Life without pain
A rare mutation in a resident of Scotland suppressed the feeling of pain and anxiety
Andrey Ukrainsky, N+1
Thanks to a specific mutation, a resident of Scotland almost does not feel pain and is not prone to anxiety.
Scientists have discovered a rare genotype in her, thanks to which the concentration of endogenous cannabinoids and related substances increases in the body. The gene and enzyme, changes in which give such an effect, are considered as a potential target for new painkillers. The description of the clinical case is published in the British Journal of Anaesthesia.
Fatty acid amide hydrolase (FAAH) is an enzyme responsible for the catabolism of various bioactive fatty acid amides (FAA), which play an important role in pain sensitivity, as well as anxiety, depression and the development of a reaction to fear. The FAA includes endocannabinoids (N-acyl ethanolamines, in particular anandamide) and substances close to them (oleoylethanolamine and palmitoylethanolamide). Switching off FAAH in laboratory mice in the experiment led to an increase in FAA concentrations and a decrease in pain sensitivity in animals. Scientists consider FAAH as a potential target for new classes of analgesics and anxiolytics. But clinical studies of FAAH inhibitors have not yet led to success.
In humans, there are variants of the FAAH gene (C385A, rs324420) in which the activity of this enzyme is reduced. It was found that they are associated with a decrease in pain sensitivity. Women who were homozygous carriers of the rs324420 allele required less anesthesia after breast cancer surgery. In addition, it has been shown that both mice and humans with such a genetic variant have lower anxiety, they are easier to forget traumatic experiences.
Researchers led by James J. Cox from University College London and Devjit Srivastava from the Department of Anesthesiology at Raigmore Hospital in Inverness, Scotland, described a clinical case of insensitivity to pain and lack of predisposition to anxiety in an elderly woman. The cause of the phenomenon was a combination of genetic factors associated with the loss of FAAH function.
Jo Cameron went to Raigmore Hospital for osteoarthritis with deformity of the carpocarpal joints on both hands. At that time she was 66 years old. The patient underwent orthopedic surgery using general anesthesia. Despite the fact that such an intervention is usually very painful, after the operation, the woman did not need painkillers, except for taking paracetamol. The reduced pain sensitivity interested the doctors and they decided to better deal with this case.
It turned out that Jo had previously been diagnosed with osteoarthritis of the femoral joint, which, according to her, proceeded without pain. At the age of 65, she underwent surgery, after which she did not require any painkillers. After both operations, when assessing pain on the intensity scale, the results were 0 out of 10, except for the first postoperative day, when this indicator was 1 out of 10. The patient had a history of intervention for varicose veins and dental treatment without anesthesia, as well as a number of injuries, including a wrist fracture and burns, in which she did not feel pain.
Given the history of painless injuries and operations, the doctors referred the patient to scientists from King's College London and Oxford University, who deal with the problems of the genetic basis of pain. Upon examination, numerous scars were found on her hands, the sensitivity of her palms and feet to pain was greatly reduced.
Scientists have noted that Joe is optimistic about life. When taking the Generalized Anxiety Disorder-7 questionnaire for the diagnosis of anxiety disorders, her result was 0 out of 21, which indicates the lowest level of anxiety. The patient reported that she never panics in dangerous situations. Similarly, the Patient Health Questionnaire-9 questionnaire found no depression in her. At the same time, according to the woman, she has regular "memory lapses".
"I knew I was carefree, but I never thought I was any different. I thought it was just me. I didn't notice anything strange until I turned 65," she said Joe Cameron to the British edition of the Guardian. She added that the findings of scientists amused her.
To sequence the exome, scientists took genomic DNA from the patient, her two children and her mother. After conducting additional studies, the patient was found to have a heterozygous microdeletion located slightly below the FAAH gene and to carry the rs324420 allele. A similar deletion was found in her son, who also reported a reduced pain threshold, but he was not a carrier of rs324420.
The microdeletion was localized in the pseudogene FAAH, which scientists called FAAH-OUT. Pseudogen expression was found in the brain and ganglia of the posterior horns of the spinal cord. The authors suggest that FAAH-OUT can encode long non-coding RNA, and microdeletion suppresses the normal function of FAAH.
To test how the combination of microdeletion and rs324420 carrier affects the concentration of bioactive fatty acid amides associated with FAAH, scientists determined their level in the patient's blood and in four people from the control group: two heterozygous and two homozygous rs324420 carriers. Joe's concentration of anandamine was 70 percent higher, and oleoylethanolamine and palmitoylethanolamide were about three times higher than those in the control group.
The level of anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamine (OEA) in the studied woman (PFS) and four people from the control group: homozygous (A,B) and heterozygous (C,D) carriers of the rs324420 allele. A drawing from an article in the British Journal of Anaesthesia.
"We found a woman with a certain genotype that reduces the activity of genes that are already considered a possible target for pain relief and treatment of anxiety," he said James Cox.
The authors suggest that such a violation of sensitivity to pain may occur in other people. The fact that the described woman was found to have this condition only at the age of 66, underscores the possibility of insufficient illumination of the problem.
To determine which FAA, in addition to those described, contribute to pain suppression, further research is required, the scientists write. In their opinion, the new information provides unique information about the role of the endocannabinoid system in pain management and points to opportunities in the development of painkillers.
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