There are many known risk factors for chronic pain conditions, yet the biological underpinnings that link these factors to abnormal processing of painful signals are only just beginning to be explored. This Review will discuss the potential mechanisms that have been proposed to underlie vulnerability and resilience toward developing chronic pain. Particular focus will be given to genetic and epigenetic processes, priming effects on a cellular level, and alterations in brain networks concerned with reward, motivation/learning and descending modulatory control. Although research in this area is still in its infancy, a better understanding of how pain vulnerability emerges has the potential to help identify individuals at risk and may open up new therapeutic avenues.
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Kehlet, H., Jensen, T.S. & Woolf, C.J. Persistent postsurgical pain: risk factors and prevention. Lancet 367, 1618–1625 (2006).
Dieppe, P.A. & Lohmander, L.S. Pathogenesis and management of pain in osteoarthritis. Lancet 365, 965–973 (2005).
Balagué, F., Mannion, A.F., Pellise, F. & Cedraschi, C. Non-specific low back pain. Lancet 379, 482–491 (2012).
Abbott, C.A., Malik, R.A., van Ross, E.R., Kulkarni, J. & Boulton, A.J. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care 34, 2220–2224 (2011).
Crow, M., Denk, F. & McMahon, S.B. Genes and epigenetic processes as prospective pain targets. Genome Med. 5, 12 (2013).
Mogil, J.S. Pain genetics: past, present and future. Trends Genet. 28, 258–266 (2012).
Cox, J.J. & Wood, J.N. No pain, more gain. Nat. Genet. 45, 1271–1272 (2013).
McMahon, S.B. NGF as a mediator of inflammatory pain. Phil. Trans. R. Soc. Lond. B 351, 431–440 (1996).
Eijkelkamp, N. et al. Neurological perspectives on voltage-gated sodium channels. Brain 135, 2585–2612 (2012).
Hocking, L.J., Morris, A.D., Dominiczak, A.F., Porteous, D.J. & Smith, B.H. Heritability of chronic pain in 2195 extended families. Eur. J. Pain 16, 1053–1063 (2012).
Malfait, A.M. et al. A role for PACE4 in osteoarthritis pain: evidence from human genetic association and null mutant phenotype. Ann. Rheum. Dis. 71, 1042–1048 (2012).
Tsantoulas, C. et al. Sensory neuron downregulation of the Kv9.1 potassium channel subunit mediates neuropathic pain following nerve injury. J. Neurosci. 32, 17502–17513 (2012).
arcOgen Consortium. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 380, 815–823 (2012).
Williams, F.M. et al. Novel genetic variants associated with lumbar disc degeneration in northern Europeans: a meta-analysis of 4600 subjects. Ann. Rheum. Dis. 72, 1141–1148 (2013).
Nyholt, D.R. et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat. Genet. 44, 1355–1359 (2012).
Esserlind, A.L. et al. Replication and meta-analysis of common variants identifies a genome-wide significant locus in migraine. Eur. J. Neurol. 20, 765–772 (2013).
Kim, H., Ramsay, E., Lee, H., Wahl, S. & Dionne, R.A. Genome-wide association study of acute post-surgical pain in humans. Pharmacogenomics 10, 171–179 (2009).
Nishizawa, D. et al. Genome-wide association study identifies a potent locus associated with human opioid sensitivity. Mol. Psychiatry published online, doi:10.1038/mp.2012.164 (27 November 2012).
Peters, M.J. et al. Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region. Ann. Rheum. Dis. 72, 427–436 (2013).
Williams, F.M. et al. Genes contributing to pain sensitivity in the normal population: an exome sequencing study. PLoS Genet. 8, e1003095 (2012).
Chesler, E.J., Wilson, S.G., Lariviere, W.R., Rodriguez-Zas, S.L. & Mogil, J.S. Influences of laboratory environment on behavior. Nat. Neurosci. 5, 1101–1102 (2002).
Fillingim, R.B. et al. The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. J. Pain 6, 159–167 (2005).
Sorge, R.E. et al. Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Nat. Med. 18, 595–599 (2012).
Lee, M. & Tracey, I. Neuro-genetics of persistent pain. Curr. Opin. Neurobiol. 23, 127–132 (2013).
Bishop, S. & Forster, S. Trait anxiety, neuroticism and the brain basis of vulnerability to affective disorder. in The Cambridge Handbook of Human Affective Neuroscience (eds. Armony, J. & Vuilleumier, P.) ch. 24 (Cambridge University Press, Cambridge, 2013).
Dulac, C. Brain function and chromatin plasticity. Nature 465, 728–735 (2010).
Tajerian, M. et al. DNA methylation of SPARC and chronic low back pain. Mol. Pain 7, 65 (2011).
Wu, H. & Zhang, Y. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev. 25, 2436–2452 (2011).
Telese, F., Gamliel, A., Skowronska-Krawczyk, D., Garcia-Bassets, I. & Rosenfeld, M.G. “Seq-ing” insights into the epigenetics of neuronal gene regulation. Neuron 77, 606–623 (2013).
Buchen, L. Neuroscience: In their nurture. Nature 467, 146–148 (2010).
Bell, J.T. et al. Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population. PLoS Genet. 8, e1002629 (2012).
Denk, F. & McMahon, S.B. Chronic pain: emerging evidence for the involvement of epigenetics. Neuron 73, 435–444 (2012).
Denk, F. et al. HDAC inhibitors attenuate the development of hypersensitivity in models of neuropathic pain. Pain 154, 1668–1679 (2013).
Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet. 27, 389–396 (2011).
Wang, Y. et al. Intrathecal 5-azacytidine inhibits global DNA methylation and methyl-CpG–binding protein 2 expression and alleviates neuropathic pain in rats following chronic constriction injury. Brain Res. 1418, 64–69 (2011).
Stresemann, C., Brueckner, B., Musch, T., Stopper, H. & Lyko, F. Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res. 66, 2794–2800 (2006).
Tajerian, M. et al. Peripheral nerve injury is associated with chronic, reversible changes in global DNA methylation in the mouse prefrontal cortex. PLoS ONE 8, e55259 (2013).
Doehring, A., Oertel, B.G., Sittl, R. & Lotsch, J. Chronic opioid use is associated with increased DNA methylation correlating with increased clinical pain. Pain 154, 15–23 (2013).
Tochiki, K.K., Cunningham, J., Hunt, S.P. & Geranton, S.M. The expression of spinal methyl-CpG–binding protein 2, DNA methyltransferases and histone deacetylases is modulated in persistent pain states. Mol. Pain 8, 14 (2012).
Downs, J. et al. Linking MECP2 and pain sensitivity: the example of Rett syndrome. Am. J. Med. Genet. A. 152A, 1197–1205 (2010).
Skene, P.J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010).
Graur, D. et al. On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE. Genome Biol. Evol. 5, 578–590 (2013).
Low, L.A. & Fitzgerald, M. Acute pain and a motivational pathway in adult rats: influence of early life pain experience. PLoS ONE 7, e34316 (2012).
Coutinho, S.V. et al. Neonatal maternal separation alters stress-induced responses to viscerosomatic nociceptive stimuli in rat. Am. J. Physiol. Gastrointest. Liver Physiol. 282, G307–G316 (2002).
Moloney, R.D. et al. Early-life stress induces visceral hypersensitivity in mice. Neurosci. Lett. 512, 99–102 (2012).
Beggs, S., Currie, G., Salter, M.W., Fitzgerald, M. & Walker, S.M. Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity. Brain 135, 404–417 (2012).
Doesburg, S.M. et al. Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age. Pain 154, 1946–1952 (2013).
Hohmeister, J. et al. Cerebral processing of pain in school-aged children with neonatal nociceptive input: an exploratory fMRI study. Pain 150, 257–267 (2010).
Reichling, D.B. & Levine, J.D. Critical role of nociceptor plasticity in chronic pain. Trends Neurosci. 32, 611–618 (2009).
Loram, L.C. et al. Prior exposure to glucocorticoids potentiates lipopolysaccharide induced mechanical allodynia and spinal neuroinflammation. Brain Behav. Immun. 25, 1408–1415 (2011).
Bogen, O., Alessandri-Haber, N., Chu, C., Gear, R.W. & Levine, J.D. Generation of a pain memory in the primary afferent nociceptor triggered by PKCepsilon activation of CPEB. J. Neurosci. 32, 2018–2026 (2012).
Johansen-Berg, H. Behavioural relevance of variation in white matter microstructure. Curr. Opin. Neurol. 23, 351–358 (2010).
Filippini, N. et al. Differential effects of the APOE genotype on brain function across the lifespan. Neuroimage 54, 602–610 (2011).
Tracey, I. et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. J. Neurosci. 22, 2748–2752 (2002).
Ploner, M., Lee, M.C., Wiech, K., Bingel, U. & Tracey, I. Prestimulus functional connectivity determines pain perception in humans. Proc. Natl. Acad. Sci. USA 107, 355–360 (2010).
Coghill, R.C., McHaffie, J.G. & Yen, Y.F. Neural correlates of interindividual differences in the subjective experience of pain. Proc. Natl. Acad. Sci. USA 100, 8538–8542 (2003).
Erpelding, N., Moayedi, M. & Davis, K.D. Cortical thickness correlates of pain and temperature sensitivity. Pain 153, 1602–1609 (2012).
Foerster, B.R. et al. Reduced insular gamma-aminobutyric acid in fibromyalgia. Arthritis Rheum. 64, 579–583 (2012).
Gwilym, S.E. et al. Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum. 61, 1226–1234 (2009).
Wanigasekera, V. et al. Baseline reward circuitry activity and trait reward responsiveness predict expression of opioid analgesia in healthy subjects. Proc. Natl. Acad. Sci. USA 109, 17705–17710 (2012).
Baliki, M.N. et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat. Neurosci. 15, 1117–1119 (2012).
Mansour, A.R. et al. Brain white matter structural properties predict transition to chronic pain. Pain 154, 2160–2168 (2013).
Baliki, M.N., Geha, P.Y., Fields, H.L. & Apkarian, A.V. Predicting value of pain and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain. Neuron 66, 149–160 (2010).
Becerra, L., Breiter, H.C., Wise, R., Gonzalez, R.G. & Borsook, D. Reward circuitry activation by noxious thermal stimuli. Neuron 32, 927–946 (2001).
Wood, P.B. et al. Fibromyalgia patients show an abnormal dopamine response to pain. Eur. J. Neurosci. 25, 3576–3582 (2007).
Schweinhardt, P., Seminowicz, D.A., Jaeger, E., Duncan, G.H. & Bushnell, M.C. The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response. J. Neurosci. 29, 4882–4887 (2009).
Leknes, S. et al. The importance of context: when relative relief renders pain pleasant. Pain 154, 402–410 (2013).
Tracey, I. & Dickenson, A. SnapShot: pain perception. Cell 148, 1308–1308.e2 (2012).
Heinricher, M.M., Tavares, I., Leith, J.L. & Lumb, B.M. Descending control of nociception: Specificity, recruitment and plasticity. Brain Res. Rev. 60, 214–225 (2009).
Lee, M.C., Zambreanu, L., Menon, D.K. & Tracey, I. Identifying brain activity specifically related to the maintenance and perceptual consequence of central sensitization in humans. J. Neurosci. 28, 11642–11649 (2008).
Eippert, F., Finsterbusch, J., Bingel, U. & Buchel, C. Direct evidence for spinal cord involvement in placebo analgesia. Science 326, 404 (2009).
Geuter, S. & Buchel, C. Facilitation of pain in the human spinal cord by nocebo treatment. J. Neurosci. 33, 13784–13790 (2013).
Weissman-Fogel, I. et al. Enhanced presurgical pain temporal summation response predicts post-thoracotomy pain intensity during the acute postoperative phase. J. Pain 10, 628–636 (2009).
Yarnitsky, D. Conditioned pain modulation (the diffuse noxious inhibitory control-like effect): its relevance for acute and chronic pain states. Curr. Opin. Anaesthesiol. 23, 611–615 (2010).
Yarnitsky, D. et al. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain 138, 22–28 (2008).
Yarnitsky, D., Granot, M., Nahman-Averbuch, H., Khamaisi, M. & Granovsky, Y. Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy. Pain 153, 1193–1198 (2012).
De Felice, M. et al. Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain 152, 2701–2709 (2011).
Wang, R. et al. Descending facilitation maintains long-term spontaneous neuropathic pain. J. Pain 14, 845–853 (2013).
Hathway, G.J., Koch, S., Low, L. & Fitzgerald, M. The changing balance of brainstem-spinal cord modulation of pain processing over the first weeks of rat postnatal life. J. Physiol. (Lond.) 587, 2927–2935 (2009).
Hathway, G.J., Vega-Avelaira, D. & Fitzgerald, M. A critical period in the supraspinal control of pain: opioid-dependent changes in brainstem rostroventral medulla function in preadolescence. Pain 153, 775–783 (2012).
Vega-Avelaira, D., McKelvey, R., Hathway, G. & Fitzgerald, M. The emergence of adolescent onset pain hypersensitivity following neonatal nerve injury. Mol. Pain 8, 30 (2012).
Smith, Y.R. et al. Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women. J. Neurosci. 26, 5777–5785 (2006).
Vincent, K. et al. Brain imaging reveals that engagement of descending inhibitory pain pathways in healthy women in a low endogenous estradiol state varies with testosterone. Pain 154, 515–524 (2013).
Tu, C.H. et al. Menstrual pain is associated with rapid structural alterations in the brain. Pain 154, 1718–1724 (2013).
Vincent, K. et al. Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain 152, 1966–1975 (2011).
Labus, J.S. et al. Sex differences in emotion-related cognitive processes in irritable bowel syndrome and healthy control subjects. Pain 154, 2088–2099 (2013).
Moayedi, M. et al. Contribution of chronic pain and neuroticism to abnormal forebrain gray matter in patients with temporomandibular disorder. Neuroimage 55, 277–286 (2011).
Chen, J.Y., Blankstein, U., Diamant, N.E. & Davis, K.D. White matter abnormalities in irritable bowel syndrome and relation to individual factors. Brain Res. 1392, 121–131 (2011).
Erpelding, N. & Davis, K.D. Neural underpinnings of behavioural strategies that prioritize either cognitive task performance or pain. Pain 154, 2060–2071 (2013).
Kuchinad, A. et al. Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J. Neurosci. 27, 4004–4007 (2007).
Villemure, C., Ceko, M., Cotton, V.A. & Bushnell, M.C. Insular cortex mediates increased pain tolerance in yoga practitioners. Cereb. Cortex published online, 10.1093/cercor/bht123 (21 May 2013).
Coggon, D.I. & Martyn, C.N. Time and chance: the stochastic nature of disease causation. Lancet 365, 1434–1437 (2005).
Hashmi, J.A. et al. Shape shifting pain: chronification of back pain shifts brain representation from nociceptive to emotional circuits. Brain 136, 2751–2768 (2013).
Segerdahl, A.R. et al. Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling. Pain 153, 1122–1127 (2012).
Ploghaus, A. et al. Dissociating pain from its anticipation in the human brain. Science 284, 1979–1981 (1999).
Bushnell, M.C., Ceko, M. & Low, L.A. Cognitive and emotional control of pain and its disruption in chronic pain. Nat. Rev. Neurosci. 14, 502–511 (2013).
Mouraux, A., Diukova, A., Lee, M.C., Wise, R.G. & Iannetti, G.D. A multisensory investigation of the functional significance of the “pain matrix”. Neuroimage 54, 2237–2249 (2011).
Garcia-Larrea, L. & Peyron, R. Pain matrices and neuropathic pain matrices: a review. Pain (in the press).
Wager, T.D. et al. An fMRI-based neurologic signature of physical pain. N. Engl. J. Med. 368, 1388–1397 (2013).
Covington, H.E. III et al. A role for repressive histone methylation in cocaine-induced vulnerability to stress. Neuron 71, 656–670 (2011).
The authors are supported by grants from the Wellcome Trust.
The authors declare no competing financial interests.
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Denk, F., McMahon, S. & Tracey, I. Pain vulnerability: a neurobiological perspective. Nat Neurosci 17, 192–200 (2014). https://doi.org/10.1038/nn.3628
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