only later that she became aware of it, noticing that she had many bruises.

Due to the absence of any pain in their patient after the thumb procedure and recent discoveries about her surgical history, the doctors anest

Endocannabinoid system

This system owes its name to the fact that it is made up of the molecular targets on which cannabis derivatives act. It includes so-called cannabinoid receptors and molecules that bind to them. Tetrahydrocannabinol (THC, the active ingredient in cannabis) binds to a particular class of cannabinoid receptors located on the surface of neurons and other nerve cells in the brain.

In the body, several molecules bind to these receptors, in particular anandamide (AEA). This lipid plays a role in pain perception (nociception), anxiety and depression. The term anandamide was born from the fusion of the words ananda (which means “bliss”, ecstatic joy”, “supreme happiness”, in Sanskrit) and “amide” because of its chemical structure.

Double genetic abnormality

Genomic map showing the location on chromosome 1 of the FAAH gene, the FAAH-OUT pseudogene and the microdeletion. Unique SNP of the FAAH gene in exon 3 (indicated by the asterisk). The microdeletion impinges on the FAAH-OUT pseudogene (promoter as well as exons 1 and 2). Neither the mother nor the daughter showed any abnormality. The son only carries a heterozygous microdeletion of the FAAH-OUT pseudogene. Habib AM, et al. Br J Anaesth 2019.

In Jo Cameron, a patient with near insensitivity to pain, part of the FAAH gene is missing. However, this gene, in the normal state, is responsible for the production of an enzyme, FAAH (for Fatty acid amid hydrolase), which degrades anandamide. In fact, this “bliss molecule” was detected in large quantities in the blood of this patient.

Sequencing of the DNA region of chromosome 1 revealed another anomaly: the single-letter change in the genetic code of the FAAH gene. This tiny variation* (called SNP by geneticists) is enough to cause partial inactivation of this gene.

The patient’s son, who also has a pain sensitivity deficit, carries the same microdeletion in his DNA but does not present the second anomaly (SNP). Several studies have previously shown that individuals with this SNP use less painkillers after surgery, have more nausea and vomiting induced by opiates in the postoperative period, and are less prone to anxiety.

A newly identified gene

Molecular biologists sought to understand how the loss of genetic material (microdeletion) could lead to insensitivity to pain. They then discovered that this microdeletion also affected another gene. Called a pseudogene by geneticists, this is, so to speak, an old version of the FAAH gene. A pseudogene is most often inactive following the acquisition of genetic mutations. In reality, this pseudogene, baptized FAAH-OUT, is still active. According to the researchers, it is possible that the microdeletion reduced the expression of the pseudogene FAAH-OUT and had the consequence of abolishing the functioning of the FAAH gene.

High blood levels of anandamide

Knowing that the FAAH gene degrades anandamide, blood tests were carried out. These revealed a 70% increase in anandamide (AEA) concentrations. These results therefore indicate that the FAAH gene is not functioning normally in this patient.

The clinical and genetic characteristics of Jo Cameron are reminiscent of what has been observed in laboratory animals in which the functioning of both copies of the FAAH gene has been abolished. In these so-called “knockout” mice, high levels of anandamide (AEA) in the brain, insensitivity to pain after local application of a source of heat or irritating substances, an ability to rapidly heal , decreased anxiety, short-term memory deficits.

A frequency may be underestimated

All in all, it appears that this woman, having never really had pain in her life, presents a genetic disorder characterized by both a small loss of genetic material and the existence of a tiny variation in a region of chromosome.

According to Devjit Srivastava (Raigmore Hospital, Inverness), James Cox (University College London) and their colleagues, it is likely that the disorder presented by Jo Cameron is more common than believed in the general population. Indeed, it is very surprising that this woman waited until the age of 67 to learn that she had genetic abnormalities responsible for her incredible insensitivity to pain, despite repeated injuries, burns and painless surgical procedures. .

An innovative line of research

According to the authors, methods** inhibiting the expression of the FAAH-OUT pseudogene could in the future be effective in inducing an analgesic and anxiolytic effect. The inactivation of this newly identified gene therefore constitutes a new avenue of therapeutic research. In any case, much more promising than that of the FAAH enzyme inhibitor molecules which have failed in humans***. It therefore remains to be hoped that research on a pain relief strategy targeting FAAH-OUT will be fruitful. In any case, Jo Cameron, always unfailingly optimistic, believes in it.

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