KFO 130:  Determinants and Modulators of Postoperative Pain

• Subject Area: Medicine ; Computer Science, Systems and Electrical Engineering
• Term: from 2005 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5397725

• Final Report Year: 2021

Final Report Abstract

Bei 10–50% aller Patienten nach chirurgischen Routine-Eingriffen gehen akute postoperative Schmerzen in Schmerzen über, die über die Akutphase und normale Heilungszeit hinaus persistieren. Persistierende Schmerzen können der Beginn einer chronischen Schmerzkrankheit sein. Die Ursache persistierender postoperativer Schmerzen sind inflammatorische Prozesse sowie intraoperative Nervenverletzungen. Risikofaktoren für persistierende Schmerzen sind u. a. vorbestehende Schmerzen und starke postoperative Schmerzen. Die Bedeutung intra- und postoperativ verabreichter Anästhetika und Analgetika, genetischer Faktoren und der psychologischen Suszeptibilität sind unbekannt. Ziel dieser KFO war es, neurobiologische, pharmakologische, genetische und psychosoziale Faktoren der postoperativen Schmerzverarbeitung zu identifizieren und Konstellationen zu charakterisieren, die den Übergang von akuten zu persistierenden Schmerzen begünstigen. Auf dieser Basis können Screeningparameter, Therapieansätze und Interventionsstrategien entwickelt werden, um der Entwicklung persistierender Schmerzen bei entsprechenden Risikopopulationen vorzubeugen. Die wichtigsten neuen Erkenntnisse, die durch die KFO erarbeitet wurden, können wie folgt zusammengefasst werden: Klinisch gebräuchliche Anästhetika und Analgetika können durch Interaktion mit nozizeptiven Membranproteinen wie TRPV1 und TRPA1 zu pronozizeptiven Effekten führen. Dieser Mechanismus trägt zur bislang unklaren Neurotoxizität von Lokalanästhetika bei und liegt dem Injektionsschmerz bei Applikation von Propofol zugrunde. Die klinische Relevanz bezüglich postoperativer Schmerzen ist unklar. Der Hyperpolarisations-aktivierte und durch zyklisches Nukleotid-gesteuerte Kationenkanal HCN2 in Nozizeptoren konnte als neues Target für die Therapie entzündlich und neuropathisch bedingter Schmerzen identifiziert werden: Neuronale HCN2-Kanäle, die nachgeschaltet zu Nozizeptoren exprimiert werden, vermitteln die thermische Hyperalgesie bei Entzündung und spielen eine wichtige Rolle sowohl bei der peripheren als auch zentralen Schmerzsensibilisierung. EP2-Prostaglandinrezeptoren spielen eine gegenüber dem EP1-Rezeptor dominierende Rolle für die entzündliche Hyperalgesie, für die postoperative Hyperalgesie leistet die Prostaglandin E2 und EP2-Rezeptor vermittelte Hemmung spinaler Glycinrezeptoren jedoch keinen signifikanten Beitrag. Die Endocannabinoid-vermittelte zentrale Hyperalgesie ist spezifisch für aktivitätsabhängige Sensibilisierungsprozesse aber nicht wesentlich für den humoral vermittelten Entzündungsschmerz oder den neuropathischen Schmerz nach peripherer Nervenläsion. Endogene pro- und antinozizeptive Systeme sind an der Modulation akuter und chronischer Schmerzzustände beteiligt und werden durch Anästhetika und Opioide moduliert. Hyperalgesie-induzierende Schmerzreize lösen kurz- und langfristige Habituationsphänomene aus. Damit assoziiert sind Aktivierungen im Hirnstamm (PAG und ventrales tegmentales Areal). Eine Narkose führte zu einer signifikanten post-interventionellen Analgesie unabhängig von der eingesetzten Anästhetika-Kombination. In vergleichenden genomweiten Expressionsanalysen in entzündeten und nicht-entzündeten Darm-Gewebe von Patienten mit M. Crohn mit hohem und niedrigem postoperativen Schmerzmittelbedarf zeigten sich 3 Gene (IRS2, TCF21 und SPIB) differentiell exprimiert. Deren Bedeutung ist Gegenstand aktueller Untersuchungen. Epigenetische Untersuchungen lassen eine veränderte Promotormethylierung des TRPA1-Gens in Crohn-Patienten vermuten, welche zur Symptomatik bei M. Crohn beitragen könnte. Das Hypervigilanz-Konzept konnte als Prädiktor für akute und persistierende postoperative Schmerzen gesichert werden. Eine einmalige starke Schmerzerfahrung ruft mindestens kurz-anhaltende Veränderungen in der attentativen und emotionalen Schmerzverarbeitung hervor. Zur kognitiv-emotionalen Schmerzbewältigung als Protektivfaktor für den langfristigen Umgang mit Folgen von Operation und Schmerzerlebnissen konnte ein multidimensionales psychologisches Prophylaxetraining identifiziert werden.

Publications

• (2005) Transdermal buprenorphine in the treatment of chronic pain. Expert Rev Neurother 5(3):315-23
  Sittl R
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• (2005): Synaptic Modulation in Pain Pathways. Reviews Physiol Biochem Pharmacol 155, 73-100
  Zeilhofer HU
  (See online at https://doi.org/10.1007/s10254-005-0043-y)
• (2005): The glycinergic control of nociception. Cell Mol Life Sci 62, 2027-35
  Zeilhofer HU
  (See online at https://doi.org/10.1007/s00018-005-5107-2)
• (2006) Transdermal buprenorphine in cancer pain and palliative care. Palliat Med 20 Suppl1: s25-30
  Sittl R
  (See online at https://doi.org/10.1191/0269216306pm1125oa)
• (2006): Analgesic strategies beyond inhibition of cyclooxygenases. Trends Pharmacol Sci 27, 467-74
  Zeilhofer HU, Brune K
  (See online at https://doi.org/10.1016/j.tips.2006.07.007)
• (2007) Brain imaging of analgesic and antihyperalgesic effects of cyclooxygenase inhibition in an experimental human pain model: a functional MRI study. Eur J Neurosci 26(5):1344-56
  Maihöfner C, Ringler R, Herrndobler F, Koppert W
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• (2007) Complex regional pain syndromes: new aspects on pathophysiology and therapy. Forschr Neurol Psychiatr 75(6):331-42
  Maihöfner C, Birklein F
  (See online at https://doi.org/10.1055/s-2006-944310)
• (2007) Klinische Pharmakologie analgetischer Substanzen. In: Postoperative Schmerztherapie, 1. Auflage, herausgegeben von Pogatzki-Zahn E, Zahn P, Van Aken H, Georg Thieme Verlag KG, Stuttgart
  Nau C, Schüttler J
  (See online at https://doi.org/10.1055/b-0034-28067)
• (2007) Loss of glycinergic and GABAergic inhibition in chronic pain – contributions of inflammation and microglia. Int Immunopharmacol 8(2):182-7
  Zeilhofer HU
  (See online at https://doi.org/10.1016/j.intimp.2007.07.009)
• (2007) Opioid-induced hyperalgesia – Pathophysiology and clinical relevance. Acute Pain 9:21-34
  Koppert W
  (See online at https://doi.org/10.1016/j.acpain.2006.11.001)
• (2007) Sensory neuron sodium channel Nav1.8 is essential for pain at low temperatures. Nature 447:855-9
  Zimmermann K, Leffler A, Babes A, Cendan CM, Carr RW, Kobayashi J, Nau C, Wood JN, Reeh PW
  (See online at https://doi.org/10.1038/nature05880)
• (2007) Studying sex and gender differences in pain and analgesia: A consensus report. Pain 132:S26-S45
  Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, Gold MS, Holdcroft A, Lautenbacher S, Mayer EA, Mogil JS, Murphy AZ, Traub RJ, the Consensus Working Group of the Sex, Gender, and Pain SIG of the IASP
  (See online at https://doi.org/10.1016/j.pain.2007.10.014)
• (2007) The impact of opioid-induced hyperalgesia for postoperative pain. Best Pract Res Clin Anaesthesiol 21(1):65-83
  Koppert W, Schmelz M
  (See online at https://doi.org/10.1016/j.bpa.2006.12.004)
• (2007): Imaging of hyperalgesia in rats by functional MRI. Eur J Pain 11:109-19
  Hess A, Sergejeva M, Budinsky L, Zeilhofer HU, Brune K
  (See online at https://doi.org/10.1016/j.ejpain.2006.01.005)
• (2007): Prostanoids in nociception and pain. Biochem Pharmacol 73, 165-74
  Zeilhofer HU
  (See online at https://doi.org/10.1016/j.bcp.2006.07.037)
• (2008) A familybased investigation of cold pain tolerance. Pain 138(1):111-8
  Birklein F, Depmeier C, Rolke R, Hansen C, Rautenstrauss B, Prawitt D, Magerl W
  (See online at https://doi.org/10.1016/j.pain.2007.11.012)
• (2008) Novel missense, insertion and deletion mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with congenital insensitivity to pain with anhidrosis. Neuromusc Disord 18:159-66
  Huehne K, Zweier C, Raab K, Odent S, Bonnaure-Mallet M, Sixou JL, Landrieu P, Goizet C, Sarlangue J, Baumann M, Eggermann T, Rauch A, Ruppert S, Stettner GM, Rautenstrauss B
  (See online at https://doi.org/10.1016/j.nmd.2007.10.005)
• (2008) Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 451:330-4
  Knabl J, Witschi R, Hösl K, Reinold H, Zeilhofer U, Ahmadi S, Brockhaus J, Sergejeva M, Hess A, Brune K, Fritschy JM, Rudolph U, Möhler H, Zeilhofer HU
  (See online at https://doi.org/10.1038/nature06493)
• (2008) The vanilloid receptor TRPV1 is activated and sensitized by local anaesthetics in rodent sensory neurons. J Clin Invest 118:763-76
  Leffler A, Fischer MJ, Rehner D, Kienel S, Kistner K, Sauer SK, Gavva NR, Reeh PW, Nau C
  (See online at https://doi.org/10.1172/jci32751)
• (2009) Differential endogenous pain modulation in complex-regional pain syndrome. Brain 132(Pt 3):788-800
  Seifert F, Kiefer G, DeCol R, Schmelz M, Maihöfner C
  (See online at https://doi.org/10.1093/brain/awn346)
• (2009) Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice. Pain 141:237-43
  Knabl J, Zeilhofer UB, Crestani F, Rudolph U, Zeilhofer HU
  (See online at https://doi.org/10.1016/j.pain.2008.10.015)
• (2009) High post surgical opioid requirements in Crohn's disease are not due to a general change in pain sensitivity. Eur J Pain 13(10):1036-42
  Huehne K, Leis S, Muenster T, Wehrfritz A, Winter S, Maihöfner C, Foertsch T, Croner R, Reis A, Winterpacht A, Rautenstrauss B
  (See online at https://doi.org/10.1016/j.ejpain.2008.12.004)
• (2009) Hypervigilance as predictor of postoperative acute pain: its predictive potency compared with experimental pain sensitivity, cortisol reactivity, and affective state. Clin J Pain 25(2):92-100
  Lautenbacher S, Huber C, Kunz M, Parthum A, Weber PG, Griessinger N, Sittl R
  (See online at https://doi.org/10.1097/ajp.0b013e3181850dce)
• (2009) Increase of propofol requirement after repeated administration for experimental anaesthesia. Eur J Anaesthesiol 26(9):799-801
  Ihmsen H, Jeleazcov C, Filitz J, Schwilden H, Schüttler J, Koppert W
  (See online at https://doi.org/10.1097/eja.0b013e32832babcb)
• (2009) Medial prefrontal cortex activity is predictive for hyperalgesia and pharmacological antihyperalgesia. J Neurosci 29(19):6167-75
  Seifert F, Bschorer K, De Col R, Filitz J, Peltz E, Koppert W, Maihöfner C
  (See online at https://doi.org/10.1523/jneurosci.4654-08.2009)
• (2009) Modulation of cortical pain processing by cyclooxygenase inhibition: a functional MRI study. Schmerz 23(2):134-44
  Herrndobler F, Koppert W, Ringler R, Maihöfner C
  (See online at https://doi.org/10.1007/s00482-008-0732-y)
• (2009) Phenotyping sensory nerve endings in vitro in the mouse. Nat Protoc 4(2):174-96
  Zimmermann K, Hein A, Hager U, Kaczmarek JS, Turnquist BP, Clapham DE, Reeh PW
  (See online at https://doi.org/10.1038/nprot.2008.223)
• (2009) Spinal endocannabinoids and CB1 receptors mediate C fiber-induced heterosynaptic pain plasticity. Science 325:760-64
  Pernía-Andrade AJ, Kato A, Witschi R, Nyilas R, Katona I, Freund TF, Watanabe M, Filitz J, Koppert W, Schüttler J, Ji G, Neugebauer V, Marsicano G, Lutz B, Vanegas H, Zeilhofer HU
  (See online at https://doi.org/10.1126/science.1171870)
• (2010) A genome-wide Drosophila screen for heat nociception identifies alpha2delta3 as an evolutionarily conserved pain gene. Cell 143(4): 628-38
  Neely GG, Hess A, Costigan M, Keene AC, Goulas S, Langeslag M, Griffin RS, Belfer I, Dai F, Smith SB, Diatchenko L, Gupta V, Xia CP, Amann S, Kreitz S, Heindl-Erdmann C, Wolz S, Ly CV, Arora S, Sarangi R, Dan D, Novatchkova M, Rosenzweig M, Gibson DG, Truong D, Schramek D, Zoranovic T, Cronin SJ, Angjeli B, Brune K, Dietzl G, Maixner W, Meixner A, Thomas W, Pospisilik JA, Alenius M, Kress M, Subramaniam S, Garrity PA, Bellen HJ, Woolf CJ, Penninger JM
  (See online at https://doi.org/10.1016/j.cell.2010.09.047)
• (2010) Aktuelle Erkenntnisse zur Pathophysiologie des CRPS I. Handchir Mikrochir Plast Chir 42(1):8-14
  Nickel FT, Maihöfner C
  (See online at https://doi.org/10.1055/s-0029-1246211)
• (2010) Analgesic and antihyperalgesic properties of propofol in a human pain model. Anesthesiology 113(2):421-8
  Bandschapp O, Filitz J, Ihmsen H, Berset A, Urwyler A, Koppert W, Ruppen W
  (See online at https://doi.org/10.1097/aln.0b013e3181e33ac8)
• (2010) Attentional and emotional mechanisms of pain processing and their related factors: a structural equations approach. Pain Res Manag 15(4):229-37
  Huber C, Kunz M, Artelt C, Lautenbacher S
  (See online at https://doi.org/10.1155/2010/516176)
• (2010) Attentional and emotional mechanisms related to pain as predictors of chronic postoperative pain: a comparison with other psychological and physiological predictors. Pain 151(3):722-31
  Lautenbacher S, Huber C, Schöfer D, Kunz M, Parthum A, Weber PG, Roman C, Griessinger N, Sittl R
  (See online at https://doi.org/10.1016/j.pain.2010.08.041)
• (2010) Block of sensory neuronal Na+ channel by the secretolytic ambroxol is associated with an interaction with local anesthetic binding sites. Eur J Pharmacol 630:19-28
  Leffler A, Reckzeh J, Nau C
  (See online at https://doi.org/10.1016/j.ejphar.2009.12.027)
• (2010) Chronische Schmerzen nach Operationen. Epidemiologie unter besonderer Berücksichtigung psychologischer Risikofaktoren. Anasthesiol Intensivmed Notfallmed Schmerzther 45(7-8):488-93
  Dimova V, Lautenbacher S
  (See online at https://doi.org/10.1055/s-0030-1262478)
• (2010) Chronische Schmerzen nach Operationen. Topthema trotz dürftiger Studienlage. Anasthesiol Intensivmed Notfallmed Schmerzther 45(7-8):478-9
  Koppert W
  (See online at https://doi.org/10.1055/s-0030-1262476)
• (2010) Combining functional magnetic resonance imaging with mouse genomics: new options in pain research. Neuroreport 21(1):29-33
  Heindl-Erdmann, C, Axmann R, Kreitz S, Zwerina J, Penninger J, Schett G, Brune K, Hess A
  (See online at https://doi.org/10.1097/wnr.0b013e3283324faf)
• (2010) Interaction of physostigmine and alfentanil in a human pain model. Br J Anaesth 104(3):359-68
  Wehrfritz AP, Ihmsen H, Schmidt S, Müller C, Filitz J, Schüttler J, Koppert W
  (See online at https://doi.org/10.1093/bja/aep372)
• (2010) Lack of genetic association of neutral endopeptidase (NEP) with complex regional pain syndrome (CRPS). Neurosci Lett 472(1):19-23
  Huehne K, Schaal U, Leis S, Uebe S, Gosso MF, van den Maagdenberg AM, Maihöfner C, Birklein F, Rautenstrauss B, Winterpacht A
  (See online at https://doi.org/10.1016/j.neulet.2010.01.044)
• (2010) Neuropathische Schmerzsyndrome und Neuroplastizität in der funktionellen Bildgebung. Schmerz 24(2):137-45
  Maihöfner C, Nickel FT, Seifert F
  (See online at https://doi.org/10.1007/s00482-010-0902-6)
• (2010) The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABA A receptors. J Biol Chem 285:34781-92
  Fischer MJ, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, Nau C
  (See online at https://doi.org/10.1074/jbc.m110.143958)
• (2010). Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia. Brain 133:1823-35
  Choi JS, Cheng X, Foster E, Leffler A, Tyrrell L, Te Morsche RH, Eastman EM, Jansen HJ, Huehne K, Nau C, Dib-Hajj SD, Drenth JP, Waxman SG
  (See online at https://doi.org/10.1093/brain/awq114)
• (2011) Activation of central sympathetic networks during innocuous and noxious somatosensory stimulation. Neuroimage 55(1):216-24
  Maihöfner C, Seifert F, Decol R
  (See online at https://doi.org/10.1016/j.neuroimage.2010.11.061)
• (2011) Activation of TRPA1 by membrane permeable local anestheticss. Mol Pain 7:62
  Leffler A, Lattrell A, Kronewald S, Niedermirtl F, Nau C
  (See online at https://doi.org/10.1186/1744-8069-7-62)
• (2011) Attentional avoidance of negative experiences as predictor of postoperative pain ratings and consumption of analgesics: comparison with other psychological predictors. Pain Med 12(4):645-53
  Lautenbacher S, Huber C, Baum C, Rossaint R, Hochrein S, Heesen M
  (See online at https://doi.org/10.1111/j.1526-4637.2011.01076.x)
• (2011) Contribution of peripheral versus central EP1 prostaglandin receptors to inflammatory pain. Neurosci Lett 495:98-101
  Johansson T, Narumiya S, Zeilhofer HU
  (See online at https://doi.org/10.1016/j.neulet.2011.03.046)
• (2011) Differential effects on sensory functions and measures of epidermal nerve fiber density after application of a lidocaine patch (5%) on healthy human skin. Eur J Pain 15:907-12
  Wehrfritz A, Namer B, Ihmsen H, Mueller C, Filitz J, Koppert W, Leffler A
  (See online at https://doi.org/10.1016/j.ejpain.2011.03.011)
• (2011) Functional and structural imaging of pain-induced neuroplasticity. Curr Opin Anaesthesiol 24(5):515-23
  Seifert F, Maihöfner C
  (See online at https://doi.org/10.1097/aco.0b013e32834a1079)
• (2011) Functional connectivity of the human insular cortex during noxious and innocuous thermal stimulation. Neuroimage 54(2):1324-35
  Peltz E, Seifert F, DeCol R, Dörfler A, Schwab S, Maihöfner C
  (See online at https://doi.org/10.1016/j.neuroimage.2010.09.012)
• (2011) HZ166, a novel GABAA receptor subtype-selective benzodiazepine site ligand, is antihyperalgesic in mouse models of inflammatory and neuropathic pain. Neuropharmacol 60:626-32
  Di Lio A, Benke D, Besson M, Desmeules J, Daali Y, Wang ZJ, Edwankar R, Cook JM, Zeilhofer HU
  (See online at https://doi.org/10.1016/j.neuropharm.2010.11.026)
• (2011) Inhibition of hyperalgesia by conditioning electrical stimulation in a human pain model. Pain 152(6):1298-303
  Nickel FT, DeCol R, Jud S, Fasching PA, Seifert F, Maihöfner C
  (See online at https://doi.org/10.1016/j.pain.2011.02.005)
• (2011) On the use of alpha-chloralose for repeated BOLD fMRI measurements in rats. J Neurosci Methods 195(2):236-40
  de Celis Alonso B, Makarova T, Hess A
  (See online at https://doi.org/10.1016/j.jneumeth.2010.12.010)
• (2011) Prediction of Experimental Pain Sensitivity by Attention to Pain-Related Stimuli in Healthy Individuals. Percept Mot Skills 112(3):926-46
  Baum C, Huber C, Schneider R, Lautenbacher S
  (See online at https://doi.org/10.2466/02.09.22.pms.112.3.926-946)
• (2011) TRPA1 and substance P mediate colitis in mice. Gastroenterology 141:1346-58
  Engel MA, Leffler A, Niedermirtl F, Babes A, Zimmermann K, Filipović MR, Izydorczyk I, Eberhardt M, Kichko TI, Mueller-Tribbensee SM, Khalil M, Siklosi N, Nau C, Ivanović-Burmazović I, Neuhuber WL, Becker C, Neurath MF, Reeh PW
  (See online at https://doi.org/10.1053/j.gastro.2011.07.002)
• (2011). Blockade of TNF-α rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A 108:3731-6
  Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns O, Doerfler A, Brune K, Schett G
  (See online at https://doi.org/10.1073/pnas.1011774108)
• (2012) Chronic pain states: pharmacological strategies to restore diminished inhibitory spinal pain control. Annu Rev Pharmacol Toxicol 52:111-33
  Zeilhofer HU, Benke D, Yevenes GE
  (See online at https://doi.org/10.1146/annurev-pharmtox-010611-134636)
• (2012) Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling. EMBO J 31(19):3795-808
  Vetter I, Touska F, Hess A, Hinsbey R, Sattler S, Lampert A, Sergejeva M, Sharov A, Collins LS, Eberhardt M, Engel M, Cabot PJ, Wood JN, Vlachová V, Reeh PW, Lewis RJ, Zimmermann K
  (See online at https://doi.org/10.1038/emboj.2012.207)
• (2012) Cognitive correlates of "neglect-like syndrome" in patients with complex regional pain syndrome. Pain 153(5):1063-73
  Kolb L, Lang C, Seifert F, Maihöfner C
  (See online at https://doi.org/10.1016/j.pain.2012.02.014)
• (2012) Endocannabinoid-dependent plasticity at spinal nociceptor synapses. J Physiol 590:4717-33
  Kato A, Punnakkal P, Pernía-Andrade AJ, von Schoultz C, Sharopov S, Nyilas R, Kátona I, Zeilhofer HU
  (See online at https://doi.org/10.1113/jphysiol.2012.234229)
• (2012) Hyperalgesia by low doses of the local anesthetic lidocaine involves cannabinoid signaling: an fMRI study in mice. Pain 153(7):1450-8
  Bosshard SC, Grandjean J, Schroeter A, Baltes C, Zeilhofer HU, Rudin M
  (See online at https://doi.org/10.1016/j.pain.2012.04.001)
• (2012) Interaction of fentanyl and buprenorphine in an experimental model of pain and central sensitization in human volunteers. Clin J Pain 28(8):705-11
  Tröster A, Ihmsen H, Singler B, Filitz J, Koppert W
  (See online at https://doi.org/10.1097/ajp.0b013e318241d948)
• (2012) Lateralization of responses to vibrissal stimulation: connectivity and information integration in the rat sensory-motor cortex assessed with fMRI. Neuroimage 62(3):2101-9
  de Celis Alonso B, Sergeyeva M, Brune K, Hess A
  (See online at https://doi.org/10.1016/j.neuroimage.2012.05.045)
• (2012) Local anestheticlike inhibition of voltage-gated Na+ channels by the partial μ-opioid receptor agonist buprenorphine. Anesthesiology 116:1335-46
  Leffler A, Frank G, Kistner K, Niedermirtl F, Koppert W, Reeh PW, Nau C
  (See online at https://doi.org/10.1097/aln.0b013e3182557917)
• (2012) Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): a possible mechanism of metabolic neuropathies. J Biol Chem 287(34):28291-306
  Eberhardt MJ, Filipovic MR, Leffler A, de la Roche J, Kistner K, Fischer MJ, Fleming T, Zimmermann K, Ivanovic-Burmazovic I, Nawroth PP, Bierhaus A, Reeh PW, Sauer SK
  (See online at https://doi.org/10.1074/jbc.m111.328674)
• (2012) Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med 18:926-33
  Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, Sauer SK, Eberhardt M, Schnölzer M, Lasitschka F, Neuhuber WL, Kichko TI, Konrade I, Elvert R, Mier W, Pirags V, Lukic IK, Morcos M, Dehmer T, Rabbani N, Thornalley PJ, Edelstein D, Nau C, Forbes J, Humpert PM, Schwaninger M, Ziegler D, Stern DM, Cooper ME, Haberkorn U, Brownlee M, Reeh PW, Nawroth PP
  (See online at https://doi.org/10.1038/nm.2750)
• (2012) Modulation of somatosensory profiles by spinal cord stimulation in primary Raynaud´s syndrome. Pain Pract 12:469-75
  Münster T, Tiebel N, Seyer H, Maihöfner C
  (See online at https://doi.org/10.1111/j.1533-2500.2012.00531.x)
• (2012) Primary erythromelalgia in a 12-year-old boy: positive response to sodium channel blockers despite negative SCN9A mutations. Klin Padiatr 224:309-12
  Jakob A, Creutzfeldt R, Staszewski O, Winterpacht A, Berner R, Hufnagel M
  (See online at https://doi.org/10.1055/s-0031-1287823)
• (2013) Altered resting-state functional connectivity in complex regional pain syndrome. J Pain 14(10):1107-1115
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