August 11, 2022

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Genes and their polymorphisms in the occurrence and development of pain

The genes and their polymorphisms in the occurrence and development of pain



The genes and their polymorphisms in the occurrence and development of pain.  Gene polymorphism, also called genetic polymorphism, is widely distributed in biological groups, leading to differences and diversity among biological groups.

Genes and their polymorphisms in the occurrence and development of pain.


Studies in recent years have found that genetic polymorphism is the basis for affecting pain sensitivity, and it is also the root cause of differences in individual efficacy and adverse reactions under standard doses of analgesic drugs. Gene polymorphisms cause individual differences in pain control and postoperative complications of opioids.

This is due to the complexity of gene sequence replication, transcription, translation and other processes that directly lead to the diversity and unpredictability of gene mutations. There are three main types of gene polymorphism: DNA fragment length polymorphism, DNA repeat sequence polymorphism and single nucleotide polymorphism (SNP).

At present, many studies have proved that SNP is an important reason for the heredity of human diseases, the susceptibility of different individuals, and the individual differences in drug metabolism. SNP mainly refers to a DNA sequence polymorphism caused by a single nucleotide variation at the genome level.

It is the most common type of human heritable variation, accounting for more than 90% of all known polymorphisms. SNPs are widespread in the human genome, with an average of 1 in every 500 to 1,000 base pairs, and their total number can reach 3 million or more.

Due to the different mechanisms of acute and chronic pain, this article focuses on chronic pain in terms of ion channels, neurotransmitter genes, action receptor genes, and drug metabolizing enzyme genes, and aims to explore the genes and their polymorphisms in the occurrence and development of pain. The role in the treatment and management of pain provides new ideas and new methods.


1. ion channel

1.1 Sodium ion channel

Voltage-gated sodium channels are essential for the transduction of sensory nerve stimulation, the occurrence of action potentials, and the release of neurotransmitters at the end of sensory neurons. Changes in the expression of voltage-gated sodium channels and post-translational modifications contribute to the sensitization of sensory neurons in chronic pain states. In the study, Emery et al. found that the importance of Nav1.7 (encoded by SCN9A) in pain control is reflected in the heterogeneity of the clinical phenotype related to its mutation:

① Functional gain mutations cause pain, such as hereditary erythema pain. It is caused by the enhanced activation of the Nav1.7 channel;

② The mutation that changes the steady state and rapidly inactivates causes the paroxysmal extreme pain disorder. Therefore, SCN9A non-functional mutations are one of the causes of congenital pain insensitivity.

Huang et al. found in further research:

① Nav1.4 is related to various neuromuscular diseases, such as normal periodic paralysis, congenital myasthenia syndrome type 16, etc.;

② 5 Nav1.8 mutations and small fiber neuropathy (1 A clinically characterized disease characterized by autonomic nerve dysfunction and distal limb burning pain) is related;

③ So far, about 60 Nav1.7 mutations have been found to cause human pain syndromes, including hereditary erythema, Paroxysmal extreme pain disorder, small fiber neuropathy, Draview syndrome and febrile seizures.


1.2  Potassium ion channel

Previous physiological studies have shown that the TRESK channel (TWIK‑related spinal cord K+ channel) is one of the main potassium channels of dorsal root ganglion (DRG) neurons, and it participates in DRG neurons in both normal and disease environments. Excitability. The TRESK dual-porous potassium channel is a novel component in the pathogenesis of migraine. Its highly specific expression pattern in DRG neurons and its role in reducing neuronal excitability under inflammatory conditions make it a treatment bias.

Good target for headaches. Laumet et al. found that nerve damage leads to a long-term decline in the expression of DRG potassium channels, increasing histone methyltransferase G9a (also known as euchromatin histone lysine N-methyltransferase 2) and histone deacetylase As well as the activity of zeste gene enhancer homolog 2, but only G9a inhibition can continue to restore the expression of potassium channels. RNA sequence analysis showed that G9a inhibition not only activated 40 silent genes related to potassium ion channels, but also decreased or upregulated 638 genes after nerve injury.

It can be seen that G9a inhibits potassium channel transcription and acutely after nerve injury. It plays a leading role in the transition of chronic pain. Selectively knocking out the G9a gene of DRG neurons can block the silencing of potassium channels and the development of chronic pain after nerve injury.


1.3 Calcium ion channel

The high-pressure activated calcium ion channel is an oligomeric complex formed by the main ion-conducting subunit Cavα1 and at least two auxiliary subunits. Gómez et al. studied the role of the transcription factor Sp1 in the mechanical allogeneic pain nerve ligation model. The results showed that the ligation of the L5/L6 spinal nerve can increase the expression of Sp1 and Cavα2δ‑1 in the DRG of rats, thereby causing pain in rats. Intrathecal injection of Sp1 inhibitor mitamycin A can reduce the functional expression of Sp1 and Cavα2δ‑1 subunits, and activate calcium channels by high pressure to reduce calcium ion currents and mechanical pain in sensory neurons, preventing rats The pain occurs.



2. Neurotransmitter genes


2.1 5-hydroxytryptamine (5‑hydroxy tryptamine, 5‑HT) neurotransmitter

Lindstedt et al. proved that there is a strong correlation between heat pain sensitivity and serotonin-transporter-linked polymorphic region (5‑HTTLPR):

 ① serotonin‑transporter‑linked polymorphic region (5‑HTTLPR) The low expression of ‑serotonin transporter, 5‑HTT) is related to relative hypoalgesia;

② The low level of 5‑HTT expression is a risk factor for chronic pain;

③ Depression is also related to the low expression of 5‑HTT, and patients with depression are more sensitive to heat Pain sensitivity is reduced.

Kunz et al. used thermal pain stimuli to assess pain thresholds, observe pain-related facial reactions, and use pain severity scores. Based on the 5‑HTTLPR genotype (biallelic) of 60 female and 67 male subjects, Kunz et al. Evaluation) Divide them into S allele carriers and non-carriers. The results of the study show that S allele carriers have lower pain thresholds and higher pain severity scores; among S allele carriers, subjective pain experience and pain catastrophic tendencies are enhanced, which suggests that S alleles may be A risk factor for the occurrence and maintenance of pain, and this risk factor works through two independent pathways: the sensory process of subjective pain experience and the enhancement effect of pain catastrophe.


2.2 Catecholamine neurotransmitter

Catecholamine-o-methyltransferase (COMT) is an enzyme that is widely expressed in the human body. It regulates the bioavailability of catecholamines and maintains and affects the physiological functions of pain, sympathetic tension, mood and inflammation. Play a key role. Meloto et al. studied the association between COMT polymorphism and pain phenotype and identified a functional marker rs165774 in the untranslated region of a new splice variant (a)-COMT. The study found that: ① individuals carrying the rs165774 small A allele have stronger resistance to the risk of musculoskeletal pain and lower sensitivity to painful stimuli; ② (a)‑COMT subtype is involved in nociceptive signal transduction The important role of (a)-COMT subtypes provides evidence and suggests that genetic variations in (a)‑COMT subtypes may lead to individual differences in pain phenotypes.


3. opioid receptor gene

μ receptors are the main receptor protein sites for analgesics such as morphine and fentanyl. OPRM1, the gene encoding μ receptor, is highly polymorphic. More than 100 variants have been identified. One of the most studied alleles is the 118 A>G polymorphism. Mura et al. found from the 118 A>G animal model that the variant receptor has a dual effect: it has a significant functional gain in response to endogenous opioids, but it loses its function to exogenous opioids. Clinical experience has shown that patients carrying this variant allele show a lower pain threshold and higher drug consumption for achieving analgesic effects, and side effects are not affected by increased opioid consumption.


Because the use of μ opioid receptor agonists can produce a large number of side effects, the choice of δ opioid receptor and kappa opioid receptor (KOR) agonists provides a new way to develop and improve opioid analgesics. The OPRD 1 gene encodes a delta opioid receptor with multiple functions such as regulatory pathways. The gene contains more than 2,000 confirmed genetic variants. Nielsen et al. found that in men, OPRD1 rs2234918T carriers and non-OPRD1 rs533123G carriers had an enhanced morphine analgesic effect on rectal heat stimulation. Custodio‑Patsey et al. studied the gender differences in the inhibition of endogenous KOR on postoperative occult pain: Compared with male mice, intrathecal injection of low-dose KOR inhibitor LY2456302 produced obvious hyperalgesia in the back horns of female mice. . Therefore, Custodio-Patsey et al. believe that the inhibitory effect of endogenous KOR on the potential pain sensitization of tissue damage is more pronounced in women.





4 Drug Metabolism Enzyme Gene


4.1 “Cytochrome P4502D6 enzyme (cytochrome P4502D6, CYP2D6)

CYP2D6 is a highly polymorphic enzyme. Codeine, tramadol and oxycodone are all metabolized by CYP2D6. Dagostino et al. retrospectively evaluated 224 patients with chronic low back pain who were treated with codeine or oxycodone. The results suggested: ① CYP2D6*6 and *9, due to reduced enzyme activity (*9) or absence (*6) Lead to treatment failure; ② CYP2D6*1/*11, *4/*6, and *41/*2N diploid have a significant correlation with chronic opioid treatment. Seripa et al. found in the multimodal postoperative pain treatment based on tramadol and ketoprofen that patients with the CYP2D6‑IM phenotype had different sedative effects in the early stage compared with the normal CYP2D6‑EM phenotype. And the sedative effect is enhanced in the slower metabolizers, and the sedative effect is reduced in the fast metabolizers.


4.2 Cytochrome P4503A4 enzyme (cytochrome P4503A4, CYP3A4)

The CYP3A4 gene polymorphism determines the pain sensitivity and the activity of drug metabolizing enzymes in patients. The mechanism is that the CYP3A4 gene polymorphism affects the replication, transcription and translation of DNA fragments, and changes the spatial structure of drug metabolizing enzymes, thereby changing The binding ability of the enzyme and the substrate affects the activity of the enzyme, as well as the metabolic process of the drug in the body and the maintenance of the blood drug concentration. Eventually, there are individual differences in analgesic effects and postoperative complications. Yuan et al. used direct sequencing to genotype CYP3A4*1G in 176 patients undergoing elective lower abdominal surgery under general anesthesia, and explored the influence of CYP3A4*1G gene polymorphism on the metabolism of fentanyl in patients undergoing lower abdominal surgery. The results of the study suggest that the plasma fentanyl concentration of patients with CYP3A4*1G alleles is significantly higher than that of normal people, and compared with CYP3A4*1/*1 wild-type or CYP3A4*1/*1G heterozygous patients, CYP3A4*1G /*1G homozygous patients need less fentanyl and tramadol to control pain.



5 Summary and Outlook

Pain is the result of the interaction between genetic factors and environmental factors, and has significant genetic heterogeneity and complexity. There are many reasons for the differentiation of most individual pain, such as ion channels, neurotransmitter system genes, action receptor genes, drug metabolism enzyme genes and other gene polymorphisms at different levels can affect pain perception and individual performance.


Uncontrolled pain will not only cause harmful effects on the body, but continuous pain will destroy the autonomy, dignity and decision-making ability of the patient, making it easier for clinical anesthesiologists to choose safe and appropriate doses of anesthetics for them. . Effective analgesia not only helps to reduce or prevent a series of stress reactions in the patient’s body, improve the quality of anesthesia and the safety of surgical patients, but also help patients recover after surgery and improve the quality of life. In addition, social factors, psychological factors, pain behavior standards, and the rationality of experimental analysis methods may all affect the accuracy of the research results.


With the improvement of people’s living standards, it is imperative to explore new pain treatment methods and promote pain control strategies. With more experimental verification and continuous improvement of research methods, it is worth looking forward to scientifically elucidating the mechanism of pain, formulating individualized medication plans and optimal pain control plans.


(source:internet, reference only)

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