Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report that GTP cyclohydrolase (GCH1), the rate-limiting enzyme for tetrahydrobiopterin (BH4) synthesis, is a key modulator of peripheral neuropathic and inflammatory pain. BH4 is an essential cofactor for catecholamine, serotonin and nitric oxide production. After axonal injury, concentrations of BH4 rose in primary sensory neurons, owing to upregulation of GCH1. After peripheral inflammation, BH4 also increased in dorsal root ganglia (DRGs), owing to enhanced GCH1 enzyme activity. Inhibiting this de novo BH4 synthesis in rats attenuated neuropathic and inflammatory pain and prevented nerve injury-evoked excess nitric oxide production in the DRG, whereas administering BH4 intrathecally exacerbated pain. In humans, a haplotype of the GCH1 gene (population frequency 15.4%) was significantly associated with less pain following diskectomy for persistent radicular low back pain. Healthy individuals homozygous for this haplotype exhibited reduced experimental pain sensitivity, and forskolin-stimulated immortalized leukocytes from haplotype carriers upregulated GCH1 less than did controls. BH4 is therefore an intrinsic regulator of pain sensitivity and chronicity, and the GTP cyclohydrolase haplotype is a marker for these traits.
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PMID:GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence. 1708 89

Liability to spontaneous and experimental pain is genetically determined and there is considerable variability in the antinociceptive effects of drugs commonly used in treating pain conditions and migraine attacks. The causes for variability involve still unknown genetic aspects. Recently, a third gene, SCN1A, was discovered as a cause of familial hemiplegic migraine (FHM). Recent advances in the genetics of pain and pain disorders include the discovery of the role of the sodium ion channel SCN9A in neuropathic pain as well as in inability to experience pain, and of GTP cyclohydrolase (GCH1) in setting the sensitivity to pain in normal individuals and modulating liability to chronic pain. Catechol-O-methyltransferase (COMT) and the cytochrome P450 variant allele CYP3A5 modulate the genetic response to opioid medications in humans. Variability in drug pharmacokinetics and adverse drug reactions of pain medications are also very much related to genetic variation, especially in CYP genes. Pharmacogenomic studies of headache and pain are still in their infancy, but these recent advances in the genetics of migraine and pain arguably hold the promise of individualised treatments and prevention of adverse drug reactions.
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PMID:Recent advances in the pharmacogenomics of pain and headache. 1750 72

Though it is clear that genomic variability plays an integral role in accounting for pain sensitivity, controversy exists over which genes are involved. While recent data suggest a "protective" (i.e., less pain) haplotype in the GTP cyclohydrolase (GCH1) gene, other research has failed to confirm this association. Possibly, the effects of single nucleotide polymorphisms (SNPs) vary depending on the pain task. The current investigation analyzed the association of five previously identified GCH1 SNPs with ratings of pain induced by topical high concentration (10%) capsaicin applied to the skin of 39 healthy human volunteers. Each of the GCH1 polymorphisms was associated with lower pain ratings. When combined, three of the five accounted for a surprisingly high 35% of the inter-individual variance in pain ratings. We conclude that SNPs of the GCH1 gene may profoundly affect the ratings of pain induced by capsaicin.
Pain 2009 Jan
PMID:Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain. 1908 Nov 90

Chronic post-surgical pain is a common, under-recognized and important clinical problem which affects millions of patients worldwide. It results from a series of neuroplastic changes associated most commonly with peripheral nerve injury at the time of surgery. Predisposing factors include the type of surgery, pre-operative and acute post-operative pain intensity, and probably psychological (e.g. pain-catastrophizing) and genetic factors [e.g. GCH1 (GTP cyclohydrolase 1) haplotype]. Preventive measures which are currently available include selection of a minimally invasive surgical technique and an aggressive multimodal perioperative analgesic regimen. Very promising therapeutic agents which target the sensitization process are currently in development.
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PMID:When pain after surgery doesn't go away... 1914 55

Inadequately treated acute and chronic pain remains a major cause of suffering and dissatisfaction in pain therapy. A cause for the variable success of pharmacologic pain therapy is the different genetic disposition of patients to develop pain or to respond to analgesics. The patient's phenotype may be regarded as the result of synergistic or antagonistic effects of several genetic variants concomitantly present in an individual. Variants modulate the risk of developing painful disease or its clinical course (e.g., migraine, fibromyalgia, low back pain). Other variants modulate the perception of pain (e.g., OPRM1 or GCH1 variants conferring modest pain protection by increasing the tone of the endogenous opioid system or decreasing nitric oxide formation). Other polymorphisms alter pharmacokinetic mechanisms controlling the local availability of active analgesic molecules at their effector sites (e.g., decreased CYP2D6 related prodrug activation of codeine to morphine). In addition, genetic variants may alter pharmacodynamic mechanisms controlling the interaction of the analgesic molecules with their target structures (e.g., opioid receptor mutations). Finally, opioid dosage requirements may be increased depending on the risk of drug addiction (e.g., DRD2 polymorphisms decreasing the functioning of the dopaminergic reward system). With the complex nature of pain involving various mechanisms of nociception, drug action, drug pharmacology, pain disease and possibly substance addiction, a multigenic or even genome wide approach to genetics could be required to base individualized pain therapy on the patient's genotype.
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PMID:Genetic modulation of the pharmacological treatment of pain. 1961 6

Genetic risk factors for pain sensitivity may also play a role in susceptibility to chronic pain disorders, in which subjects have low pain thresholds. The aim of this study was to determine if proposed functional single nucleotide polymorphisms (SNPs) in the GTP cyclohydrolase (GCH1) and mu opioid receptor (OPRM1) genes previously associated with pain sensitivity affect susceptibility to chronic widespread pain (CWP). Pain data was collected using body manikins via questionnaire at three time-points over a four year period from subjects aged 25-65 in the North-West of England as part of a population based cohort study, EPIFUND. CWP was defined at each time point using standard criteria. Three SNPs forming a proposed "pain-protective" haplotype in GCH1 (rs10483639, rs3783641 and rs8007267) and two SNPs in OPRM1 (rs1777971 (A118G) and rs563649) were genotyped in cases with persistent CWP (CWP present at >or=2 time-points) and controls who were pain-free at all time-points. The expectation-maximisation algorithm was used to estimate haplotype frequencies. The frequency of the "pain-protective" (CAT - C allele of rs10483639, A allele of rs3783641 and T allele of rs8007267) haplotype was compared to the frequency of the other haplotypes between cases and controls using the chi2 test. Allele frequencies and carriage of the minor allele was compared between cases and controls using chi2 tests for the OPRM1 SNPs. The frequency of the proposed GCH1 "pain-protective" haplotype (CAT) did not significantly differ between cases and controls and no significant associations were observed between the OPRM1 SNPs and CWP. In conclusion, there was no evidence of association between proposed functional SNPs, previously reported to influence pain sensitivity, in GCH1 and OPRM1 with CWP. Further evidence of null association in large independent cohorts is required to truly exclude these SNPs as genetic risk factors for CWP.
Mol Pain 2009 Sep 23
PMID:Do genetic predictors of pain sensitivity associate with persistent widespread pain? 1977 52

The aftermath of sequencing the human genome has birthed many efforts to utilize an individual's genetic information in order to tailor optimal treatment strategies - so-called personalized medicine. An individual's genetic information may eventually help diagnosis and treatment, as well selecting optimal pharmacologic agents based partly on how well they reach their target, how well they will bind to and produce an effect at their targets, how well they will be metabolized, and the profile of their adverse effects. It also appears that clinicians may be able to utilize an individual's genetic information to ascertain a subject's risk or susceptibility of developing a particular medical condition. Although, this has not been widely utilized in pain medicine at this point, the future may revolutionize the role of genetic information in the evaluation and management of various pain conditions. One reason for variations in therapeutic outcomes from different pharmacologic pain treatments is the different genetic disposition of patient to develop pain or to respond to analgesics. The patient's phenotype may represent a conglomerate of several different genetic variants concomitantly present in an individual. Genetic variants may modulate the risk of developing a painful condition, or may modulate the perception of pain (e.g. OPRM1 or GCH1 variants conferring modest "protection" from pain by increasing the tone of the endogenous opioid system or decreasing nitric oxide formation). Other genetic polymorphisms may alter pharmacokinetic mechanisms (e.g. CYP2D6 related prodrug activation of codeine to morphine), alter pharmacodynamic mechanisms (e.g. opioid receptor mutations), or alter other analgesic effects (e.g. diminished euphoric effects from opioids potentially due to DRD2 polymorphisms decreasing the functioning of the dopaminergic reward system). This article theorizes that genetic alterations including functional polymorphisms of Nrf2 (a master regulator of the transcription of multiple antioxidants) may render certain subjects more or less susceptible to developing complex regional pain syndrome after surgery or trauma. If this hypothesis is correct, knowing this information may translate into significant and "far-reaching" effects on clinical decision-making surrounding the management of pain in patients who may be more susceptible to develop complex regional pain syndrome. Furthermore, it could lead to the development of novel prevention or intervention strategies, in efforts to prevent, abort, or ameliorate the development of and/or effectively treat complex regional pain syndrome.
Pain Physician
PMID:The role of genomic oxidative-reductive balance as predictor of complex regional pain syndrome development: a novel theory. 2011 66

Cancer pain patients need variable opioid doses. Preclinical and clinical studies suggest that opioid efficacy is related to genetic variability. However, the studies have small samples, findings are not replicated, and several candidate genes have not been studied. Therefore, a study of genetic variability with opioid doses in a large population using a confirmatory validation population was warranted. We recruited 2294 adult European patients using a World Health Organization (WHO) step III opioid and analyzed single nucleotide polymorphisms (SNPs) in genes with a putative influence on opioid mechanisms. The patients' mean age was 62.5 years, and the average pain intensity was 3.5. The patients' primary opioids were morphine (n=830), oxycodone (n=446), fentanyl (n=699), or other opioids (n=234). Pain intensity, time on opioids, age, gender, performance status, and bone or CNS metastases predicted opioid dose and were included as covariates. The patients were randomly divided into 1 development sample and 1 validation sample. None of 112 SNPs in the 25 candidate genes OPRM1, OPRD1, OPRK1, ARRB2, GNAZ, HINT1, Stat6, ABCB1, COMT, HRH1, ADRA2A, MC1R, TACR1, GCH1, DRD2, DRD3, HTR3A, HTR3B, HTR2A, HTR3C, HTR3D, HTR3E, HTR1, or CNR1 showed significant associations with opioid dose in both the development and the validation analyzes. These findings do not support the use of pharmacogenetic analyses for the assessed SNPs to guide opioid treatment. The study also demonstrates the importance of validating findings obtained in genetic association studies to avoid reporting spurious associations as valid findings. To elicit knowledge about new genes that influence pain and the need for opioids, strategies other than the candidate gene approach is needed.
Pain 2011 May
PMID:Influence from genetic variability on opioid use for cancer pain: a European genetic association study of 2294 cancer pain patients. 2139 39

Sickle cell disease (SCD) is a chronic illness, and the major complication, pain, results in complex multidimensional problems that affect an individual's ability to maintain adequate quality of life in multiple areas. Chronic SCD pain is inadequately treated, because it is not well understood, and the degree of chronic pain, clinical presentation, and sequela complications can vary from patient to patient, even among individuals with the same SCD genotype. The reason for this variation is unknown, but the underlying cause might be genetic. Researchers have not explored the contribution of a genomic variable to the occurrence of heterogeneous chronic SCD pain. Previous research on the guanosine triphosphate cyclohydrolase (GCH1) gene suggests that in some cases, phenotypic heterogeneity in human sensitivity to pain correlates with underlying genotypic variations in the GCH1 gene. These findings imply that genotypic variations might also explain why some SCD patients experience more chronic pain than others.
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PMID:Genomics and pain research in sickle cell disease: an explanation of heterogeneity? 2180 43

Noncoding polymorphisms of the GTP cyclohydrolase gene (GCH1) reduce the risk for chronic pain in humans suggesting GCH1 inhibitors as analgesics. We assessed the effects of the GCH1 inhibitor diaminohydroxypyrimidine (DAHP) on nociception and inflammation in a mouse melanoma and a sarcoma cancer pain model, and its co-effects with morphine in terms of analgesic efficacy and respiratory depression. GCH1 inhibition did not reduce the tumor-evoked nociceptive hypersensitivity of the tumor-bearing paw. However, DAHP reduced melanoma- and sarcoma-evoked systemic hyperalgesia as determined by analyzing contralateral paws. GCH1 inhibition increased the inflammatory edema and infiltration with polymorphonuclear leukocytes surrounding the tumor but reduced the tumor-evoked microglia activation in the spinal cord suggesting that an increase of the local immune attack against the tumor may avoid general pain hypersensitivity. When used in combination with morphine at high or low doses, GCH1 inhibition increased and prolonged the analgesic effects of the opioid. It did not, however, increase the respiratory depression caused by morphine. Conversely, the GCH1-product, tetrahydrobiopterin, caused hyperalgesia, antagonized antinociceptive effects of morphine, and aggravated morphine-evoked respiratory depression, the latter mimicked by a cGMP analog suggesting that respiratory effects were partly mediated through the BH4-NO-cGMP pathway. The observed effects of GCH1 inhibition in the tumor model and its enhancement of morphine-evoked antinociception without increase of morphine toxicity suggest that GCH1 inhibitors might be useful as co-therapeutics for opioids in cancer patients.
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PMID:Inhibition of GTP cyclohydrolase reduces cancer pain in mice and enhances analgesic effects of morphine. 2270


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