Abstract
SUMMARY
Pain is a significant national burden in terms of patient suffering, expenditure and lost productivity. Understanding pain is fundamental to improving evaluation, treatment and innovation in the management of acute and persistent pain syndromes. Pain perception begins in the periphery, and then ascends in several tracts, relaying at different levels. Pain signals arrive in the thalamus and midbrain structures which form the pain neuromatrix, a constantly shifting set of networks and connections that determine conscious perception. Several cortical regions become active simultaneously during pain perception; activity in the cortical pain matrix evolves over time to produce a complex pain perception network. Dysfunction at any level has the potential to produce unregulated, persistent pain.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Committee on Advancing Pain Research Care, and Education, Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. The National Academies Press, Washington, DC, USA (2011).
- 2 Taxonomy ITFO. Part III. Pain terms, a current list with definitions and notes on usage. In: Classification of Chronic Pain. Merskey H, Bogduk N (Eds). IASP Press, Seattle, WA, USA, 209–214 (1994).
- 3 . TRP channels and pain. Ann. Rev. Cell Devel. Biol. 29, 355–384 (2013).
- 4 . Pain hypersensitivity mechanisms at a glance. Dis. Model Mech. 6(4), 889–895 (2013).•• This review summarizes the peripheral receptor nocioception process and provides an excellent illustration of the different mechanisms through which persistent pain can arise in the nerve ending.
- 5 . Novel classes of responsive and unresponsive C nociceptors in human skin. J. Neurosci. 15(1 Pt 1), 333–341 (1995).
- 6 . Role of different brain areas in peripheral nerve injury-induced neuropathic pain. Brain Res. 1381, 187–201 (2011).
- 7 . Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions. Annu. Rev. Neurosci. 24, 737–777 (2001).
- 8 . The antero-posterior heterogeneity of the ventral tegmental area. Neuroscience 282C, 198–216 (2014).
- 9 Nerve growth factor of red nucleus involvement in pain induced by spared nerve injury of the rat sciatic nerve. Neurochem. Res. 34(9), 1612–1618 (2009).
- 10 Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology 52(2), 415–422 (2007).
- 11 . Pro-nociceptive action of cholecystokinin in the periaqueductal grey: a role in neuropathic and anxiety-induced hyperalgesic states. Neurosci. Biobehav. Rev. 32(4), 852–862 (2008).
- 12 . The role of the periaqueductal gray in the modulation of pain in males and females: are the anatomy and physiology really that different? Neural Plast. 462879 (2009).
- 13 . Descending modulation of pain the GABA disinhibition hypothesis of analgesia. Curr. Opin. Neurobiol. 29, 159–164 (2014).
- 14 Ca(v)3.2 T-type Ca2+ channel-dependent activation of ERK in paraventricular thalamus modulates acid-induced chronic muscle pain. J. Neurosci. 30(31), 10360–10368 (2010).
- 15 . Unmasking the mysteries of the habenula in pain and analgesia. Prog. Neurobiol. 96(2), 208–219 (2012).
- 16 . Descending modulation of neuropathic hypersensitivity by dopamine D2 receptors in or adjacent to the hypothalamic A11 cell group. Pharmacol. Res. 59(5), 355–363 (2009).
- 17 . Effect of memantine on the levels of neuropeptides and microglial cells in the brain regions of rats with neuropathic pain. J. Mol. Neurosci. 39(3), 380–390 (2009).
- 18 . Thalamus and pain. Acta Anaesthesiol. Taiwan 51(2), 73–80 (2013).
- 19 . Afferent projections to the dorsal thalamus of the rat as shown by retrograde lectin transport–I. The mediodorsal nucleus. Neuroscience 24(3), 1035–1049 (1988).
- 20 . The organization of projections from the mediodorsal nucleus of the thalamus to orbital and medial prefrontal cortex in macaque monkeys. J. Comp. Neurol. 337(1), 1–31 (1993).
- 21 . The cerebellum and pain passive integrator or active participator? Brain Res. Rev. 65(1), 14–27 (2010).
- 22 . Brain regions associated with psychological pain implications for a neural network and its relationship to physical pain. Brain Imaging Behav. 7(1), 1–14 (2013).
- 23 . Cerebellar loops: a review of the nucleocortical pathway. Cerebellum 13(3), 378–385 (2014).
- 24 . Pain matrices and neuropathic pain matrices: a review. Pain 154(Suppl. 1), S29–S43 (2013).•• The cortical pain matrix model.
- 25 . The dynamic pain connectome. Trends Neurosci. 38(2), 86–95 (2015).•• The dynamic pain connectome in the cortex.
- 26 . Limbic associated pelvic pain: a hypothesis to explain the diagnostic relationships and features of patients with chronic pelvic pain. Med. Hypotheses 69(2), 282–286 (2007).
- 27 . Pain and suffering. Clin. J. Pain 16(2 Suppl.), S2–S6 (2000).
- 28 . Rhythms of the Brain. Oxford University Press, USA (2011).•• An excellent and readable explanation of electrical activity in the brain.
- 29 . A default mode of brain function. Proc. Natl Acad. Sci. USA 98(2), 676–682 (2001).• An introduction to the default mode network in the cortex.
- 30 . Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J. Neurosci. 28(6), 1398–1403 (2008).
- 31 Enhanced medial prefrontal-default mode network functional connectivity in chronic pain and its association with pain rumination. J. Neurosci. 34(11), 3969–3975 (2014).
- 32 . Cingulate Neurobiology and Sisease. Oxford University Press, Oxford, UK (2009).• A comprehensive text on the different functions of the cingulate cortex.
- 33 . Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6(7), 533–544 (2005).
- 34 . Submodalities of emotion in the context of cingulate subregions. Cortex 59, 197–202 (2014).
- 35 . Limbic systems for emotion and for memory, but no single limbic system. Cortex 62, 1159–157 (2015).
- 36 Dorsal anterior cingulate cortex: a role in reward-based decision making. Proc. Natl Acad. Sci. USA 99(1), 523–528 (2002).
- 37 . Cingulotomy for medically refractory cancer pain. Neurosurg. Focus 35(3), E1 (2013).
- 38 . Abnormal thalamocortical activity in patients with Complex Regional Pain Syndrome (CRPS) type I. Pain 150(1), 41–51 (2010).
- 39 . Thalamocortical dysrhythmia and chronic pain. Pain 150(1), 4–5 (2010).• A decription of pain based on interaction between the thalamus and cortex.
- 40 . Brain dynamics underlying the nonlinear threshold for access to consciousness. PLoS Biol. 5(10), e260 (2007).
- 41 Brain structural and psychometric alterations in chronic low back pain. Eur. Spine J. 22(9), 1958–1964 (2013).
- 42 . Cognitive control, hierarchy, and the rostro-caudal organization of the frontal lobes. Trends Cogn. Sci. 12(5), 193–200 (2008).
- 43 . Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn. Sci. 15(2), 85–93 (2011).
- 44 Association of neural and physiological responses during voluntary emotion suppression. Neuroimage 29(3), 721–733 (2006).
- 45 . The importance of context: when relative relief renders pain pleasant. Pain 154(3), 402–410 (2013).
- 46 . Spatial sensory organization and body representation in pain perception. Curr. Biol. 23(4), R164–R176 (2013).
- 47 Somatotopic representation of pain in the primary somatosensory cortex (S1) in humans. Clin. Neurophysiol. 124(7), 1422–1430 (2013).
- 48 . Cortical representation of pain in primary sensory-motor areas (S1/M1) – a study using intracortical recordings in humans. Hum. Brain Mapp. 34(10), 2655–2668 (2013).
- 49 . Phantom limbs and the concept of a neuromatrix. Trends Neurosci. 13(3), 88–92 (1990).• The first description of a neuromatrix for pain perception.
- 50 . Imaging of acute versus pathological pain in humans. Eur. J. Pain 9(2), 163–165 (2005).
- 51 Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum. Mol. Genet. 14(1), 135–143 (2005).
- 52 Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131(2), 391–404 (2007).
- 53 . The pain matrix reloaded: a salience detection system for the body. Prog. Neurobiol. 93(1), 111–124 (2011).
- 54 . The posterior insular-opercular region and the search of a primary cortex for pain. Neurophysiol. Clin. 42(5), 299–313 (2012).
- 55 . Stimulation in the human somatosensory thalamus can reproduce both the affective and sensory dimensions of previously experienced pain. Nat. Med. 1(9), 910–913 (1995).
- 56 . Does the insula tell our brain that we are in pain? Pain 152(4), 946–951 (2011).
- 57 . The ‘where’ and the ‘when’ of the BOLD response to pain in the insular cortex. Discussion on amplitudes and latencies. Neuroimage 64, 466–475 (2013).
- 58 . Neurocognitive aspects of pain perception. Trends Cogn. Sci. 12(8), 306–313 (2008).
- 59 Effect of hypnotic pain modulation on brain activity in patients with temporomandibular disorder pain. Pain 151(3), 825–833 (2010).
- 60 . Meta-analytic evidence for common and distinct neural networks associated with directly experienced pain and empathy for pain. Neuroimage 54(3), 2492–2502 (2011).
- 61 . Conscious, preconscious, and subliminal processing: a testable taxonomy. Trends Cogn. Sci. 10(5), 204–211 (2006).
- 62 . A non-elaborative mental stance and decoupling of executive and pain-related cortices predicts low pain sensitivity in Zen meditators. Pain 152(1), 150–156 (2011).
- 63 Brain dysfunction in fibromyalgia and somatization disorder using proton magnetic resonance spectroscopy: a controlled study. Acta Psychiatr. Scand. 126(2), 115–125 (2012).
- 64 . Painful stimuli evoke potentials recorded over the human anterior cingulate gyrus. J. Neurophysiol. 79(4), 2231–2234 (1998).
- 65 . Dissociated neural representations of pain expressions of different races. Cereb. Cortex
doi:10.1093/cercor/bhu314 (2015) (Epub ahead of print). - 66 . Pain catastrophizing and EEG-alpha asymmetry. Clin. J. Pain (2014) (Epub ahead of print).
- 67 Dysfunctional pain modulation in somatoform pain disorder patients. Eur. Arch. Psychiatry Clin. Neurosci. 261(4), 267–275 (2011).
- 68 Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J. Neurosci. 24(46), 10410–10415 (2004).
- 69 . Brain source connectivity reveals the visceral pain network. Neuroimage 60(1), 37–46 (2012).• A review of visceral pain and cortical activity.
- 70 . Brain functional and anatomical changes in chronic prostatitis/chronic pelvic pain syndrome. J. Urol. 186(1), 117–124 (2011).
- 71 . Functional MRI of the brain during orgasm in women. Annu. Rev. Sex Res. 16, 62–86 (2005).
- 72 Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain. Pain 152(12), 2701–2709 (2011).
- 73 . The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans. Pain 144(1–2), 16–19 (2009).
- 74 . Meditation reduces pain-related neural activity in the anterior cingulate cortex, insula, secondary somatosensory cortex, and thalamus. Front. Psychol. 5, 1489 (2014).
- 75 . Temporal changes in cortical activation during conditioned pain modulation (CPM), a LORETA study. Pain 152(7), 1469–1477 (2011).
- 76 . Placebo effects. from the neurobiological paradigm to translational implications. Neuron 84(3), 623–637 (2014).•• A review of placebo analgesia mechanisms.
- 77 IASP Taxonomy. www.iasp-pain.org/taxonomy.
- 78 . Predictors of persistent pain after total knee arthroplasty: a systematic review and meta-analysis. Br. J. Anaesth. 114(4), 551–561 (2015).• Persistant pain mechanisms described.
- 79 . Nociceptor sensitization in pain pathogenesis. Nat. Med. 16(11), 1248–1257 (2010).
- 80 . Chronic musculoskeletal pain review of mechanisms and biochemical biomarkers as assessed by the microdialysis technique. J. Pain Res. 7, 313–326 (2014).
- 81 Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density. Pain 154(11), 2500–2511 (2013).
- 82 . Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc. Natl Acad. Sci. USA 96(14), 7723–7730 (1999).
- 83 . Detailed characterization of neuro-immune responses following neuropathic injury in mice. Brain Res. 1405, 95–108 (2011).
- 84 . The neurobiology of skeletal pain. Eur. J. Neurosci. 39(3), 508–519 (2014).
- 85 Differential sensitization of silent nociceptors to low pH stimulation by prostaglandin E2 in human volunteers. Eur. J. Pain 19(2), 159–166 (2014).• Silent nociceptor activation in chronic pain.
- 86 . Interstitial cystitis and chronic pelvic pain new insights in neuropathology, diagnosis, and treatment. Clin. Obstet. Gynecol. 46(4), 811–823 (2003).
- 87 . Peripheral nerve injury produces a sustained shift in the balance between glutamate release and uptake in the dorsal horn of the spinal cord. Pain 153(12), 2422–2431 (2012).
- 88 . Models and mechanisms of hyperalgesia and allodynia. Physiol. Rev. 89(2), 707–758 (2009).
- 89 . Roles of the rostroventromedial medulla and the spinal 5-HT(1A) receptor in descending antinociception induced by motor cortex stimulation in the neuropathic rat. Neurosci. Lett. 476(3), 133–137 (2010).
- 90 Neuropeptide Y modulates c-Fos protein expression in the cuneate nucleus and contributes to mechanical hypersensitivity following rat median nerve injury. J. Neurotrauma. 26(9), 1609–1621 (2009).
- 91 . Upregulation of the GABA transporter GAT-1 in the gracile nucleus in the spared nerve injury model of neuropathic pain. Neurosci. Lett. 480(2), 132–137 (2010).
- 92 . Bilateral lesions in the area of the nucleus locus coeruleus affect the development of hyperalgesia during carrageenan-induced inflammation. Brain Res. 726(1–2), 233–236 (1996).
- 93 . Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain. Neuroscience 160(1), 174–185 (2009).
- 94 . Are psychoactive substance (opioid)-dependent chronic pain patients hyperalgesic? Pain Pract. 11(4), 337–343 (2011).
- 95 . Evidence for a central component of post-injury pain hypersensitivity. Nature 306(5944), 686–688 (1983).
- 96 . MRI structural brain changes associated with sensory and emotional function in a rat model of long-term neuropathic pain. Neuroimage 47(3), 1007–1014 (2009).
- 97 . Phantom sensations generated by thalamic microstimulation. Nature 391(6665), 385–387 (1998).
- 98 . Striatal dopamine D2 receptors attenuate neuropathic hypersensitivity in the rat. Exp. Neurol. 205(2), 536–546 (2007).
- 99 . NMDA receptor-independent synaptic plasticity in the central amygdala in the rat model of neuropathic pain. Pain 127(1–2), 161–172 (2007).
- 100 . Hemispheric lateralization of a molecular signal for pain modulation in the amygdala. Mol. Pain 4, 24 (2008).
- 101 . Forebrain pain mechanisms. Brain Res. Rev. 60(1), 226–242 (2009).
- 102 . Insular cortex lesion diminishes neuropathic and inflammatory pain-like behaviours. Eur. J. Pain 15(2), 132–138 (2011).
- 103 Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat. Neuroscience 120(4), 1093–1104 (2003).
- 104 . Enhanced quantal release of excitatory transmitter in anterior cingulate cortex of adult mice with chronic pain. Mol. Pain 5, 4 (2009).
- 105 Analgesic effect of milnacipran is associated with c-Fos expression in the anterior cingulate cortex in the rat neuropathic pain model. Neurosci. Res. 64(4), 380–384 (2009).
- 106 Chronic constriction injury reduces cannabinoid receptor 1 activity in the rostral anterior cingulate cortex of mice. Brain Res. 1339, 18–25 (2010).
- 107 . Continuous perfusion with morphine of the orbitofrontal cortex reduces allodynia and hyperalgesia in a rat model for mononeuropathy. Neurosci. Lett. 364(1), 27–31 (2004).
- 108 A single subcutaneous injection of ozone prevents allodynia and decreases the over-expression of pro-inflammatory caspases in the orbito-frontal cortex of neuropathic mice. Eur. J. Pharmacol. 603(1–3), 42–49 (2009).
- 109 . Restoration of altered somatosensory cortical representation with spinal cord stimulation therapy in a patient with complex regional pain syndrome: a magnetoencephalography case study. Neuromodulation 17(1), 22–26; discussion 26–27 (2014).
- 110 . Sleep features and central sensitization symptoms in primary headache patients. J. Headache Pain 15, 64 (2014).
- 111 . Latent profile analysis of pelvic floor muscle pain in patients with chronic pelvic pain. Minerva Ginecol. 65(1), 69–78 (2013).
- 112 . Phenotyping chronic pelvic pain based on latent class modeling of physical examination. Pain Res. Treat. 891301 (2013).
- 113 Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker. Pain 153(1), 80–85 (2012).
- 114 Congenital insensitivity to pain novel SCN9A missense and in-frame deletion mutations. Hum. Mutat. 31(9), E1670–E1686 (2010).
- 115 A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain 151(2), 337–344 (2010).
- 116 . Activation of alpha2 adrenoceptors inhibited NMDA receptor-mediated nociceptive transmission in spinal dorsal horn of mice with inflammatory pain. Neuropharmacology 77, 185–192 (2014).
- 117 . MeCP2 repression of G9a in regulation of pain and morphine reward. J. Neurosci. 34(27), 9076–9087 (2014).
- 118 . The spinal anti-inflammatory mechanism of motor cortex stimulation: cause of success and refractoriness in neuropathic pain? J. Neuroinflammation 12(1), 10 (2015).
- 119 . A systematic review of the efficacy and general safety of antibodies to NGF in the treatment of OA of the hip or knee. Osteoarthritis Cartilage 23(Suppl. 1), S8–S17 (2015).
- 120 Investigation of central nervous system dysfunction in chronic pelvic pain using magnetic resonance spectroscopy and noninvasive brain stimulation. Pain Pract. 15(5), 423–432 (2015).
- 121 . A pilot efficacy trial of tDCS for the treatment of refractory chronic pelvic pain. Brain Stimul. 2(2), 103–107 (2009).
- 122 . Invasive stimulation therapies for the treatment of refractory pain. Discov. Med. 14(77), 237–246 (2012).