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Pain and genes: Genetic contribution to pain variability, chronic pain and analgesic responses
European Journal of Pain Supplements 4 (2010) 197–201
Contents lists available at ScienceDirect
European Journal of Pain Supplements journal homepage: www.EuropeanJournalPain.com
Pain and genes: Genetic contribution to pain variability, chronic pain and analgesic responses Anette T. Møller ⇑, Troels S. Jensen Department of Neurology and Danish Pain Research Center, University Hospital of Aarhus, Denmark
a r t i c l e Keywords: Pain Genetics Experimental pain Analgesics
i n f o
a b s t r a c t Pain afflicts up to 20% of the population in the Western World and represents a challenge for clinicians and scientists because of a large interindividual variability in: (a) pain sensitivity, (b) in development of chronic pain and (c) in the response to analgesics. The personal and socioeconomic costs are considerable. The genetic approach to investigate pain has identified several potential areas of interest to understand genetic predisposition, the occurrence of pain and the variability of pain in human and in mice. In this paper, we will focus on genetic methods and variables influencing pain and pharmacotherapy elucidating the complexity of the area. Examples of promising candidate genes and allelic variables have been intensively studied and the number has been increasing during recent years with more or less reproducible results. Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
1. Introduction
2. Genetic studies in mouse and man
The perception of pain evoked as a result of external stimuli, tissue damage or disease is highly individual in humans as is the risk for development of chronic pain. Epidemiological investigations have shown a high and still increasing prevalence of chronic pain disorders. In the western community the prevalence is about 20% (Breivik et al., 2006). The processing of sensory information is influenced by the individual’s genetic predisposition, former experience with painful stimuli, physiological and psychological, social and cultural circumstances (Turk, 2002). In accordance with this, the International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. As pain is signaling actual or potential damage, the individual response to such damage is demonstrated by a change of behavior. Sometimes however, chronic pain develops and both in acute and chronic pain analgesics may be needed – the effect of which also display a large interindividual variability. The lack of predictability for the behavioral response to a noxious stimulus, for the development of chronic pain after injury and for the pain relief by analgesics has puzzled researchers and clinicians for decades. One potential joker in this game may be related to genetic variability.
A large numbers of publication during the last decade have added to the field of pain genetics. The genetic pain studies have mainly been carried out along three lines: (1) studies on pain perception following noxious stimulation, (2) the risk for development of pain and (3) the efficacy of analgesics in either humans or animals (primarily mice). These studies have provided insight into molecular mechanisms (voltage gated sodium and calcium channels, cytokine-receptors, neurotransmitters, metabolism, etc.) of pain and heritable pain conditions. Most often the molecular basis is found to be caused by variations in the genome (single nucleotide polymorphisms – SNP’s). SNP’s are DNA sequence variations occurring when a single nucleotide in the genome differs between members of a species or paired chromosomes in an individual. SNP’s may affect levels of transcription, splicing, stability and expression of RNA by altering the amino acid sequence, sometimes with functional consequences. Variations in the DNA sequences of humans can also affect how humans develop diseases and respond to drugs and are used by researchers for comparing regions of the genome between cohorts. Studies in mice have the advantage of the possibility for selective breeding, transgenic techniques (producing knockout mice), chemical mutagenesis and studying gene expression changes after neuropathic and inflammatory injuries applied to the animals. A database of so far 305 possible pain-relevant genes in mice have been established (LaCroix-Fralish et al., 2007). The current knowledge of pain genetics in human come from twin studies, association studies and coupling analysis. Twin
⇑ Corresponding author. Address: Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus, Denmark. Tel.: +4521745502. E-mail address: [email protected] (A.T. Møller).
1754-3207/$36.00 Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.eujps.2010.09.010
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A.T. Møller, T.S. Jensen / European Journal of Pain Supplements 4 (2010) 197–201
studies are epidemiological studies, by which it is possible to clarify whether genetic factors are involved in the presence or development of a trait. Using these techniques the genetic contribution in mice is between 30% and 60% depending on the pain modality applied (Mogil et al., 1999a,b) whereas in classical twin studies in humans approximately 60% of the variance in cold-pressor pain and 26% of the variance in heat pain sensitivity is genetically mediated (Nielsen et al., 2005, 2008). So far no major genetic contribution for pressure pain thresholds has been demonstrated (MacGregor et al., 1997). The interpretation of twin studies should be done with caution in particular when generalizing from one pain modality to another. The localization and identification of a relevant gene involved in a specific trait requires the use of linkage analysis and association studies. For linkage analysis large families with patients in several generations are needed. In association studies a known candidate gene is needed and furthermore a large patient group, with the risk of variation of a trait in different ethnic and geographic groups. A model for identification of relevant human candidate genes or polymorphisms based on three factors has been set (Belfer et al., 2004): (1) involvement in the pain process shown by research on animals or basic research. (2) Frequency of the allele and (3) likelihood that the polymorphism alters function (change of base, aminoacid, protein expression or change in quantity of mRNA). Variation in DNA sequences (SNP’s) in these candidate genes are possible the cause of some of the large interindividual variation in pain perception.
3. The genetics of experimental pain and pain perception The genetic influence on the reaction on experimental induced pain and pain thresholds is still largely unknown. Several studies have been published, but only a few have been replicated. Table 1 shows some of the correlations made between genes and experimental pain stimuli. The above mentioned methods are used to identify the genomic areas associated with variability in pain sensitivity, and the examination of single nucleotide polymorphisms (SNP)are used to determine the more precisely localization. One of the best examined genes are the catechol-O-methyltransferase (COMT)-gene. Studies have shown that catecholamines are involved in the processing of pain although the precise mechanism is still to be detected. COMT metabolize catecholamine and encephalin and therefore functions as a modulator for neurotransmission of pain. A high level of COMT give rise to a high level of enkephalin, an endogen opioid which activate and upregulate lopioid receptors centrally, hyperpolarizes cell membranes and reduces the transmission of signals. The polymorphism val158met in the COMT-gene changes the enzymatic activity of COMT. The gene has codominant alleles causing homozygotes for the rarer allele (met/met) to have at lower enzyme activity and consequently an increased sensory rating of pain in response to muscular infusion of hypertonic saline than heterozygote (met/val) and homozygote with the more frequent allele (val/val) (Diatchenko et al., 2005; Zubieta et al., 2003). The difference was also found on the level of receptors with PET scans showing that individuals with met/ met genotype had reduced l-opioid receptor activation in CNS involved in known modulation and processing of pain perception and fMRI showing a higher blood oxygen level dependent response in the anterior cingular cortex (Mobascher et al., 2010). Furthermore one haplotype (the specific sequence of four polymorphisms known in the gene) may be involved in thermal pain, temporal summation of thermal pain, ischemic pain and pressure pain due to the production of an enzyme-activity 11 times lower than the one produced by the haplotype associated with low pain reaction (Diatchenko et al., 2006).
Another well-studied gene is the opioid receptor delta 1 (OPRD1), especially focused on the gender specific difference in function. Certain diseases have a higher prevalence amongst women (migraine, fibromyalgia) and females have been found experimentally to have a lower pain threshold for pressure pain and electrical stimulation for review: (Fillingim et al., 2009). Polymorphisms in the gene encoding the l-opioid receptor OPRM1 has been linked to pressure pain sensitivity and, supporting the importance of the gene in pain perception, the OPRM1 has also been shown to affect pain-related cortical activity (Fillingim et al., 2005; Huang et al., 2008; Lotsch and Geisslinger, 2006). Furthermore the opioid analgesic requirements are affected by a polymorphism in this gene (Sia et al., 2008). Human reaction to pain stimuli, however, relies in part also on psychosocial and cultural environments making the interpretation of experimental pain studies difficult. Tegeder et al. (2008) provided strong evidence for the association of GCH1 coding for GTP cyclohydrolase in experimental and clinical pain states, involved in chronic lumbar root pain and identified a ‘‘pain protecting” haplotype. Another study indicated that GCH1 gene may affect the ratings of pain induced by capsaicin (Campbell et al., 2009). In mammals several sodium and calcium channels are known to affect the processing of noxious stimuli both in the peripheral and central nervous system. Mutations in genes encoding some of the voltage gated ion channels have been associated with changes in neuronal excitability and in causing specific diseases. The most extensively examined gene is SCN9A located on chromosome 2 and encoding the voltage gated sodium channel Nav1.7 (Dib-Hajj et al., 2007). Generally voltage gated sodium channels are activated by cooling. Recently the SCN10A encoding the voltage gated sodium channel Nav1.8 was found not to be activated by cooling, probably explaining the sensitization of nociceptors. Mutations in another voltage gated sodium channel Nav1.7 is responsible for three human pain disorders (Table 2). Mutations activating the gene cause severe episodic pain and primary erythromelalgia whereas mutations causing loss of function causes complete absence of pain (Reimann et al., 2010). 4. Genetic components in the development of chronic pain The susceptibility for development of chronic pain after a physical trauma varies. Studies indicate that the preoperative experimental pain response can predict the risk of persistent postoperative pain states. The associations have been shown for preoperative thermal threshold and pain following caesarian section, preoperative pressure pain threshold and the risk for development of phantom pain and preoperative cold pain tolerance and the development of pain after laparoscopic cholecystectomy (Edwards et al., 2005). Whether the polymorphism possibly involved in preoperative pain perception also play a role for the development of postoperative chronic pain, remains to be seen. 5. Genetic components in the etiology of diseases dominated by pain A number of clinical pain states have a clear heritable element as shown by pedigrees and twin studies. The genetic contribution to specific painful disorders have been investigated resulting in a calculated contribution between 35% and 68% investigating migraine, spinal pain, low back pain, neck pain in females and in fibromyalgia (Gervil et al., 1999; Hartvigsen et al., 2009; Honkasalo et al., 1995; MacGregor et al., 2004; Markkula et al., 2009).
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Table 1 Genetic studies where the relation between SNP’s, diseases and experimental pain has been investigated and where pain is the primary symptom. TMD, temporomandibular disorder; SLE, systemic lupus erythematosus; MS, multiple sclerosis; NIDDM, non-insulin-dependent diabetes mellitus; CRPS, complex regional pain syndrome. Gene
Encodes
Possible function
Reported disease association
Reported correlation to experimental pain
COMT
Catechol-Omethyltransferase
Enzymatic control of catecholamins
Fibromyagia
Pain sensitivity to hypertone saline injection
Schizophrenia TMD Opiod-use
Pressure pain Thermal pain and tolerance threshold Temporal summation of heat pain Ischemic pain and tolerance threshold Punctate mechanical stimuli Pressure pain
OPRM1
Opioid receptor l1
Receptor (exogene and endogene opioid)
OPRD1
Opioid receptor d1
Opioid receptor
IL-1b
Interleukin 1b
Proinflammatory
IL-1RA
Cytokine modulator
TNF
Proinflammatory
OIpioid and alcohol addiction and tolerance
Anorexia nervosa Opiod addiction Low back pain Burning mouth syndrome Vulvar vestibulit Morfin tolerance Parkinsons disease Arthritis BaselineCRP-concentrations Graves disease SLE Colitis ulcerosa Diabetic nephropathy MS progression Vulvar vestibulitis Neuropatic pain Malaria 8cerebral) Periodontitis Astma Juvenile rheumatoid arthritis NIDDM-development Intervertebral disc disease Pelvic pain syndrome Doparesponsive dystonia Low back pain Opioid analgesia
IL-6
IL-10 GCH1
GTP cyclohydrolase 1
MC1R SCN11A SCN9A
Melanocortin-1 receptor Nav1.9 Nav1.7
SCN10A
Nav1.8
SCN3A HLA-A, -B, -D
Nav1.3 Major histocompatibility complex
BH4 modifier
Erythormelalgia Acute paroxysmal pain (anden mutation) CIS (7,8,9 I wood)
Ischemic pain Heat pain Electrical pain Analgesic efficacy of opioids Heatpain thresholds Gender differnces Mechanical allodynia Hypersensitivity
Inflammatory pain
Pain threshold Peripheral pain (lower threshold of activation) Mechanoisensation
Nociceptive neuroner, cold pain Mechanosensation Postherpetic neuralgia CRPS
Table 2 Hereditable pain conditions, related genes, location and gene-product. Hereditable pain conditions
Gene
Protein
Phenotype
HSAN-1
SPTLC1 (9q22.1–q22.3) Unknown (3p24–p22) RAB7A (3q21) Unknown WNK1 (12p13.33) lkbKAP (9q31) NTRK1 (1q21–q22) SCN9A (2q24) SCN9A (2q24) SCN9A (2q24) CACNA1A (19p13) ATP1A2 (1q21–q23) SCNA1 (2q24)
Serine palmitoyltransferase Unknown Ras-related protein Rab-7a Unknown WNK lysine deficient protein kinase 1 Inhibitor of kappa light polypeptide gene enhancer NGF receptor TrkA Nav1.7 Nav1.7 Nav1.7 Calcium channel a-subunit Na+/K+-ATPase Sodium channel a-subunit coding
HSAN-1 A HSAN-1 B HSAN-1 C HSAN-1 D Loss of all sensation Pain free – familial dysautonomia CIS Cronic inflammation Mechanical induced pain Insenstitivit to acute pain FHM1 FHM2 FHM3
HSAN-2 HSAN-3 HSAN-4 Erythromelalgia Familial rectal pain Insensitivity to pain Familial hemiplegic migraine
CIS: congenital insensitivity to pain. HSAN: hereditary sensory and autonomic neuropathy.
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Only a few diseases have been identified with a clear genetic monogenic mode of inheritance (Table 2). These include hereditary sensory and autonomic neuropathies (HSAN1–4) with diminished pain sensation caused by mutation in four different genes. Even though probably more diseases with monogenic inheritance will be identified, most pain-related diseases probably will be multifactorial and the genetic component caused by genomic variations. Correlations between SNP’s and pain syndromes have been examined by association studies, but very few have been reproduced by independent groups, and some have shown contra dictionary results. 6. Genetics affecting analgesia Inadequately treated acute and chronic pain remains a major cause of suffering and dissatisfaction in pain therapy. The highly variable success of pharmacological pain treatment may be caused by the different genetic predisposition to develop pain and responding to analgesics (for review see (Foulkes and Wood, 2008). A range of genetic variations altering the effectiveness of analgesic drugs have been identified. Some genes are involved in the pharmacokinetics and thereby availability of drugs. The drugmetabolizing enzymes cytochrome P450 enzymes (CYP) and its subgroups area important because they are responsible for approximately 80% of phase 1 metabolism (metabolizing codeine (to morphine), NSAIDs, Tramadol, Oxycodone, Tricyclic antidepressants, methadone). Four phenotypes are described: the phenotypes of poor metabolizers, intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers the phenotype having impact on the efficiency of the drug and the adverse events (which are not always positive correlated with the efficiency). Other genes are involved in the pharmacodynamics of medicine and the interaction with the target structure (e.g., variations in PTGS may alter the COX1 and COX2 expression, variation in OPRM alter the expression and function of the primary binding site of opioids and variation in COMT may play a role in analgesia as well as in pain). Furthermore a negative correlation between nociceptive sensitivity and analgesic sensitivity both in mice and human have been identified, and it has been suggested that the genetic influence in this finding is in the efficacy of endogenous analgesic mechanisms rather than in the perception of the single stimulus (Edwards, 2005; Elmer et al., 1998; Gervil et al., 1999; Hartvigsen et al., 2009; Honkasalo et al., 1995; Wilson et al., 2003a,b). 7. Discussion In pain research linkage and association studies can be problematic and should be interpreted with caution because most pain conditions and the pain perception itself are polygenic and multifactorial disorders. It has been difficult to reproduce the results from association studies, and there are many pitfalls in the interpretation of these. The heterogeneity of the investigated groups are one of the major problem which may be the reason for the lack of reproducibility. Heterogeneity is difficult to deal with, as gender, age, temper and ethnicity have been shown to interact with polymorphisms in certain genes and may influence the experimental pain sensitivity. The sequencing of the human genome gives rise to a method (linkage disequilibrium mapping) a full genome scan where researchers take advantage of the fact that the genome is arranged in haploblocks (polymorphisms inherited together). The method is, however, costly. Pain genetics is complicated and research is difficult, time consuming and expensive. Increased knowledge of pain genes furthermore, like all genetic research, gives rise to ethical considerations. In genetic counseling, inherited pain syndromes can be
problematic because the phenotype (disease clinical presentation) depends on psychosocial factors along with the genetic. The future perspectives, screening patients for eventual relevant gene-status with the possibility of optimizing the treatment and prophylaxis, surgical as well as pharmacological will be the reward of such an effort. The large human and social-economical profit from evaluation the risk of a patient developing postoperative, neurogene or musculoskeletal pain is huge. The possibility of individualizing the information and the analgesic treatment lies ahead. The information that pain perception partly is genetically defined may reduce the social isolation and stigmata. The understanding of genetic factors influencing pain will thereby increase the quality of life for at large group of patients. Conflict of interest statement None declared. References Belfer I, Wu T, Kingman A, Krishnaraju RK, Goldman D, Max MB. Candidate gene studies of human pain mechanisms: methods for optimizing choice of polymorphisms and sample size. Anesthesiology 2004;100:1562–72. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006;10:287–333. Campbell CM, Edwards RR, Carmona C, Uhart M, Wand G, Carteret A, et al. Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain. Pain 2009;141:114–8. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005;14:135–43. Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I, Max MB, et al. Catechol-Omethyltransferase gene polymorphisms are associated with multiple painevoking stimuli. Pain 2006;125:216–24. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Na v 1. 7 and human pain disorders. Trends Neurosci 2007;30:555–63. Edwards RR. Individual differences in endogenous pain modulation as a risk factor for chronic pain. Neurology 2005;65:437–43. Edwards RR, Sarlani E, Wesselmann U, Fillingim RB. Quantitative assessment of experimental pain perception: multiple domains of clinical relevance. Pain 2005;114:315–9. Elmer GI, Pieper JO, Negus SS, Woods JH. Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests. Pain 1998;75:129–40. Fillingim RB, Kaplan L, Staud R, Ness TJ, Glover TL, Campbell CM, et al. The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J Pain 2005;6:159–67. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley III JL. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009;10:447–85. Foulkes T, Wood JN. Pain genes. PLoS Genet 2008;4:e1000086. Gervil M, Ulrich V, Kyvik KO, Olesen J, Russell MB. Migraine without aura: a population-based twin study. Ann Neurol 1999;46:606–11. Hartvigsen J, Nielsen J, Kyvik KO, Fejer R, Vach W, Iachine I, et al. Heritability of spinal pain and consequences of spinal pain: a comprehensive genetic epidemiologic analysis using a population-based sample of 15,328 twins ages 20–71 years. Arthritis Rheum 2009;61:1343–51. Honkasalo ML, Kaprio J, Winter T, Heikkila K, Sillanpaa M, Koskenvuo M. Migraine and concomitant symptoms among 8167 adult twin pairs. Headache 1995;35:70–8. Huang CJ, Liu HF, Su NY, Hsu YW, Yang CH, Chen CC, et al. Association between human opioid receptor genes polymorphisms and pressure pain sensitivity in females*. Anaesthesia 2008;63:1288–95. LaCroix-Fralish ML, Ledoux JB, Mogil JS. The pain genes database: an interactive web browser of pain-related transgenic knockout studies. Pain 2007;131:3–4. Lotsch J, Geisslinger G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J 2006;6:200–10. MacGregor AJ, Griffiths GO, Baker J, Spector TD. Determinants of pressure pain threshold in adult twins: evidence that shared environmental influences predominate. Pain 1997;73:253–7. MacGregor AJ, Andrew T, Sambrook PN, Spector TD. Structural, psychological, and genetic influences on low back and neck pain: a study of adult female twins. Arthritis Rheum 2004;51:160–7. Markkula R, Jarvinen P, Leino-Arjas P, Koskenvuo M, Kalso E, Kaprio J. Clustering of symptoms associated with fibromyalgia in a Finnish Twin Cohort. Eur J Pain 2009;13:744–50.
A.T. Møller, T.S. Jensen / European Journal of Pain Supplements 4 (2010) 197–201 Mobascher A, Brinkmeyer J, Thiele H, Toliat MR, Steffens M, Warbrick T, et al. The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation. Mol Pain 2010;6:32. Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P, et al. Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 1999a;80:67–82. Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P, et al. Heritability of nociception II. ‘Types’ of nociception revealed by genetic correlation analysis. Pain 1999b;80:83–93. Nielsen CS, Price DD, Vassend O, Stubhaug A, Harris JR. Characterizing individual differences in heat-pain sensitivity. Pain 2005;119:65–74. Nielsen CS, Stubhaug A, Price DD, Vassend O, Czajkowski N, Harris JR. Individual differences in pain sensitivity: genetic and environmental contributions. Pain 2008;136:21–9. Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA 2010;107:5148–53.
201
Sia AT, Lim Y, Lim EC, Goh RW, Law HY, Landau R, et al. A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 2008;109:520–6. Tegeder I, Adolph J, Schmidt H, Woolf CJ, Geisslinger G, Lotsch J. Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype. Eur J Pain 2008;12:1069–77. Turk DC. Remember the distinction between malignant and benign pain? Well, forget it. Clin J Pain 2002;18:75–6. Wilson SG, Bryant CD, Lariviere WR, Olsen MS, Giles BE, Chesler EJ, et al. The heritability of antinociception II: pharmacogenetic mediation of three over-thecounter analgesics in mice. J Pharmacol Exp Ther 2003a;305:755–64. Wilson SG, Smith SB, Chesler EJ, Melton KA, Haas JJ, Mitton B, et al. The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics. J Pharmacol Exp Ther 2003b;304:547–59. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003;299:1240–3.
Contents lists available at ScienceDirect
European Journal of Pain Supplements journal homepage: www.EuropeanJournalPain.com
Pain and genes: Genetic contribution to pain variability, chronic pain and analgesic responses Anette T. Møller ⇑, Troels S. Jensen Department of Neurology and Danish Pain Research Center, University Hospital of Aarhus, Denmark
a r t i c l e Keywords: Pain Genetics Experimental pain Analgesics
i n f o
a b s t r a c t Pain afflicts up to 20% of the population in the Western World and represents a challenge for clinicians and scientists because of a large interindividual variability in: (a) pain sensitivity, (b) in development of chronic pain and (c) in the response to analgesics. The personal and socioeconomic costs are considerable. The genetic approach to investigate pain has identified several potential areas of interest to understand genetic predisposition, the occurrence of pain and the variability of pain in human and in mice. In this paper, we will focus on genetic methods and variables influencing pain and pharmacotherapy elucidating the complexity of the area. Examples of promising candidate genes and allelic variables have been intensively studied and the number has been increasing during recent years with more or less reproducible results. Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
1. Introduction
2. Genetic studies in mouse and man
The perception of pain evoked as a result of external stimuli, tissue damage or disease is highly individual in humans as is the risk for development of chronic pain. Epidemiological investigations have shown a high and still increasing prevalence of chronic pain disorders. In the western community the prevalence is about 20% (Breivik et al., 2006). The processing of sensory information is influenced by the individual’s genetic predisposition, former experience with painful stimuli, physiological and psychological, social and cultural circumstances (Turk, 2002). In accordance with this, the International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. As pain is signaling actual or potential damage, the individual response to such damage is demonstrated by a change of behavior. Sometimes however, chronic pain develops and both in acute and chronic pain analgesics may be needed – the effect of which also display a large interindividual variability. The lack of predictability for the behavioral response to a noxious stimulus, for the development of chronic pain after injury and for the pain relief by analgesics has puzzled researchers and clinicians for decades. One potential joker in this game may be related to genetic variability.
A large numbers of publication during the last decade have added to the field of pain genetics. The genetic pain studies have mainly been carried out along three lines: (1) studies on pain perception following noxious stimulation, (2) the risk for development of pain and (3) the efficacy of analgesics in either humans or animals (primarily mice). These studies have provided insight into molecular mechanisms (voltage gated sodium and calcium channels, cytokine-receptors, neurotransmitters, metabolism, etc.) of pain and heritable pain conditions. Most often the molecular basis is found to be caused by variations in the genome (single nucleotide polymorphisms – SNP’s). SNP’s are DNA sequence variations occurring when a single nucleotide in the genome differs between members of a species or paired chromosomes in an individual. SNP’s may affect levels of transcription, splicing, stability and expression of RNA by altering the amino acid sequence, sometimes with functional consequences. Variations in the DNA sequences of humans can also affect how humans develop diseases and respond to drugs and are used by researchers for comparing regions of the genome between cohorts. Studies in mice have the advantage of the possibility for selective breeding, transgenic techniques (producing knockout mice), chemical mutagenesis and studying gene expression changes after neuropathic and inflammatory injuries applied to the animals. A database of so far 305 possible pain-relevant genes in mice have been established (LaCroix-Fralish et al., 2007). The current knowledge of pain genetics in human come from twin studies, association studies and coupling analysis. Twin
⇑ Corresponding author. Address: Department of Neurology and Danish Pain Research Center, Aarhus University Hospital, Nørrebrogade 44, 8000 Aarhus, Denmark. Tel.: +4521745502. E-mail address: [email protected] (A.T. Møller).
1754-3207/$36.00 Ó 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.eujps.2010.09.010
198
A.T. Møller, T.S. Jensen / European Journal of Pain Supplements 4 (2010) 197–201
studies are epidemiological studies, by which it is possible to clarify whether genetic factors are involved in the presence or development of a trait. Using these techniques the genetic contribution in mice is between 30% and 60% depending on the pain modality applied (Mogil et al., 1999a,b) whereas in classical twin studies in humans approximately 60% of the variance in cold-pressor pain and 26% of the variance in heat pain sensitivity is genetically mediated (Nielsen et al., 2005, 2008). So far no major genetic contribution for pressure pain thresholds has been demonstrated (MacGregor et al., 1997). The interpretation of twin studies should be done with caution in particular when generalizing from one pain modality to another. The localization and identification of a relevant gene involved in a specific trait requires the use of linkage analysis and association studies. For linkage analysis large families with patients in several generations are needed. In association studies a known candidate gene is needed and furthermore a large patient group, with the risk of variation of a trait in different ethnic and geographic groups. A model for identification of relevant human candidate genes or polymorphisms based on three factors has been set (Belfer et al., 2004): (1) involvement in the pain process shown by research on animals or basic research. (2) Frequency of the allele and (3) likelihood that the polymorphism alters function (change of base, aminoacid, protein expression or change in quantity of mRNA). Variation in DNA sequences (SNP’s) in these candidate genes are possible the cause of some of the large interindividual variation in pain perception.
3. The genetics of experimental pain and pain perception The genetic influence on the reaction on experimental induced pain and pain thresholds is still largely unknown. Several studies have been published, but only a few have been replicated. Table 1 shows some of the correlations made between genes and experimental pain stimuli. The above mentioned methods are used to identify the genomic areas associated with variability in pain sensitivity, and the examination of single nucleotide polymorphisms (SNP)are used to determine the more precisely localization. One of the best examined genes are the catechol-O-methyltransferase (COMT)-gene. Studies have shown that catecholamines are involved in the processing of pain although the precise mechanism is still to be detected. COMT metabolize catecholamine and encephalin and therefore functions as a modulator for neurotransmission of pain. A high level of COMT give rise to a high level of enkephalin, an endogen opioid which activate and upregulate lopioid receptors centrally, hyperpolarizes cell membranes and reduces the transmission of signals. The polymorphism val158met in the COMT-gene changes the enzymatic activity of COMT. The gene has codominant alleles causing homozygotes for the rarer allele (met/met) to have at lower enzyme activity and consequently an increased sensory rating of pain in response to muscular infusion of hypertonic saline than heterozygote (met/val) and homozygote with the more frequent allele (val/val) (Diatchenko et al., 2005; Zubieta et al., 2003). The difference was also found on the level of receptors with PET scans showing that individuals with met/ met genotype had reduced l-opioid receptor activation in CNS involved in known modulation and processing of pain perception and fMRI showing a higher blood oxygen level dependent response in the anterior cingular cortex (Mobascher et al., 2010). Furthermore one haplotype (the specific sequence of four polymorphisms known in the gene) may be involved in thermal pain, temporal summation of thermal pain, ischemic pain and pressure pain due to the production of an enzyme-activity 11 times lower than the one produced by the haplotype associated with low pain reaction (Diatchenko et al., 2006).
Another well-studied gene is the opioid receptor delta 1 (OPRD1), especially focused on the gender specific difference in function. Certain diseases have a higher prevalence amongst women (migraine, fibromyalgia) and females have been found experimentally to have a lower pain threshold for pressure pain and electrical stimulation for review: (Fillingim et al., 2009). Polymorphisms in the gene encoding the l-opioid receptor OPRM1 has been linked to pressure pain sensitivity and, supporting the importance of the gene in pain perception, the OPRM1 has also been shown to affect pain-related cortical activity (Fillingim et al., 2005; Huang et al., 2008; Lotsch and Geisslinger, 2006). Furthermore the opioid analgesic requirements are affected by a polymorphism in this gene (Sia et al., 2008). Human reaction to pain stimuli, however, relies in part also on psychosocial and cultural environments making the interpretation of experimental pain studies difficult. Tegeder et al. (2008) provided strong evidence for the association of GCH1 coding for GTP cyclohydrolase in experimental and clinical pain states, involved in chronic lumbar root pain and identified a ‘‘pain protecting” haplotype. Another study indicated that GCH1 gene may affect the ratings of pain induced by capsaicin (Campbell et al., 2009). In mammals several sodium and calcium channels are known to affect the processing of noxious stimuli both in the peripheral and central nervous system. Mutations in genes encoding some of the voltage gated ion channels have been associated with changes in neuronal excitability and in causing specific diseases. The most extensively examined gene is SCN9A located on chromosome 2 and encoding the voltage gated sodium channel Nav1.7 (Dib-Hajj et al., 2007). Generally voltage gated sodium channels are activated by cooling. Recently the SCN10A encoding the voltage gated sodium channel Nav1.8 was found not to be activated by cooling, probably explaining the sensitization of nociceptors. Mutations in another voltage gated sodium channel Nav1.7 is responsible for three human pain disorders (Table 2). Mutations activating the gene cause severe episodic pain and primary erythromelalgia whereas mutations causing loss of function causes complete absence of pain (Reimann et al., 2010). 4. Genetic components in the development of chronic pain The susceptibility for development of chronic pain after a physical trauma varies. Studies indicate that the preoperative experimental pain response can predict the risk of persistent postoperative pain states. The associations have been shown for preoperative thermal threshold and pain following caesarian section, preoperative pressure pain threshold and the risk for development of phantom pain and preoperative cold pain tolerance and the development of pain after laparoscopic cholecystectomy (Edwards et al., 2005). Whether the polymorphism possibly involved in preoperative pain perception also play a role for the development of postoperative chronic pain, remains to be seen. 5. Genetic components in the etiology of diseases dominated by pain A number of clinical pain states have a clear heritable element as shown by pedigrees and twin studies. The genetic contribution to specific painful disorders have been investigated resulting in a calculated contribution between 35% and 68% investigating migraine, spinal pain, low back pain, neck pain in females and in fibromyalgia (Gervil et al., 1999; Hartvigsen et al., 2009; Honkasalo et al., 1995; MacGregor et al., 2004; Markkula et al., 2009).
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Table 1 Genetic studies where the relation between SNP’s, diseases and experimental pain has been investigated and where pain is the primary symptom. TMD, temporomandibular disorder; SLE, systemic lupus erythematosus; MS, multiple sclerosis; NIDDM, non-insulin-dependent diabetes mellitus; CRPS, complex regional pain syndrome. Gene
Encodes
Possible function
Reported disease association
Reported correlation to experimental pain
COMT
Catechol-Omethyltransferase
Enzymatic control of catecholamins
Fibromyagia
Pain sensitivity to hypertone saline injection
Schizophrenia TMD Opiod-use
Pressure pain Thermal pain and tolerance threshold Temporal summation of heat pain Ischemic pain and tolerance threshold Punctate mechanical stimuli Pressure pain
OPRM1
Opioid receptor l1
Receptor (exogene and endogene opioid)
OPRD1
Opioid receptor d1
Opioid receptor
IL-1b
Interleukin 1b
Proinflammatory
IL-1RA
Cytokine modulator
TNF
Proinflammatory
OIpioid and alcohol addiction and tolerance
Anorexia nervosa Opiod addiction Low back pain Burning mouth syndrome Vulvar vestibulit Morfin tolerance Parkinsons disease Arthritis BaselineCRP-concentrations Graves disease SLE Colitis ulcerosa Diabetic nephropathy MS progression Vulvar vestibulitis Neuropatic pain Malaria 8cerebral) Periodontitis Astma Juvenile rheumatoid arthritis NIDDM-development Intervertebral disc disease Pelvic pain syndrome Doparesponsive dystonia Low back pain Opioid analgesia
IL-6
IL-10 GCH1
GTP cyclohydrolase 1
MC1R SCN11A SCN9A
Melanocortin-1 receptor Nav1.9 Nav1.7
SCN10A
Nav1.8
SCN3A HLA-A, -B, -D
Nav1.3 Major histocompatibility complex
BH4 modifier
Erythormelalgia Acute paroxysmal pain (anden mutation) CIS (7,8,9 I wood)
Ischemic pain Heat pain Electrical pain Analgesic efficacy of opioids Heatpain thresholds Gender differnces Mechanical allodynia Hypersensitivity
Inflammatory pain
Pain threshold Peripheral pain (lower threshold of activation) Mechanoisensation
Nociceptive neuroner, cold pain Mechanosensation Postherpetic neuralgia CRPS
Table 2 Hereditable pain conditions, related genes, location and gene-product. Hereditable pain conditions
Gene
Protein
Phenotype
HSAN-1
SPTLC1 (9q22.1–q22.3) Unknown (3p24–p22) RAB7A (3q21) Unknown WNK1 (12p13.33) lkbKAP (9q31) NTRK1 (1q21–q22) SCN9A (2q24) SCN9A (2q24) SCN9A (2q24) CACNA1A (19p13) ATP1A2 (1q21–q23) SCNA1 (2q24)
Serine palmitoyltransferase Unknown Ras-related protein Rab-7a Unknown WNK lysine deficient protein kinase 1 Inhibitor of kappa light polypeptide gene enhancer NGF receptor TrkA Nav1.7 Nav1.7 Nav1.7 Calcium channel a-subunit Na+/K+-ATPase Sodium channel a-subunit coding
HSAN-1 A HSAN-1 B HSAN-1 C HSAN-1 D Loss of all sensation Pain free – familial dysautonomia CIS Cronic inflammation Mechanical induced pain Insenstitivit to acute pain FHM1 FHM2 FHM3
HSAN-2 HSAN-3 HSAN-4 Erythromelalgia Familial rectal pain Insensitivity to pain Familial hemiplegic migraine
CIS: congenital insensitivity to pain. HSAN: hereditary sensory and autonomic neuropathy.
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Only a few diseases have been identified with a clear genetic monogenic mode of inheritance (Table 2). These include hereditary sensory and autonomic neuropathies (HSAN1–4) with diminished pain sensation caused by mutation in four different genes. Even though probably more diseases with monogenic inheritance will be identified, most pain-related diseases probably will be multifactorial and the genetic component caused by genomic variations. Correlations between SNP’s and pain syndromes have been examined by association studies, but very few have been reproduced by independent groups, and some have shown contra dictionary results. 6. Genetics affecting analgesia Inadequately treated acute and chronic pain remains a major cause of suffering and dissatisfaction in pain therapy. The highly variable success of pharmacological pain treatment may be caused by the different genetic predisposition to develop pain and responding to analgesics (for review see (Foulkes and Wood, 2008). A range of genetic variations altering the effectiveness of analgesic drugs have been identified. Some genes are involved in the pharmacokinetics and thereby availability of drugs. The drugmetabolizing enzymes cytochrome P450 enzymes (CYP) and its subgroups area important because they are responsible for approximately 80% of phase 1 metabolism (metabolizing codeine (to morphine), NSAIDs, Tramadol, Oxycodone, Tricyclic antidepressants, methadone). Four phenotypes are described: the phenotypes of poor metabolizers, intermediate metabolizers, extensive metabolizers and ultrarapid metabolizers the phenotype having impact on the efficiency of the drug and the adverse events (which are not always positive correlated with the efficiency). Other genes are involved in the pharmacodynamics of medicine and the interaction with the target structure (e.g., variations in PTGS may alter the COX1 and COX2 expression, variation in OPRM alter the expression and function of the primary binding site of opioids and variation in COMT may play a role in analgesia as well as in pain). Furthermore a negative correlation between nociceptive sensitivity and analgesic sensitivity both in mice and human have been identified, and it has been suggested that the genetic influence in this finding is in the efficacy of endogenous analgesic mechanisms rather than in the perception of the single stimulus (Edwards, 2005; Elmer et al., 1998; Gervil et al., 1999; Hartvigsen et al., 2009; Honkasalo et al., 1995; Wilson et al., 2003a,b). 7. Discussion In pain research linkage and association studies can be problematic and should be interpreted with caution because most pain conditions and the pain perception itself are polygenic and multifactorial disorders. It has been difficult to reproduce the results from association studies, and there are many pitfalls in the interpretation of these. The heterogeneity of the investigated groups are one of the major problem which may be the reason for the lack of reproducibility. Heterogeneity is difficult to deal with, as gender, age, temper and ethnicity have been shown to interact with polymorphisms in certain genes and may influence the experimental pain sensitivity. The sequencing of the human genome gives rise to a method (linkage disequilibrium mapping) a full genome scan where researchers take advantage of the fact that the genome is arranged in haploblocks (polymorphisms inherited together). The method is, however, costly. Pain genetics is complicated and research is difficult, time consuming and expensive. Increased knowledge of pain genes furthermore, like all genetic research, gives rise to ethical considerations. In genetic counseling, inherited pain syndromes can be
problematic because the phenotype (disease clinical presentation) depends on psychosocial factors along with the genetic. The future perspectives, screening patients for eventual relevant gene-status with the possibility of optimizing the treatment and prophylaxis, surgical as well as pharmacological will be the reward of such an effort. The large human and social-economical profit from evaluation the risk of a patient developing postoperative, neurogene or musculoskeletal pain is huge. The possibility of individualizing the information and the analgesic treatment lies ahead. The information that pain perception partly is genetically defined may reduce the social isolation and stigmata. The understanding of genetic factors influencing pain will thereby increase the quality of life for at large group of patients. Conflict of interest statement None declared. References Belfer I, Wu T, Kingman A, Krishnaraju RK, Goldman D, Max MB. Candidate gene studies of human pain mechanisms: methods for optimizing choice of polymorphisms and sample size. Anesthesiology 2004;100:1562–72. Breivik H, Collett B, Ventafridda V, Cohen R, Gallacher D. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain 2006;10:287–333. Campbell CM, Edwards RR, Carmona C, Uhart M, Wand G, Carteret A, et al. Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain. Pain 2009;141:114–8. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005;14:135–43. Diatchenko L, Nackley AG, Slade GD, Bhalang K, Belfer I, Max MB, et al. Catechol-Omethyltransferase gene polymorphisms are associated with multiple painevoking stimuli. Pain 2006;125:216–24. Dib-Hajj SD, Cummins TR, Black JA, Waxman SG. From genes to pain: Na v 1. 7 and human pain disorders. Trends Neurosci 2007;30:555–63. Edwards RR. Individual differences in endogenous pain modulation as a risk factor for chronic pain. Neurology 2005;65:437–43. Edwards RR, Sarlani E, Wesselmann U, Fillingim RB. Quantitative assessment of experimental pain perception: multiple domains of clinical relevance. Pain 2005;114:315–9. Elmer GI, Pieper JO, Negus SS, Woods JH. Genetic variance in nociception and its relationship to the potency of morphine-induced analgesia in thermal and chemical tests. Pain 1998;75:129–40. Fillingim RB, Kaplan L, Staud R, Ness TJ, Glover TL, Campbell CM, et al. The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J Pain 2005;6:159–67. Fillingim RB, King CD, Ribeiro-Dasilva MC, Rahim-Williams B, Riley III JL. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009;10:447–85. Foulkes T, Wood JN. Pain genes. PLoS Genet 2008;4:e1000086. Gervil M, Ulrich V, Kyvik KO, Olesen J, Russell MB. Migraine without aura: a population-based twin study. Ann Neurol 1999;46:606–11. Hartvigsen J, Nielsen J, Kyvik KO, Fejer R, Vach W, Iachine I, et al. Heritability of spinal pain and consequences of spinal pain: a comprehensive genetic epidemiologic analysis using a population-based sample of 15,328 twins ages 20–71 years. Arthritis Rheum 2009;61:1343–51. Honkasalo ML, Kaprio J, Winter T, Heikkila K, Sillanpaa M, Koskenvuo M. Migraine and concomitant symptoms among 8167 adult twin pairs. Headache 1995;35:70–8. Huang CJ, Liu HF, Su NY, Hsu YW, Yang CH, Chen CC, et al. Association between human opioid receptor genes polymorphisms and pressure pain sensitivity in females*. Anaesthesia 2008;63:1288–95. LaCroix-Fralish ML, Ledoux JB, Mogil JS. The pain genes database: an interactive web browser of pain-related transgenic knockout studies. Pain 2007;131:3–4. Lotsch J, Geisslinger G. Relevance of frequent mu-opioid receptor polymorphisms for opioid activity in healthy volunteers. Pharmacogenomics J 2006;6:200–10. MacGregor AJ, Griffiths GO, Baker J, Spector TD. Determinants of pressure pain threshold in adult twins: evidence that shared environmental influences predominate. Pain 1997;73:253–7. MacGregor AJ, Andrew T, Sambrook PN, Spector TD. Structural, psychological, and genetic influences on low back and neck pain: a study of adult female twins. Arthritis Rheum 2004;51:160–7. Markkula R, Jarvinen P, Leino-Arjas P, Koskenvuo M, Kalso E, Kaprio J. Clustering of symptoms associated with fibromyalgia in a Finnish Twin Cohort. Eur J Pain 2009;13:744–50.
A.T. Møller, T.S. Jensen / European Journal of Pain Supplements 4 (2010) 197–201 Mobascher A, Brinkmeyer J, Thiele H, Toliat MR, Steffens M, Warbrick T, et al. The val158met polymorphism of human catechol-O-methyltransferase (COMT) affects anterior cingulate cortex activation in response to painful laser stimulation. Mol Pain 2010;6:32. Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P, et al. Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception. Pain 1999a;80:67–82. Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P, et al. Heritability of nociception II. ‘Types’ of nociception revealed by genetic correlation analysis. Pain 1999b;80:83–93. Nielsen CS, Price DD, Vassend O, Stubhaug A, Harris JR. Characterizing individual differences in heat-pain sensitivity. Pain 2005;119:65–74. Nielsen CS, Stubhaug A, Price DD, Vassend O, Czajkowski N, Harris JR. Individual differences in pain sensitivity: genetic and environmental contributions. Pain 2008;136:21–9. Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, et al. Pain perception is altered by a nucleotide polymorphism in SCN9A. Proc Natl Acad Sci USA 2010;107:5148–53.
201
Sia AT, Lim Y, Lim EC, Goh RW, Law HY, Landau R, et al. A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology 2008;109:520–6. Tegeder I, Adolph J, Schmidt H, Woolf CJ, Geisslinger G, Lotsch J. Reduced hyperalgesia in homozygous carriers of a GTP cyclohydrolase 1 haplotype. Eur J Pain 2008;12:1069–77. Turk DC. Remember the distinction between malignant and benign pain? Well, forget it. Clin J Pain 2002;18:75–6. Wilson SG, Bryant CD, Lariviere WR, Olsen MS, Giles BE, Chesler EJ, et al. The heritability of antinociception II: pharmacogenetic mediation of three over-thecounter analgesics in mice. J Pharmacol Exp Ther 2003a;305:755–64. Wilson SG, Smith SB, Chesler EJ, Melton KA, Haas JJ, Mitton B, et al. The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics. J Pharmacol Exp Ther 2003b;304:547–59. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, et al. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science 2003;299:1240–3.