Biological pathways and genetic variables involved in pain (original) (raw)
Related papers
2018
The intervention of the genetic factor in pain have a decisive importance not only for the effectiveness of the therapeutic strategy but also for avoiding the adverse (unwanted) effects of the drug molecules. The human genome assures by coding and synthesizing the functional protein structures participating in the mechanisms of receiving, conducting and projection of pain sensitivity in superior nerve centers as perception and interpretation of pro-nociceptive and antinociceptive molecules as well as modulation of pharmacokinetics and pharmacodynamics of analgesics. Genes with an indirect pain impact are a large number of genes, each having a little contribution to the interindividual variability of pain parameters in humans and to response type to analgesic therapy reflected by the required dose, administration time and efficiency. Epigenetic factors with effects on the mechanisms of pain and the patient's analgesic responses types are numerous and of wide diversity.
Genetic contributions to pain: a review of findings in humans
Oral Diseases, 2008
Pain represents the major motivating factor for which individuals seek healthcare, and pain responses are characterized by substantial inter-individual differences. Increasing evidence suggests that genetic factors contribute significantly to individual differences in responses to both clinical and experimental pain. The purpose of this review article was to summarize the current literature regarding genetic contributions to pain, highlighting findings relevant to oral pain where available. A brief discussion of methodologic considerations is followed by a review of findings regarding genetic influences on clinical pain. Next, the literature examining genetic contributions to experimental pain responses is presented, emphasizing genetic associations that have been replicated in multiple cohorts. It is hoped that an enhanced understanding of genetic contributions to pain responses will ultimately improve diagnosis and treatment of clinical pain conditions.
European Journal of Pharmacology, 2007
Neuropathic pain conditions can encompass a diverse constellation of signs and symptoms consisting of sensory deficits, allodynia and hyperalgesia. Animal models of neuropathic pain have enabled the identification of key pathophysiological changes occurring within nociceptive pathways as a result of injury, and serve an invaluable role for preclinical screening of novel analgesic candidates. We have produced the first systematic description of the development and maintenance, and the pharmacological sensitivity of nociceptive behaviours in four rat strains with different genetic background (outbred Sprague-Dawley and inbred Brown Norway, Lewis and Fischer 344 rats), using the spared nerve injury model of peripheral neuropathic pain. Hindpaw mechanical hypersensitivity was evident from 7 to 30 days post-injury in all four strains, developing most quickly and severely in Fischer 344 rats; Lewis rats were least affected. Morphine (6 but not 3 mg/kg, s.c.) and gabapentin (100 but not 50 mg/kg, s.c.) had significant antiallodynic and antihyperalgesic actions in all four strains after spared nerve injury, although marked differences in potency across strains were observed. Two strains (Fischer 344 rats and Lewis) were insensitive to the antihyperalgesic properties of gaboxadol (15 mg/kg) whereas gaboxadol (6 mg/kg) was equipotent to morphine (6 mg/kg) in two other strains (Sprague-Dawley and Brown Norway). The observed pharmacogenetic variations have important implications for the preclinical testing of drugs, and provide a basis for development of pharmacogenomics in neuropathic pain.
Anesthesia & Analgesia, 2006
In this prospective, observational study we explored whether A118G single nucleotide polymorphism in the human -opioid receptor (MOR) gene could explain the inter-individual differences in opioid analgesic requirements in patients with acute postoperative pain and chronic pain. The frequency of the wild-type A118 MOR (major) and variant G118 MOR (minor) alleles in the subjects with chronic, noncancer pain (n ϭ 121) and opioid-naïve subjects with acute postoperative pain (n ϭ 101), serving as the control group, were examined. The relationships among the A118G MOR genotype, opioid requirements, and the numerical pain score were analyzed in both groups. The frequency of the minor allele was significantly lower in the subjects with chronic pain when compared with the group with acute postoperative pain (0.079 versus 0.158; P ϭ 0.009 by 2 test). No statistically significant association was observed between the presence of A118G MOR polymorphism and the average postoperative pain score or the doses of morphine used in the immediate postoperative period. In the high-quartile, opioid utilization, chronic pain patients, the homozygotic carriers of the major allele required significantly higher opioid dose than did the carriers of the minor allele.
Human Molecular Genetics, 2004
Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P 5 0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.
Recent advances in the understanding of genetic susceptibility to chronic pain and somatic symptoms
Current rheumatology reports, 2011
Regional (e.g., low back) and widespread chronic pain disorders are common in the general population and are known to be heritable. Recent research suggests that genetic factors increase the risk of developing chronic pain independent of the site of pain. Candidate gene studies have been conducted on key pathways to elucidate susceptibility genes that are likely to be involved in both the sensory and affective components of pain. Findings have been largely equivocal, predominantly due to small sample size, but larger studies of pain in general population samples are being conducted. Interesting candidate genes from animal models and monogenic pain disorders are beginning to emerge. Recent advances in genetics research have yet to make an impact in the pain field but provide considerable scope for future research efforts.
Current Oncology Reports, 2020
Purpose of Review Pain is multifactorial and complex, often with a genetic component. Pharmacogenomics is a relative new field, which allows for the development of a truly unique and personalized therapeutic approach in the treatment of pain. Recent Findings Until recently, drug mechanisms in humans were determined by testing that drug in a population and calculating response averages. However, some patients will inevitably fall outside of those averages, and it is nearly impossible to predict who those outliers might be. Pharmacogenetics considers a patient's unique genetic information and allows for anticipation of that individual's response to medication. Summary Pharmacogenomic testing is steadily making progress in the management of pain by being able to identify individual differences in the perception of pain and susceptibility and sensitivity to drugs based on genetic markers. This has a huge potential to increase efficacy and reduce the incidence of iatrogenic drug dependence and addiction. The streamlining of relevant polymorphisms of genes encoding receptors, transporters, and drug-metabolizing enzymes influencing the pain phenotype can be an important guide to develop safe new strategies and approaches to personalized pain management. Additionally, some challenges still prevail and preclude adoption of pharmacogenomic testing universally. These include lack of knowledge about pharmacogenomic testing, inadequate standardization of the process of data handling, questionable benefits about the clinical and financial aspects of pharmacogenomic testing-guided therapy, discrepancies in clinical evidence supporting these tests, and doubtful reimbursement of the tests by health insurance agencies.
The Role of Genetic Polymorphisms in Chronic Pain Patients
International journal of molecular sciences, 2018
It is estimated that the total annual financial cost for pain management in the U.S. exceeds 100 billion dollars. However, when indirect costs are included, such as functional disability and reduction in working hours, the cost can reach more than 300 billion dollars. In chronic pain patients, the role of pharmacogenetics is determined by genetic effects on various pain types, as well as the genetic effect on drug safety and efficacy. In this review article, we discuss genetic polymorphisms present in different types of chronic pain, such as fibromyalgia, low back pain, migraine, painful peripheral diabetic neuropathy and trigeminal neuralgia. Furthermore, we discuss the role of CYP450 enzymes involved in metabolism of drugs, which have been used for treatment of chronic pain (amitriptyline, duloxetine, opioids, etc.). We also discuss how pharmacogenetics can be applied towards improving drug efficacy, shortening the time required to achieve therapeutic outcomes, reducing risks of s...