Humans are very different when it comes to pain. Some get painful piercings and tattoos; others can not stand even a flu shot. Interindividual variability is one of the main characteristics of human pain on every level including the processing of nociceptive impulses at the periphery, modification of pain signal in the central nervous system, perception of pain, and response to analgesic strategies. As for many other complex behaviors, the sources of this variability come from both nurture (environment) and nature (genes). Here, I will discuss how these factors contribute to human pain separately and via interplay and how epigenetic mechanisms add to the complexity of their effects. “Pain is inevitable. Suffering is optional.” (Zen Aphorism) 1. Nurture and Pain Pain perception (meaning not just physiological processing of nociceptive signal but rather conscious recognition and awareness of painful stimulus) can be modulated and modified (enhanced or abolished) by many “environmental” factors including psychological and personality-related factors such as previous pain experiences, emotionality and cognition, somatization and catastrophizing, presence of acute and chronic stressful life events, fatigue, anxiety, fear, boredom and anticipation of more pain, as well as socioeconomic factors (e.g., social support, acceptance, incentives, education, occupation and quality of life). In addition, pain behavior is different among genders and ethnicities, and varies with age. In addition, some clinical and medical factors correlate with risk for increased severity or chronicity of many painful conditions. 1.1. Cultural Factors The experience of pain is one of the fundamental human senses and most ancient protective survival skills. However, the ways in which people express and treat pain change across time and origin and are influenced by cultural and social factors [1–4]. Although there are similarities in word descriptors among cultural groups, with the word “pain” characterizing the most intense and unpleasant discomfort, the word “hurt” characterizing less severe discomfort, and “ache” describing minimal and bearable pain [5], cross-cultural differences in the copying styles and attitudes towards pain medication have been also noticed [6]. It has been suggested that “people in Eastern cultures have higher pain tolerance than those in the West” [7, 8]. This assumption is partly caused by the fact that painful rituals and ceremonials are widely accepted in Africa, India, and Middle East, and they may reflect overall pain behavior as turning inward, private and
References
[1]
M. S. Bates, “Ethnicity and pain: a biocultural model,” Social Science and Medicine, vol. 24, no. 1, pp. 47–50, 1987.
[2]
L. Montes-Sandoval, “An analysis of the concept of pain,” Journal of Advanced Nursing, vol. 29, no. 4, pp. 935–941, 1999.
[3]
G. B. Rollman, “Culture and pain,” in Cultural Clinical Psychology: Theory, Research, and Practice, S. S. Kazarian and D. R. Evans, Eds., pp. 267–286, Oxford University Press, New York, NY, USA, 1998.
[4]
J. Streltzer, “Pain,” in Culture and Psychopathology, W. S. Tseng and J. Streltzer, Eds., pp. 87–100, Brunner/Mazel, New York, NY, USA, 1997.
[5]
F. Gaston-Johansson, M. Albert, E. Fagan, and L. Zimmerman, “Similarities in pain descriptions of four different ethnic-culture groups,” Journal of Pain and Symptom Management, vol. 5, no. 2, pp. 94–100, 1990.
[6]
R. Moore and I. Brodsgaard, “Cross-cultural investigations of pain,” in Task Force on Epidemiology of the International Association for the Study of Pain, pp. 53–80, International Association for the Study of Pain Press, Seattle, Wash, USA, 1999.
[7]
S. Nayak, S. C. Shiflett, S. Eshun, and F. M. Levine, “Culture and gender effects in pain beliefs and the prediction of pain tolerance,” Cross-Cultural Research, vol. 34, no. 2, pp. 135–151, 2000.
[8]
I. Khalaf and L. C. Callister, “Cultural meanings of childbirth: muslim women living in Jordan,” Journal of Holistic Nursing, vol. 15, no. 4, pp. 373–388, 1997.
[9]
L. C. Callister, “Cultural influences on pain perceptions and behaviors,” Home Health Care Management & Practice, vol. 15, no. 3, pp. 207–211, 2003.
[10]
D. C. Turk, Ed., Psychological Approaches to Pain Management: A Practitioner's Handbook, Guilford Press, New York, NY, USA, 1996.
[11]
D. F. Zatzick and J. E. Dimsdale, “Cultural variations in response to painful stimuli,” Psychosomatic Medicine, vol. 52, no. 5, pp. 544–557, 1990.
[12]
W. P. Chapman and C. M. Jones, “Variations in cutaneous and visceral pain sensitivity in normal subjects,” The Journal of Clinical Investigation, vol. 23, no. 1, pp. 81–91, 1944.
[13]
R. R. Edwards and R. B. Fillingim, “Ethnic differences in thermal pain responses,” Psychosomatic Medicine, vol. 61, pp. 346–354, 1999.
[14]
D. Sheffield, P. L. Biles, H. Orom, W. Maixner, and D. S. Sheps, “Race and sex differences in cutaneous pain perception,” Psychosomatic Medicine, vol. 62, no. 4, pp. 517–523, 2000.
[15]
N. E. Walsh, L. Schoenfeld, S. Ramamurthy, and J. Hoffman, “Normative model for cold pressor test,” American Journal of Physical Medicine and Rehabilitation, vol. 68, no. 1, pp. 6–11, 1989.
[16]
K. M. Woodrow, G. D. Friedman, A. B. Siegelaub, and M. F. Collen, “Pain tolerance: differences according to age, sex and race,” Psychosomatic Medicine, vol. 34, no. 6, pp. 548–556, 1972.
[17]
R. R. Edwards, D. M. Doleys, R. B. Fillingim, and D. Lowery, “Ethnic differences in pain tolerance: clinical implications in a chronic pain population,” Psychosomatic Medicine, vol. 63, no. 2, pp. 316–323, 2001.
[18]
J. Faucett, N. Gordon, and J. Levine, “Differences in postoperative pain severity among four ethnic groups,” Journal of Pain and Symptom Management, vol. 9, no. 6, pp. 383–389, 1994.
[19]
S. F. White, M. A. Asher, S. M. Lai, and D. C. Burton, “Patients' perceptions of overall function, pain, and appearance after primary posterior instrumentation and fusion for idiopathic scoliosis,” Spine, vol. 24, no. 16, pp. 1693–1700, 1999.
[20]
D. Sheffield, D. S. Kirby, P. L. Biles, and D. S. Sheps, “Comparison of perception of angina pectoris during exercise testing in African-Americans versus caucasians,” American Journal of Cardiology, vol. 83, no. 1, pp. 106–108, 1999.
[21]
W. Breitbart, M. V. McDonald, B. Rosenfeld et al., “Pain in ambulatory AIDS patients. I: pain characteristics and medical correlates,” Pain, vol. 68, no. 2-3, pp. 315–321, 1996.
[22]
M. B. Sherwood, A. Garcia-Siekavizza, M. I. Meltzer, A. Hebert, A. F. Burns, and S. McGorray, “Glaucoma's impact on quality of life and its relation to clinical indicators: a pilot study,” Ophthalmology, vol. 105, no. 3, pp. 561–566, 1998.
[23]
P. Creamer, M. Lethbridge-Cejku, and M. C. Hochberg, “Determinants of pain severity in knee osteoarthritis: effect of demographic and psychosocial variables using 3 pain measures,” Journal of Rheumatology, vol. 26, no. 8, pp. 1785–1792, 1999.
[24]
A. J. Selim, G. Fincke, X. S. Ren et al., “Racial differences in the use of lumbar spine radiographs: results from the veterans health study,” Spine, vol. 26, no. 12, pp. 1364–1369, 2001.
[25]
C. L. Edwards, R. B. Fillingim, and F. Keefe, “Race, ethnicity and pain,” Pain, vol. 94, no. 2, pp. 133–137, 2001.
[26]
K. H. Todd, C. Deaton, A. P. D'Adamo, and L. Goe, “Ethnicity and analgesic practice,” Annals of Emergency Medicine, vol. 35, no. 1, pp. 11–16, 2000.
[27]
R. Clark, N. B. Anderson, V. R. Clark, and D. R. Williams, “Racism as a Stressor for African Americans: a biopsychosocial model,” American Psychologist, vol. 54, no. 10, pp. 805–816, 1999.
[28]
M. D. McNeilly, E. L. Robinson, N. B. Anderson et al., “Effects of racist provocation and social support on cardiovascular reactivity in african american women,” International Journal of Behavioral Medicine, vol. 2, no. 4, pp. 321–338, 1995.
[29]
S. A. James, S. A. Hartnett, and W. D. Kalsbeek, “John henryism and blood pressure differences among black men,” Journal of Behavioral Medicine, vol. 6, no. 3, pp. 259–278, 1983.
[30]
M. S. Bates, Biocultural Dimensions of Chronic Pain: Implications for Treatment of Multiethnic Populations, State University of New York Press, New York, NY, USA, 1996.
[31]
F. M. Levine and L. L. de Simone, “The effects of experimenter gender on pain report in male and female subjects,” Pain, vol. 44, no. 1, pp. 69–72, 1991.
[32]
I. Kállai, A. Barke, and U. Voss, “The effects of experimenter characteristics on pain reports in women and men,” Pain, vol. 112, no. 1-2, pp. 142–147, 2004.
[33]
D. Ruau, L. Y. Liu, J. D. Clark, M. S. Angst, and A. J. Butte, “Sex differences in reported pain across 11,000 patients captured in electronic medical records,” Journal of Pain, vol. 13, no. 3, pp. 228–234, 2012.
[34]
G. B. Rollman and S. Lautenbacher, “Sex differences in musculoskeletal pain,” Clinical Journal of Pain, vol. 17, no. 1, pp. 20–24, 2001.
[35]
R. B. Fillingim and W. Maixner, “Gender differences in the responses to noxious stimuli,” Pain Forum, vol. 4, no. 4, pp. 209–221, 1995.
[36]
J. L. Riley III, M. E. Robinson, E. A. Wise, C. D. Myers, and R. B. Fillingim, “Sex differences in the perception of noxious experimental stimuli: a meta-analysis,” Pain, vol. 74, no. 2-3, pp. 181–187, 1998.
[37]
R. B. Fillingim, C. D. King, M. C. Ribeiro-Dasilva, B. Rahim-Williams, and J. L. Riley III, “Sex, gender, and pain: a review of recent clinical and experimental findings,” Journal of Pain, vol. 10, no. 5, pp. 447–485, 2009.
[38]
R. B. Fillingim, M. R. Wallace, D. M. Herbstman, M. Ribeiro-Dasilva, and R. Staud, “Genetic contributions to pain: a review of findings in humans,” Oral Diseases, vol. 14, no. 8, pp. 673–682, 2008.
[39]
I. Lund and T. Lundeberg, “Is it all about sex? Acupuncture for the treatment of pain from a biological and gender perspective,” Acupuncture in Medicine, vol. 26, no. 1, pp. 33–45, 2008.
[40]
R. B. Fillingim, “Sex differences in analgesic responses: evidence from experimental pain models,” European Journal of Anaesthesiology, Supplement, vol. 19, no. 26, pp. 16–24, 2002.
[41]
O. A. Alabas, O. A. Tashani, G. Tabasam, and M. I. Johnson, “Gender role affects experimental pain responses: a systematic review with meta-analysis,” European Journal of Pain, vol. 16, no. 9, pp. 1211–1223, 2012.
[42]
R. M. Craft, J. S. Mogil, and A. Maria Aloisi, “Sex differences in pain and analgesia: the role of gonadal hormones,” European Journal of Pain, vol. 8, no. 5, pp. 397–411, 2004.
[43]
A. M. Aloisi and M. Bonifazi, “Sex hormones, central nervous system and pain,” Hormones and Behavior, vol. 50, no. 1, pp. 1–7, 2006.
[44]
C. A. Niven and T. Murphy-Black, “Memory for labor pain: a review of the literature,” Birth, vol. 27, pp. 244–253, 2000.
[45]
J. K. Zubieta, Y. R. Smith, J. A. Bueller et al., “μ-opioid receptor-mediated antinociceptive responses differ in men and women,” Journal of Neuroscience, vol. 22, no. 12, pp. 5100–5107, 2002.
[46]
J. A. McRoberts, J. Li, H. S. Ennes, and E. A. Mayer, “Sex-dependent differences in the activity and modulation of N-methyl-d-aspartic acid receptors in rat dorsal root ganglia neurons,” Neuroscience, vol. 148, no. 4, pp. 1015–1020, 2007.
[47]
C. D. Myers, J. L. Riley III, and M. E. Robinson, “Psychosocial contributions to sex-correlated differences in pain,” Clinical Journal of Pain, vol. 19, no. 4, pp. 225–232, 2003.
[48]
C. Miller and S. E. Newton, “Pain perception and expression: the influence of gender, personal self-efficacy, and lifespan socialization,” Pain Management Nursing, vol. 7, no. 4, pp. 148–152, 2006.
[49]
M. E. Robinson, J. L. Riley III, and C. D. Myers, “Psychosocial contributions to sex-related differences in pain responses,” in Sex, Gender, and Pain, R. B. Fillingim, Ed., pp. 41–68, IASP Press, Seattle, Wash, USA, 2000.
[50]
S. J. Gibson and R. D. Helme, “Age-related differences in pain perception and report,” Clinics in Geriatric Medicine, vol. 17, no. 3, pp. 433–456, 2001.
[51]
A. R. Moore and D. Clinch, “Underlying mechanisms of impaired visceral pain perception in older people,” Journal of the American Geriatrics Society, vol. 52, no. 1, pp. 132–136, 2004.
[52]
K. Fecho, N. R. Miller, S. A. Merritt, N. Klauber-Demore, C. S. Hultman, and W. S. Blau, “Acute and persistent postoperative pain after breast surgery,” Pain Medicine, vol. 10, no. 4, pp. 708–715, 2009.
[53]
E. Alves Nogueira Fabro, A. Bergmann, B. do Amaral e Silva et al., “Post-mastectomy pain syndrome: incidence and risks,” Breast, vol. 21, no. 3, pp. 321–325, 2012.
[54]
U. Jakobsson, R. Klevsg？rd, A. Westergren, and I. R. Hallberg, “Old people in pain: a comparative study,” Journal of Pain and Symptom Management, vol. 26, no. 1, pp. 625–636, 2003.
[55]
C. Miaskowski, “The impact of age on a patient's perception of pain and ways it can be managed,” Pain Management Nursing, vol. 1, supplement 1, no. 3, pp. 2–7, 2000.
[56]
A. D. Kaye, A. Baluch, and J. T. Scott, “Pain management in the elderly population: a review,” Ochsner Journal, vol. 10, no. 3, pp. 179–187, 2010.
[57]
M. Hanks-Bell, K. Halvey, and J. A. Paice, “Pain assessment and management in aging,” Online Journal of Issues in Nursing, vol. 9, no. 3, article 8, 2004.
[58]
W. Pentland, M. McColl, and C. Rosenthal, “The effect of aging and duration of disability on long term health outcomes following spinal cord injury,” Paraplegia, vol. 33, no. 7, pp. 367–373, 1995.
[59]
K. F. Koltyn, “Analgesia following exercise: a review,” Sports Medicine, vol. 29, no. 2, pp. 85–98, 2000.
[60]
C. A. Ray and J. R. Carter, “Central modulation of exercise-induced muscle pain in humans,” Journal of Physiology, vol. 585, no. 1, pp. 287–294, 2007.
[61]
J. Nijs, E. Kosek, J. van Oosterwijck, and M. Meeus, “Dysfunctional endogenous analgesia during exercise in patients with chronic pain: to exercise or not to exercise?” Pain Physician, vol. 15, supplement 3, pp. ES205–ES213, 2012.
[62]
L. Brosseau, G. A. Wells, P. Tugwell et al., “Ottawa panel evidence-based clinical practice guidelines for aerobic fitness exercises in the management of fibromyalgia: part 1,” Physical Therapy, vol. 88, no. 7, pp. 857–871, 2008.
[63]
M. J. Stewart, C. G. Maher, K. M. Refshauge, R. D. Herbert, N. Bogduk, and M. Nicholas, “Randomized controlled trial of exercise for chronic whiplash-associated disorders,” Pain, vol. 128, no. 1-2, pp. 59–68, 2007.
[64]
M. J. Jansen, W. Viechtbauer, A. F. Lenssen, E. J. M. Hendriks, and A. A. de Bie Rob, “Strength training alone, exercise therapy alone, and exercise therapy with passive manual mobilisation each reduce pain and disability in people with knee osteoarthritis: a systematic review,” Journal of Physiotherapy, vol. 57, no. 1, pp. 11–20, 2011.
[65]
M. van Middelkoop, S. M. Rubinstein, A. P. Verhagen, R. W. Ostelo, B. W. Koes, and M. W. van Tulder, “Exercise therapy for chronic nonspecific low-back pain,” Best Practice and Research: Clinical Rheumatology, vol. 24, no. 2, pp. 193–204, 2010.
[66]
Y. Shi, T. N. Weingarten, C. B. Mantilla, W. M. Hooten, and D. O. Warner, “Smoking and pain: pathophysiology and clinical implications,” Anesthesiology, vol. 113, no. 4, pp. 977–992, 2010.
[67]
R. B. Kanarek and C. Carrington, “Sucrose consumption enhances the analgesic effects of cigarette smoking in male and female smokers,” Psychopharmacology, vol. 173, no. 1, pp. 57–63, 2004.
[68]
K. A. Perkins, J. E. Grobe, R. L. Stiller et al., “Effects of nicotine on thermal pain detection in humans,” Experimental and Clinical Psychopharmacology, vol. 2, no. 1, pp. 95–106, 1994.
[69]
K. M. Woodrow and L. G. Eltherington, “Feeling no pain: alcohol as an analgesic,” Pain, vol. 32, no. 2, pp. 159–163, 1988.
[70]
H. I. Andersson, G. Ejlertsson, and I. Leden, “Widespread musculoskeletal chronic pain associated with smoking. An epidemiological study in a general rural population,” Scandinavian Journal of Rehabilitation Medicine, vol. 30, no. 3, pp. 185–191, 1998.
[71]
P. H. Ferreira, M. B. Pinheiro, G. C. Machado, and M. L. Ferreira, “Is alcohol intake associated with low back pain? A systematic review of observational studies,” Manual Therapy, 2012.
[72]
U. John, M. Hanke, C. Meyer, H. V？lzke, S. E. Baumeister, and D. Alte, “Tobacco smoking in relation to pain in a national general population survey,” Preventive Medicine, vol. 43, pp. 477–481, 2006.
[73]
K. B. Thelin Bronner, P. Wennberg, H. K？llmén, and M. L. Schult, “Alcohol habits in patients with long-term musculoskeletal pain: comparison with a matched control group from the general population,” International Journal of Rehabilitation Research, vol. 35, no. 2, pp. 130–137, 2012.
[74]
L. Hestbaek, C. Leboeuf-Yde, and K. O. Kyvik, “Are lifestyle-factors in adolescence predictors for adult low back pain? A cross-sectional and prospective study of young twins,” BMC Musculoskeletal Disorders, vol. 7, article 27, 2006.
[75]
M. J. L. Sullivan, B. Thorn, J. A. Haythornthwaite et al., “Theoretical perspectives on the relation between catastrophizing and pain,” Clinical Journal of Pain, vol. 17, no. 1, pp. 52–64, 2001.
[76]
R. R. Edwards, G. Mensing, C. Cahalan et al., “Alteration in pain modulation in women with persistent pain after lumpectomy: influence of catastrophizing,” Journal of Pain and Symptom Management, 2012.
[77]
H. ？. Sertel Berk, “The biopsychosocial factors that serve as predictors of the outcome of surgical modalities for chronic pain,” Agri, vol. 22, no. 3, pp. 93–97, 2010.
[78]
D. A. Fishbain, J. E. Lewis, J. Gao, B. Cole, and R. Steele Rosomoff, “Is chronic pain associated with somatization/hypochondriasis? An evidence-based structured review,” Pain Practice, vol. 9, no. 6, pp. 449–467, 2009.
[79]
G. D. Slade, L. Diatchenko, K. Bhalang et al., “Influence of psychological factors on risk of temporomandibular disorders,” Journal of Dental Research, vol. 86, no. 11, pp. 1120–1125, 2007.
[80]
K. L. Schreiber, M. O. Martel, H. Shnol et al., “Persistent pain in postmastectomy patients: comparison of psychophysical, medical, surgical, and psychosocial characteristics between patients with and without pain,” Pain, 2012.
[81]
M. T. Smith and J. A. Haythornthwaite, “How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature,” Sleep Medicine Reviews, vol. 8, no. 2, pp. 119–132, 2004.
[82]
R. R. Edwards, D. M. Almeida, B. Klick, J. A. Haythornthwaite, and M. T. Smith, “Duration of sleep contributes to next-day pain report in the general population,” Pain, vol. 137, no. 1, pp. 202–207, 2008.
[83]
M. T. Smith, E. M. Wickwire, E. G. Grace et al., “Sleep disorders and their association with laboratory pain sensitivity in temporomandibular joint disorder,” Sleep, vol. 32, no. 6, pp. 779–790, 2009.
[84]
Y. C. Lee, B. Lu, R. R. Edwards et al., “The role of sleep problems in central pain processing in rheumatoid arthritis,” Arthritis & Rheumatism, vol. 65, no. 1, pp. 59–68, 2013.
[85]
L. F. Buenaver, P. J. Quartana, E. G. Grace et al., “Evidence for indirect effects of pain catastrophizing on clinical pain among myofascial temporomandibular disorder participants: the mediating role of sleep disturbance,” Pain, vol. 153, no. 6, pp. 1159–1166, 2012.
[86]
MTUS, “Chronic Pain Medical Treatment Guidelines,” pp. 1–127, 2009.
[87]
K. G. Andersen and H. Kehlet, “Persistent pain after breast cancer treatment: a critical review of risk factors and strategies for prevention,” Journal of Pain, vol. 12, no. 7, pp. 725–746, 2011.
[88]
J. Hunter, B. Smith, and M. Gribbin, “Demographic variables and chronic pain,” Clinical Journal of Pain, vol. 17, supplement 4, pp. S14–S19, 2001.
[89]
R. R. Edwards, J. A. Haythornthwaite, M. J. Sullivan, and R. B. Fillingim, “Catastrophizing as a mediator of sex differences in pain: differential effects for daily pain versus laboratory-induced pain,” Pain, vol. 111, no. 3, pp. 335–341, 2004.
[90]
M. T. Smith, R. R. Edwards, U. D. McCann, and J. A. Haythomthwaite, “The effects of sleep deprivation on pain inhibition and spontaneous pain in women,” Sleep, vol. 30, no. 4, pp. 494–505, 2007.
[91]
I. Belfer, H. Shnol, and P. Finelli, “Molecular genetics of variability in human pain,” in eLS, John Wiley & Sons, Chichester, UK, 2013.
[92]
H. Manev and N. Dimitrijevic, “Drosophila model for in vivo pharmacological analgesia research,” European Journal of Pharmacology, vol. 491, no. 2-3, pp. 207–208, 2004.
[93]
W. D. Tracey Jr., R. I. Wilson, G. Laurent, and S. Benzer, “Painless, a Drosophila gene essential for nociception,” Cell, vol. 113, no. 2, pp. 261–273, 2003.
[94]
S. Y. Xu, C. L. Cang, X. F. Liu et al., “Thermal nociception in adult Drosophila: behavioral characterization and the role of the painless gene,” Genes, Brain and Behavior, vol. 5, no. 8, pp. 602–613, 2006.
[95]
G. G. Neely, A. Hess, M. Costigan et al., “A genome-wide Drosophila screen for heat nociception identifies α2δ3 as an evolutionarily conserved pain gene,” Cell, vol. 143, no. 4, pp. 628–638, 2010.
[96]
W. A. Catterall, “Structure and regulation of voltage-gated Ca2+ channels,” Annual Review of Cell and Developmental Biology, vol. 16, pp. 521–555, 2000.
[97]
C. V. Ly, C. K. Yao, P. Verstreken, T. Ohyama, and H. J. Bellen, “straightjacket is required for the synaptic stabilization of cacophony, a voltage-gated calcium channel α1 subunit,” Journal of Cell Biology, vol. 181, no. 1, pp. 157–170, 2008.
[98]
G. G. Neely, S. Rao, M. Costigan et al., “Construction of a global pain systems network highlights phospholipid signaling as a regulator of heat nociception,” PLOS Genetics, vol. 8, no. 12, Article ID e1003071, 2012.
[99]
M. J. Field, P. J. Cox, E. Stott et al., “Identification of the α2-δ-1 subunit of voltage-calcium calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 46, pp. 17537–17542, 2006.
[100]
R. H. Dworkin, A. B. O'Connor, M. Backonja et al., “Pharmacologic management of neuropathic pain: evidence-based recommendations,” Pain, vol. 132, no. 3, pp. 237–251, 2007.
[101]
J. D. Rose, R. Arlinghaus, S. J. Cooke et al., “Can fish really feel pain?” Fish and Fisheries, 2013.
[102]
R. W. Elwood, “Pain and suffering in invertebrates?” Institute of Laboratory Animal Resources Journal, vol. 52, no. 2, pp. 175–184, 2011.
[103]
W. R. Lariviere and J. S. Mogil, “The genetics of pain and analgesia in laboratory animals,” Methods in Molecular Biology, vol. 617, pp. 261–278, 2010.
[104]
P. A. Miller, “Thing or Two About Twins National Geographic,” January 2012.
[105]
F. Galton, “The history of twins, as a criterion of the relative powers of nature and nurture (1,2),” International Journal of Epidemiology, vol. 41, no. 4, pp. 905–911, 2012.
[106]
T. A. Norbury, A. J. MacGregor, J. Urwin, T. D. Spector, and S. B. McMahon, “Heritability of responses to painful stimuli in women: a classical twin study,” Brain, vol. 130, no. 11, pp. 3041–3049, 2007.
[107]
C. S. Nielsen, G. P. Knudsen, and ó. A. Steingrímsdóttir, “Twin studies of pain,” Clinical Genetics, vol. 82, no. 4, pp. 331–340, 2012.
[108]
M. B. Max and W. F. Stewart, “The molecular epidemiology of pain: a new discipline for drug discovery,” Nature Reviews Drug Discovery, vol. 7, pp. 647–658, 2008.
[109]
F. Reimanna, J. J. Cox, I. Belfer et al., “Pain perception is altered by a nucleotide polymorphism in SCN9A,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 11, pp. 5148–5153, 2010.
[110]
Y. P. Goldberg, J. Macfarlane, M. L. Macdonald et al., “Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations,” Clinical Genetics, vol. 71, no. 4, pp. 311–319, 2007.
[111]
S. G. Waxman and S. Dib-Hajj, “Erythermalgia: molecular basis for an inherited pain syndrome,” Trends in Molecular Medicine, vol. 11, no. 12, pp. 555–562, 2005.
[112]
J. P. H. Drenth and S. G. Waxman, “Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders,” Journal of Clinical Investigation, vol. 117, no. 12, pp. 3603–3609, 2007.
[113]
C. Han, S. D. Dib-Hajj, Z. Lin et al., “Early- and late-onset inherited erythromelalgia: genotypephenotype correlation,” Brain, vol. 132, no. 7, pp. 1711–1722, 2009.
[114]
N. Skeik, T. W. Rooke, M. D. Davis et al., “Severe case and iterature review of primary erythromelalgia: novel SCN9Agene mutation,” Vascular Medicine, vol. 17, no. 1, pp. 44–49, 2012.
[115]
J. P. H. Drenth, R. H. M. te Morsche, G. Guillet, A. Taieb, R. L. Kirby, and J. B. M. J. Jansen, “SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels,” Journal of Investigative Dermatology, vol. 124, no. 6, pp. 1333–1338, 2005.
[116]
Y. Yang, Y. Wang, S. Li et al., “Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia,” Journal of Medical Genetics, vol. 41, no. 3, pp. 171–174, 2004.
[117]
J. S. Choi, F. Boralevi, O. Brissaud et al., “Paroxysmal extreme pain disorder: a molecular lesion of peripheral neurons,” Nature Reviews Neurology, vol. 7, no. 1, pp. 51–55, 2011.
[118]
A. Lampert, A. O. O'Reilly, P. Reeh, and A. Leffler, “Sodium channelopathies and pain,” Pflugers Archiv, vol. 460, no. 2, pp. 249–263, 2010.
[119]
C. R. Fertleman, M. D. Baker, K. A. Parker et al., “SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes,” Neuron, vol. 52, no. 5, pp. 767–774, 2006.
[120]
J. J. Cox, F. Reimann, A. K. Nicholas et al., “An SCN9A channelopathy causes congenital inability to experience pain,” Nature, vol. 444, no. 7121, pp. 894–898, 2006.
[121]
M. Auer-Grumbach, P. de Jonghe, K. Verhoeven et al., “Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review,” Archives of Neurology, vol. 60, no. 3, pp. 329–334, 2003.
[122]
K. Verhoeven, K. Coen, E. de Vriendt et al., “SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I,” Neurology, vol. 62, no. 6, pp. 1001–1002, 2004.
[123]
R. G. Lafrenière, M. L. E. MacDonald, M. P. Dubé et al., “Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the study of Canadian genetic isolates,” American Journal of Human Genetics, vol. 74, no. 5, pp. 1064–1073, 2004.
[124]
S. L. Anderson, R. Coli, I. W. Daly et al., “Familial dysautonomia is caused by mutations of the IKAP gene,” American Journal of Human Genetics, vol. 68, no. 3, pp. 753–758, 2001.
[125]
S. Rosemberg, S. K. Nagahashi Marie, and S. Kliemann, “Congenital insensitivity to pain with anhidrosis (hereditary sensory and autonomic neuropathy type IV),” Pediatric Neurology, vol. 11, no. 1, pp. 50–56, 1994.
[126]
E. Einarsdottir, A. Carlsson, J. Minde et al., “A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception,” Human Molecular Genetics, vol. 13, no. 8, pp. 799–805, 2004.
[127]
J. Minde, G. Toolanen, T. Andersson et al., “Familial insensitivity to pain (HSAN V) and a mutation in the NGFB gene. A neurophysiological and pathological study,” Muscle and Nerve, vol. 30, no. 6, pp. 752–760, 2004.
[128]
H. Houlden, R. H. M. King, A. Hashemi-Nejad et al., “A novel TRK A (NTRK1) mutation associated with hereditary sensory and autonomic neuropathy type V,” Annals of Neurology, vol. 49, no. 4, pp. 521–525, 2001.
[129]
Y. Miura, S. Mardy, Y. Awaya et al., “Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families,” Human Genetics, vol. 106, no. 1, pp. 116–124, 2000.
[130]
“Headache Classification Committee of the International Headache Society The international classification of headache disorders, 2nd edition,” Cephalalgia, vol. 24, pp. 1–160, 2004.
[131]
P. Montagna, “Molecular genetics of migraine headaches: a review,” Cephalalgia, vol. 20, no. 1, pp. 3–14, 2000.
[132]
A. Di Cristofori, L. Fusi, A. Gomitoni, et al., “R583Q CACNA1A variant in SHM1 and ataxia: case report and literature update,” The Journal of Headache and Pain, vol. 13, no. 5, pp. 419–423, 2012.
[133]
Y. P. Goldberg, S. N. Pimstone, R. Namdari et al., “Human Mendelian pain disorders: a key to discovery and validation of novel analgesics,” Clinical Genetics, vol. 82, no. 4, pp. 367–373, 2012.
[134]
L. Diatchenko, A. G. Nackley, I. E. Tchivileva, S. A. Shabalina, and W. Maixner, “Genetic architecture of human pain perception,” Trends in Genetics, vol. 23, no. 12, pp. 605–613, 2007.
[135]
L. Diatchenko, A. G. Nackley, G. D. Slade, R. B. Fillingim, and W. Maixner, “Idiopathic pain disorders—pathways of vulnerability,” Pain, vol. 123, no. 3, pp. 226–230, 2006.
[136]
E. E. Young, W. R. Lariviere, and I. Belfer, “Genetic basis of pain variability: recent advances,” Journal of Medical Genetics, vol. 49, no. 1, pp. 1–9, 2012.
[137]
I. Tegeder, M. Costigan, R. S. Griffin et al., “GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistence,” Nature Medicine, vol. 12, no. 11, pp. 1269–1277, 2006.
[138]
J. L？tsch, P. Klepstad, A. Doehring, and O. Dale, “A GTP cyclohydrolase 1 genetic variant delays cancer pain,” Pain, vol. 148, no. 1, pp. 103–106, 2010.
[139]
D. H. Kim, F. Dai, I. Belfer et al., “Polymorphic variation of the guanosine triphosphate cyclohydrolase 1 gene predicts outcome in patients undergoing surgical treatment for lumbar degenerative disc disease,” Spine, vol. 35, no. 21, pp. 1909–1914, 2010.
[140]
M. Costigan, I. Belfer, R. S. Griffin et al., “Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1,” Brain, vol. 133, no. 9, pp. 2519–2527, 2010.
[141]
J. N. Ablin, H. Cohen, and D. Buskila, “Mechanisms of disease: genetics of fibromyalgia,” Nature Clinical Practice. Rheumatology, vol. 2, pp. 671–678, 2006.
[142]
M. Narita, N. Nishigami, N. Narita et al., “Association between serotonin transporter gene polymorphism and chronic fatigue syndrome,” Biochemical and Biophysical Research Communications, vol. 311, no. 2, pp. 264–266, 2003.
[143]
B. de Vries, J. Haan, R. R. Frants, A. M. J. M. van den Maagdenberg, and M. D. Ferrari, “Genetic biomarkers for migraine,” Headache, vol. 46, no. 7, pp. 1059–1068, 2006.
[144]
H. Herken, E. Erdal, N. Mutlu et al., “Possible association of temporomandibular joint pain and dysfunction with a polymorphism in the serotonin transporter gene,” American Journal of Orthodontics and Dentofacial Orthopedics, vol. 120, no. 3, pp. 308–313, 2001.
[145]
I. Belfer and S. Segall, “COMT genetic variants and pain,” Drugs of Today, vol. 47, no. 6, pp. 457–467, 2011.
[146]
T. Lotta, J. Vidgren, C. Tilgmann et al., “Kinetics of human soluble and membrane-bound catechol O- methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme,” Biochemistry, vol. 34, no. 13, pp. 4202–4210, 1995.
[147]
J. Chen, B. K. Lipska, N. Halim et al., “Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mrna, protein, and enzyme activity in postmortem human brain,” American Journal of Human Genetics, vol. 75, no. 5, pp. 807–821, 2004.
[148]
A. G. Nackley, S. A. Shabalina, I. E. Tchivileva et al., “Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure,” Science, vol. 314, no. 5807, pp. 1930–1933, 2006.
[149]
P. Voelker, B. E. Sheese, M. K. Rothbart, and M. I. Posner, “Variations in catechol-O-methyltransferase gene interact with parenting to influence attention in early development,” Neuroscience, vol. 164, no. 1, pp. 121–130, 2009.
[150]
H. Cohen, L. Neumann, Y. Glazer, R. P. Ebstein, and D. Buskila, “The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val158Met and fibromyalgia,” Clinical and Experimental Rheumatology, vol. 27, supplement 56, no. 5, pp. S51–S56, 2009.
[151]
F. R. Barbosa, J. B. Matsuda, M. Mazucato et al., “Influence of catechol-O-methyltransferase (COMT) gene polymorphisms in pain sensibility of Brazilian fibromialgia patients,” Rheumatology International, vol. 32, no. 2, pp. 427–430, 2012.
[152]
G. Vargas-Alarcón, J. M. Fragoso, D. Cruz-Robles et al., “Catechol-O-methyltransferase gene haplotypes in Mexican and Spanish patients with fibromyalgia,” Arthritis Research and Therapy, vol. 9, no. 5, article R110, 2007.
[153]
M. Emin Erdal, H. Herken, M. Yilmaz, and Y. A. Bayazit, “Significance of the catechol-O-methyltransferase gene polymorphism in migraine,” Molecular Brain Research, vol. 94, no. 1-2, pp. 193–196, 2001.
[154]
K. Hagen, E. Pettersen, L. J. Stovner, F. Skorpen, and J. A. Zwart, “The association between headache and Val158Met polymorphism in the catechol-O-methyltransferase gene: the HUNT Study,” Journal of Headache and Pain, vol. 7, no. 2, pp. 70–74, 2006.
[155]
S. Cevoli, M. Mochi, C. Scapoli et al., “A genetic association study of dopamine metabolism-related genes and chronic headache with drug abuse,” European Journal of Neurology, vol. 13, no. 9, pp. 1009–1013, 2006.
[156]
L. Diatchenko, G. D. Slade, A. G. Nackley et al., “Genetic basis for individual variations in pain perception and the development of a chronic pain condition,” Human Molecular Genetics, vol. 14, no. 1, pp. 135–143, 2005.
[157]
K. T. Hall, A. J. Lembo, I. Kirsch et al., “Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome,” PLoS One, vol. 7, no. 10, Article ID e48135, 2012.
[158]
P. Karling, ？. Danielsson, M. Wikgren et al., “The relationship between the Val158Met catechol-O-methyltransferase (COMT) polymorphism and irritable bowel syndrome,” PLoS ONE, vol. 6, no. 3, Article ID e18035, 2011.
[159]
S. A. McLean, L. Diatchenko, Y. M. Lee et al., “Catechol O-methyltransferase haplotype predicts immediate musculoskeletal neck pain and psychological symptoms after motor vehicle collision,” Journal of Pain, vol. 12, no. 1, pp. 101–107, 2011.
[160]
J. E. Reeder, T. K. Byler, D. C. Foster et al., “Polymorphism in the SCN9A voltage-gated sodium channel gene associated with interstitial cystitis/bladder pain syndrome,” Urology, vol. 81, no. 1, pp. 210.e1–210.e4, 2013.
[161]
D. C. Foster, T. M. Sazenski, and C. J. Stodgell, “Impact of genetic variation in interleukin-1 receptor antagonist and melanocortin-1 receptor genes on vulvar vestibulitis syndrome,” Journal of Reproductive Medicine for the Obstetrician and Gynecologist, vol. 49, no. 7, pp. 503–509, 2004.
[162]
E. Barkhordari, N. Rezaei, B. Ansaripour et al., “Proinflammatory cytokine gene polymorphisms in irritable bowel syndrome,” Journal of Clinical Immunology, vol. 30, no. 1, pp. 74–79, 2010.
[163]
H. Kim, H. Lee, J. Rowan, J. Brahim, and R. A. Dionne, “Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans,” Molecular Pain, vol. 2, article 24, 2006.
[164]
F. Dai, I. Belfer, C. E. Schwartz et al., “Association of catechol-O-methyltransferase genetic variants with outcome in patients undergoing surgical treatment for lumbar degenerative disc disease,” Spine Journal, vol. 10, no. 11, pp. 949–957, 2010.
[165]
D. H. Kim and C. E. Schwartz, “The genetics of pain: implications for evaluation and treatment of spinal disease,” Spine Journal, vol. 10, no. 9, pp. 827–840, 2010.
[166]
L. Ala-Kokko, “Genetic risk factors for lumbar disc disease,” Annals of Medicine, vol. 34, no. 1, pp. 42–47, 2002.
[167]
S. K. Ballas, K. Gupta, and P. Adams-Graves, “Sickle cell pain: a critical reappraisal,” Blood, vol. 120, no. 18, pp. 3647–3656, 2012.
[168]
G. Lettre, V. G. Sankaran, M. A. C. Bezerra et al., “DNA polymorphisms at the BCL11A, HBS1L-MYB, and β-globin loci associate with fetal hemoglobin levels and pain crises in sickle cell disease,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, pp. 11869–11874, 2008.
[169]
A. M. Al-Subaie, N. A. Fawaz, N. Mahdi et al., “Human platelet alloantigens (HPA) 1, HPA2, HPA3, HPA4, and HPA5 polymorphisms in sickle cell anemia patients with vaso-occlusive crisis,” European Journal of Haematology, vol. 83, no. 6, pp. 579–585, 2009.
[170]
H. H. Al-Habboubi, N. Mahdi, T. M. Abu-Hijleh, F. M. Abu-Hijleh, M. S. Sater, and W. Y. Almawi, “The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease,” European Journal of Haematology, vol. 89, no. 5, pp. 403–409, 2012.
[171]
I. I. Gottesman and T. D. Gould, “The endophenotype concept in psychiatry: etymology and strategic intentions,” American Journal of Psychiatry, vol. 160, no. 4, pp. 636–645, 2003.
[172]
T. D. Cannon and M. C. Keller, “Endophenotypes in the genetic analyses of mental disorders,” Annual Review of Clinical Psychology, vol. 2, pp. 267–290, 2006.
[173]
G. Pavlakovic and F. Petzke, “The role of quantitative sensory testing in the evaluation of musculoskeletal pain conditions,” Current Rheumatology Reports, vol. 2, pp. 455–461, 2010.
[174]
A. K. Suokas, D. A. Walsh, D. F. McWilliams et al., “Quantitative sensory testing in painful osteoarthritis: a systematic review and meta-analysis,” Osteoarthritis Cartilage, vol. 20, no. 10, pp. 1075–1085, 2012.
[175]
D. B. Pfau, C. Geber, F. Birklein, and R. D. Treede, “Quantitative sensory testing of neuropathic pain patients: potential mechanistic and therapeutic implications,” Current Pain and Headache Reports, vol. 16, no. 3, pp. 199–206, 2012.
[176]
J. D. Greenspan, “Quantitative assessment of neuropathic pain,” Current Pain and Headache Reports, vol. 5, no. 2, pp. 107–113, 2001.
[177]
L. Diatchenko, A. G. Nackley, G. D. Slade et al., “Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli,” Pain, vol. 125, no. 3, pp. 216–224, 2006.
[178]
F. Lindstedt, J. Berrebi, E. Greayer et al., “Conditioned pain modulation is associated with common Polymorphisms in the serotonin transporter gene,” PLoS ONE, vol. 6, no. 3, Article ID e18252, 2011.
[179]
D. D. McKemy, W. M. Neuhausser, and D. Julius, “Identification of a cold receptor reveals a general role for TRP channels in thermosensation,” Nature, vol. 416, no. 6876, pp. 52–58, 2002.
[180]
E. B. Liem, T. V. Joiner, K. Tsueda, and D. I. Sessler, “Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads,” Anesthesiology, vol. 102, no. 3, pp. 509–514, 2005.
[181]
M. Martínez-Jauand, C. Sitges, V. Rodríguez et al., “Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene,” European Journal of Pain, vol. 17, no. 1, pp. 16–27, 2013.
[182]
A. Binder, D. May, R. Baron et al., “Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients,” PLoS ONE, vol. 6, no. 3, Article ID e17387, 2011.
[183]
U. Klotz, “The role of pharmacogenetics in the metabolism of antiepileptic drugs: pharmacokinetic and therapeutic implications,” Clinical Pharmacokinetics, vol. 46, no. 4, pp. 271–279, 2007.
[184]
U. M. Stamer and F. Stüber, “The pharmacogenetics of analgesia,” Expert Opinion on Pharmacotherapy, vol. 8, no. 14, pp. 2235–2245, 2007.
[185]
B. G. Oertel, R. Schmidt, A. Schneider, G. Geisslinger, and J. L？tsch, “The μ-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers,” Pharmacogenetics and Genomics, vol. 16, no. 9, pp. 625–636, 2006.
[186]
C. Walter and J. L？tsch, “Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment,” Pain, vol. 146, no. 3, pp. 270–275, 2009.
[187]
W. Zhang, J. J. Yuan, Q. C. Kan, L. R. Zhang, Y. Z. Chang, and Z. Y. Wang, “Study of the OPRM1 A118G genetic polymorphism associated with postoperative nausea and vomiting induced by fentanyl intravenous analgesia,” Minerva Anestesiologica, vol. 77, no. 1, pp. 33–39, 2011.
[188]
Q. Liao, D. J. Chen, F. Zhang et al., “Effect of CYP3A4？18B polymorphisms and interactions with OPRM1 A118G on postoperative fentanyl requirements in patients undergoing radical gastrectomy,” Molecular Medicine Reports, vol. 7, no. 3, pp. 901–908, 2013.
[189]
Y. Kolesnikov, B. Gabovits, A. Levin, E. Voiko, and A. Veske, “Combined catechol-O-methyltransferase and μ-opioid receptor gene polymorphisms affect morphine postoperative analgesia and central side effects,” Anesthesia and Analgesia, vol. 112, no. 2, pp. 448–453, 2011.
[190]
J. L？tsch, C. Skarke, S. Gr？sch, J. Darimont, H. Schmidt, and G. Geisslinger, “The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine,” Pharmacogenetics, vol. 12, no. 1, pp. 3–9, 2002.
[191]
T. T. Rakv？g, P. Klepstad, C. Baar et al., “The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients,” Pain, vol. 116, no. 1-2, pp. 73–78, 2005.
[192]
T. T. Rakv？g, J. R. Ross, H. Sato, F. Skorpen, S. Kaasa, and P. Klepstad, “Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain,” Molecular Pain, vol. 4, pp. 64–76, 2008.
[193]
J. L？tsch, R. Schmidt, G. Vetter et al., “Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein,” Journal of Neurochemistry, vol. 83, no. 2, pp. 241–248, 2002.
[194]
L. Coulbault, M. Beaussier, C. Verstuyft et al., “Environmental and genetic factors associated with morphine response in the postoperative period,” Clinical Pharmacology & Therapeutics, vol. 79, no. 4, pp. 316–324, 2006.
[195]
D. Campa, A. Gioia, A. Tomei, P. Poli, and R. Barale, “Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief,” Clinical Pharmacology & Therapeutics, vol. 83, no. 4, pp. 559–566, 2008.
[196]
H. J. Park, H. K. Shinn, S. H. Ryu, H. S. Lee, C. S. Park, and J. H. Kang, “Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans,” Clinical Pharmacology & Therapeutics, vol. 81, no. 4, pp. 539–546, 2007.
[197]
J. Kirchheiner, H. Schmidt, M. Tzvetkov et al., “Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication,” Pharmacogenomics Journal, vol. 7, no. 4, pp. 257–265, 2007.
[198]
L. Bertilsson, M. L. Dahl, F. Sjoqvist et al., “Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine,” The Lancet, vol. 341, no. 8836, p. 63, 1993.
[199]
J. S. Mogil, J. Ritchie, S. B. Smith et al., “Melanocortin-1 receptor gene variants affect pain and μ-opioid analgesia in mice and humans,” Journal of Medical Genetics, vol. 42, no. 7, pp. 583–587, 2005.
[200]
J. S. Mogil, S. G. Wilson, E. J. Chesler et al., “The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 8, pp. 4867–4872, 2003.
[201]
A. Muralidharan and M. T. Smith, “Pain, analgesia and genetics,” Journal of Pharmacy and Pharmacology, vol. 63, no. 11, pp. 1387–1400, 2011.
[202]
T. Foulkes and J. N. Wood, “Pain genes,” PLoS Genetics, vol. 4, no. 7, Article ID e1000086, 2008.
[203]
M. L. LaCroix-Fralish, J. B. Ledoux, and J. S. Mogil, “The Pain Genes Database: an interactive web browser of pain-related transgenic knockout studies,” Pain, vol. 131, no. 1-2, pp. 3.e1–3.e4, 2007.
[204]
J. S. Mogil, “Pain genetics: past, present and future,” Trends in Genetics, vol. 28, no. 6, pp. 258–266, 2012.
[205]
M. Schürks, “Genetics of migraine in the age of genome-wide association studies,” The Journal of Headache and Pain, vol. 13, no. 1, pp. 1–9, 2012.
[206]
H. Kim, E. Ramsay, H. Lee, S. Wahl, and R. A. Dionne, “Genome-wide association study of acute post-surgical pain in humans,” Pharmacogenomics, vol. 10, no. 2, pp. 171–179, 2009.
[207]
A. G. Day-Williams, L. Southam, K. Panoutsopoulou et al., “A variant in MCF2L is associated with osteoarthritis,” The American Journal of Human Genetics, vol. 89, no. 3, pp. 446–450, 2011.
[208]
J. N. Painter, C. A. Anderson, D. R. Nyholt et al., “Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis,” Nature Genetics, vol. 43, no. 1, pp. 51–54, 2011.
[209]
M. J. Peters, L. Broer, H. L. Willemen et al., “Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15. 2 region,” Annals of the Rheumatic Diseases, vol. 72, no. 3, pp. 427–436, 2013.
[210]
D. Nishizawa, K. Fukuda, S. Kasai et al., “Genome-wide association study identifies a potent locus associated with human opioid sensitivity,” Molecular Psychiatry, 2012.
[211]
W. C. Clark, J. C. Yang, and M. N. Janal, “Altered pain and visual sensitivity in humans: the effects of acute and chronic stress,” Annals of the New York Academy of Sciences, vol. 467, pp. 116–129, 1986.
[212]
E. B. Blanchard, J. M. Lackner, J. Jaccard et al., “The role of stress in symptom exacerbation among IBS patients,” Journal of Psychosomatic Research, vol. 64, no. 2, pp. 119–128, 2008.
[213]
D. Hoy, P. Brooks, F. Blyth, and R. Buchbinder, “The Epidemiology of low back pain,” Best Practice and Research: Clinical Rheumatology, vol. 24, no. 6, pp. 769–781, 2010.
[214]
G. Chrousos and P. Gold, “The concepts of stress and stress system disorders,” The Journal of the American Medical Association, vol. 267, pp. 1224–1252, 1992.
[215]
B. S. McEwen and M. Kalia, “The role of corticosteroids and stress in chronic pain conditions,” Metabolism: Clinical and Experimental, vol. 59, supplement 1, pp. S9–S15, 2010.
[216]
J. S. Mogil, R. E. Sorge, M. L. LaCroix-Fralish et al., “Pain sensitivity and vasopressin analgesia are mediated by a gene-sex-environment interaction,” Nature Neuroscience, vol. 14, no. 12, pp. 1569–1573, 2011.
[217]
M. Schmelz, “Translating nociceptive processing into human pain models,” Experimental Brain Research, vol. 196, no. 1, pp. 173–178, 2009.
[218]
Y. Xiao, I. J. Russell, and Y. G. Liu, “A brain-derived neurotrophic factor polymorphism Val66Met identifies fibromyalgia syndrome subgroup with higher body mass index and C-reactive protein,” Rheumatology International, vol. 32, no. 8, pp. 2479–2485, 2012.
[219]
L. Lei, L. Ye, H. Liu et al., “Passive smoking, cytochrome P450 gene polymorphisms and dysmenorrhea,” European Journal of Epidemiology, vol. 23, no. 7, pp. 475–481, 2008.
[220]
E. Reitman, J. Conell-Price, J. Evansmith et al., “β2-adrenergic receptor genotype and other variables that contribute to labor pain and progress,” Anesthesiology, vol. 114, no. 4, pp. 927–939, 2011.
[221]
E. C. Tan, E. C. P. Lim, Y. Y. Teo, Y. Lim, H. Y. Law, and A. T. Sia, “Ethnicity and OPRM variant independently predict pain perception and patient-controlled analgesia usage for post-operative pain,” Molecular Pain, vol. 5, article 32, 2009.
[222]
B. A. Hastie, J. L. Riley III, L. Kaplan et al., “Ethnicity interacts with the OPRM1 gene in experimental pain sensitivity,” Pain, vol. 153, no. 8, pp. 1610–1619, 2012.
[223]
H. Kim, J. K. Neubert, A. San Miguel et al., “Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament,” Pain, vol. 109, no. 3, pp. 488–496, 2004.
[224]
P. H. Finan, A. J. Zautra, M. C. Davis, K. Lemery-Chalfant, J. Covault, and H. Tennen, “Genetic influences on the dynamics of pain and affect in fibromyalgia,” Health Psychology, vol. 29, no. 2, pp. 134–142, 2010.
[225]
T. W. Lee, Y. W. Y. Yu, C. J. Hong, S. J. Tsai, H. C. Wu, and T. J. Chen, “The effects of catechol-O-methyl-transferase polymorphism Val158Met on functional connectivity in healthy young females: a resting EEG study,” Brain Research, vol. 1377, pp. 21–31, 2011.
[226]
M. B. Olsen, L. M. Jacobsen, E. I. Schistad et al., “Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: evidence of a sex and genotype interaction,” The Journal of Neuroscience, vol. 32, no. 29, pp. 9831–9834, 2012.
[227]
R. Fejer, J. Hartvigsen, and K. O. Kyvik, “Sex differences in heritability of neck pain,” Twin Research and Human Genetics, vol. 9, no. 2, pp. 198–204, 2006.
[228]
C. Wang, Y. Cheng, T. Liu et al., “A computational model for sex-specific genetic architecture of complex traits in humans: implications for mapping pain sensitivity,” Molecular Pain, vol. 4, article 13, 2008.
[229]
N. J. Manek and A. J. MacGregor, “Epidemiology of back disorders: prevalence, risk factors, and prognosis,” Current Opinion in Rheumatology, vol. 17, no. 2, pp. 134–140, 2005.
[230]
R. J. Thompson Jr., K. M. Gil, M. R. Abrams, and G. Phillips, “Psychological adjustment of adults with sickle cell anemia: stability over 20 months, correlates, and predictors,” Journal of Clinical Psychology, vol. 52, pp. 253–266, 1996.
[231]
R. Fejer, J. Hartvigsen, and K. O. Kyvik, “Heritability of neck pain: a population-based study of 33 794 Danish twins,” Rheumatology, vol. 45, no. 5, pp. 589–594, 2006.
[232]
A. Bird, “Perceptions of epigenetics,” Nature, vol. 447, no. 7143, pp. 396–398, 2007.
[233]
E. Jablonka, “Epigenetic variations in heredity and evolution,” Clinical Pharmacology & Therapeutics, vol. 92, no. 6, pp. 683–688, 2012.
[234]
H. Vossen, G. Kenis, B. Rutten, J. van Os, H. Hermens, and R. Lousberg, “The genetic influence on the cortical processing of experimental pain and the moderating effect of pain status,” PLoS ONE, vol. 5, no. 10, Article ID e13641, 2010.
[235]
J. Vojinovic, N. Damjanov, C. D'Urzo et al., “Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis,” Arthritis and Rheumatism, vol. 63, no. 5, pp. 1452–1458, 2011.
[236]
K. Klein, C. Ospelt, and S. Gay, “Epigenetic contributions in the development of rheumatoid arthritis,” Arthritis Research & Therapy, vol. 14, no. 6, article 227, 2012.
[237]
C. Ospelt and S. Gay, “The role of resident synovial cells in destructive arthritis,” Best Practice and Research: Clinical Rheumatology, vol. 22, no. 2, pp. 239–252, 2008.
[238]
L. N. Reynard and J. Loughlin, “Genetics and epigenetics of osteoarthritis,” Maturitas, vol. 71, no. 3, pp. 200–204, 2012.
[239]
A. Hellman and A. Chess, “Extensive sequence-influenced DNA methylation polymorphism in the human genome,” Epigenetics and Chromatin, vol. 3, no. 1, article 11, 2010.
[240]
J. T. Bell, A. A. Pai, J. K. Pickrell et al., “DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines,” Genome Biology, vol. 12, no. 1, article R10, 2011.
[241]
L. N. Reynard, C. Bui, E. G. Canty-Laird, D. A. Young, and J. Loughlin, “Expression of the osteoarthritis-associated gene GDF5 is modulated epigenetically by DNA methylation,” Human Molecular Genetics, vol. 20, pp. 3450–3460, 2011.
[242]
F. Denk and S. B. McMahon, “Chronic pain: emerging evidence for the involvement of epigenetics,” Neuron, vol. 73, no. 3, pp. 435–444, 2012.
[243]
K. T. Sibille, L. Witek-Janusek, H. L. Mathews, and R. B. Fillingim, “Telomeres and epigenetics: potential relevance to chronic pain,” Pain, vol. 153, no. 9, pp. 1789–1793, 2012.
[244]
M. Tajerian, S. Alvarado, M. Millecamps et al., “DNA methylation of SPARC and chronic low back pain,” Molecular Pain, vol. 7, article 65, 2011.
[245]
C. R. Bain and A. D. Shaw, “Genetics and epigenetics in perioperative medicine,” Current Opinion in Critical Care, vol. 18, no. 5, pp. 548–554, 2012.
[246]
S. M. Géranton, “Targeting epigenetic mechanisms for pain relief,” Current Opinion in Pharmacology, vol. 12, no. 1, pp. 35–41, 2012.
[247]
Nature, “Time for the epigenome,” Nature, vol. 463, p. 587, 2010.
[248]
H. Kim, D. Clark, and R. A. Dionne, “Genetic contributions to clinical pain and analgesia: avoiding pitfalls in genetic research,” Journal of Pain, vol. 10, no. 7, pp. 663–693, 2009.
[249]
Q. Shi, C. S. Cleeland, P. Klepstad, et al., “Biological pathways and genetic variables involved in pain,” Quality of Life Research, vol. 19, no. 10, pp. 1407–1417, 2010.
[250]
M. B. Max, T. Wu, S. J. Atlas et al., “A clinical genetic method to identify mechanisms by which pain causes depression and anxiety,” Molecular Pain, vol. 2, article 14, 2006.
[251]
H. T. Bjornsson, M. Daniele Fallin, and A. P. Feinberg, “An integrated epigenetic and genetic approach to common human disease,” Trends in Genetics, vol. 20, no. 8, pp. 350–358, 2004.
[252]
I. Belfer and F. Dai, “Phenotyping and genotyping neuropathic pain,” Current Pain and Headache Reports, vol. 14, no. 3, pp. 203–212, 2010.
[253]
L. Almasy, “The role of phenotype in gene discovery in the whole genome sequencing era,” Human Genetics, vol. 131, no. 10, pp. 1533–1540, 2012.
[254]
L. H. Chadwick, “The NIH roadmap epigenomics program data resource,” Epigenomics, vol. 4, no. 3, pp. 317–324, 2012.
[255]
B. E. Bernstein, J. A. Stamatoyannopoulos, J. F. Costello et al., “The NIH roadmap epigenomics mapping consortium,” Nature Biotechnology, vol. 28, no. 10, pp. 1045–1048, 2010.
