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The International Association for the Study of Pain (IASP) Pain and nociception

Neuronal Mechanisms of Pain. Rolf-Detlef Treede, Chair of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University. The International Association for the Study of Pain (IASP) Pain and nociception Nociceptive signal processing in the p eripheral nervous system

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The International Association for the Study of Pain (IASP) Pain and nociception

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  1. Neuronal Mechanisms of Pain Rolf-Detlef Treede, Chair of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University • The International Association for the Study of Pain (IASP) • Pain and nociception • Nociceptive signal processing in the peripheral nervous system • Nociceptive signal processing in the central nervous system • Endogenous pain control systems • Plasticity of the nociceptive system Disclosures (2009-2015): Employment: Heidelberg University Advisor: Astellas, Astra-Zeneca, Boehringer Ingelheim, Galderma, Glaxo Smith Kline, Grünenthal, Lilly, Merz, Merck-Sharpe & Dohme, Pfizer, Sanofi, Schwarz-Pharma/UCB Shareholder: none Honoraria: lectures for Astellas, AWD, Boehringer Ingelheim, Dr. Kade, Nycomed, Grünenthal, Lilly, Mundipharma, Pfizer, Schwarz-Pharma/UCB Grants: BMBF, DFG, EU, NIH, Dr. Kade, Boehringer Ingelheim, Astellas, AbbVie Reviewer: several public funding sources

  2. World Congress on Pain September 26 - 30, 2016 Vision Statement: Working together for pain relief throughout the world Mission: IASP brings together scientists, clinicians, and health care providers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide Rolf-Detlef Treede President of IASP www.iasp-pain.org

  3. IASP Chapters in 92 Countries Ireland 227 chapter members, 33 IASP members, 16 both Pain Medicine Specialization, EU presidency

  4. IASP: for you World Congress on Pain September 26 - 30, 2016 World Congress on Pain Reduced registration for IASP’s biennual meeting Journal PAIN The leading publication on pain research and treatment. Pain: Clinical Updates The latest information on a variety of clinical topics in the pain field. IASP e-Newsletter Feature articles, event information on IASP, chapter and SIG news, job postings … Discount on Books from IASP Press Grants and Fellowships Grants, awards, and fellowships for the exclusive benefit of IASP members. Special Interest Groups SIGs offer members a forum to discuss specific interests in depth. Representation and RecognitionParticipate in an international body with more than 7,900 members in 133 countries. Committees Provide input on international pain-related issues through IASP committee membership. Look for upcoming programme www.iasp-pain.org

  5. IASP World Congress on Pain • Biennial gathering of pain experts from around the world • World’s largest pain-related meeting • Diverse lineup of plenary lectures, topical workshops, and poster sessions September 26-30, 2016 Yokohama, Japan September 12-16, 2018 Boston, Massachusetts, USA

  6. A journal for original research on the nature, mechanisms, and treatment of pain • Provides a forum for dissemination of research in the basic and clinical sciences of multidisciplinary interest • The premier and most-cited journal on the subject of pain • Impact Factor: 5.836

  7. Pain: Clinical Updates • IASP’s clinical newsletter, published six times per year, provides accurate and timely information about pain research and therapy • Recent titles include: • Diagnosis, Prevalence, Characteristics, and Treatment of Central Poststroke Pain • Halting the March of Painful Diabetic Neuropathy • Expanding Patients’ Access to Help in Managing Their Chronic Pain • Painful Traumatic Trigeminal Neuropathy

  8. Pain: E-Monthly IASP’s monthly e-newsletter for members provides news about the pain field and information about the association and activities of our members, chapters, and Special Interest Groups

  9. Global Year Against PainIASP sponsors and promotes a year-long initiative to raise international awareness of a different aspect of pain that has global implications. 2004–05: Pain Relief is a Human Right 2005–06: Pain in Children 2006–07: Pain in Older Persons 2007–08: Pain in Women 2008–09: Cancer Pain 2009–10: Musculoskeletal Pain 2010–11: Acute Pain 2011–12: Headache 2012–13: Visceral Pain 2013-14: Orofacial Pain 2014-15: Neuropathic Pain 2016: Pain in the Joints 2017: Pain after Surgery

  10. Thank You! See you at the IASP World Congress on Pain September 26-30, 2016 Yokohama, Japan September 12-16, 2018 Boston, Massachusetts, USA Working together for pain relief throughout the world Visit www.iasp-pain.org

  11. Emotional experience: Pain • IASP definition of pain: An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage. Merskey H, Albe-Fessard D, Bonica JJ, Carmon A, Dubner R, Kerr FWL, Lindblom U, Mumford JM, Nathan PW, Noordenbos W, Pagni CA, Renaer MJ, Sternbach RA, Sunderland S (1979) Pain terms: a list with definitions and notes on usage. Recommended by the IASP subcommittee on taxonomy. Pain 6:249-252.

  12. Sensory signal processing: Nociception Sir Charles Scott Sherrington (1857-1952) defined nociceptors as sense organs that respond to noxious stimuli; he defined noxious stimuli as those that either threaten or actually produce damage. IASP definition of nociception: The neural processes of encoding and processing noxious stimuli. Loeser JD, Treede RD (2008) The Kyoto protocol of IASP Basic Pain Terminology. Pain 137: 473–477

  13. Stimulus encoding by a polymodal C-Nociceptor: Nociception warns before tissue damage occurs Treede (2001) In: Zenz, Jurna: Lehrbuch der Schmerztherapie, Kapitel A3, Abb. 2

  14. „Cool Wool“: desigend not to activate nociceptors CSIRO Division of Textile & Fibre Technology Wool fibers (50 µm diameter) activate nociceptors „fabric evoked prickle“ Garnsworthy, Gully, Kenins, Mayfield, Westerman (1988) Identification of the physical stimulus and the neural basis of fabric-evoked prickle. Journal of Neurophysiology 59:1083-1097.

  15. Nociceptive brain areas from Apkarian et al. 2005 B A SI SII, insula ACC, MCC, PFC

  16. Pain and nociception Nociception: a function of a specific sensory system Nociceptive system: a warning system with an adequate stimulus Pain: a result of network activity in the brain NociceptionPain Third-person perspective First-person perspective Stimulus-related Perception-related Sensory discrimination Suffering

  17. Peripheral nociceptive neurons Transduction of noxious stimuli into generator potentíals Caterina, Schumacher, Tominaga, Rosen, Levine, Julius (1997) Nature 389: 816-824, Schwarz, Greffrath, Büsselberg, Treede (2000) J Physiol 528: 539-549

  18. Peripheral nociceptive neurons Transformation of generator potentials into action potentials Sodium channels: open closed inactivated Greffrath, Schwarz, Büsselberg, Treede (2009) J Neurophysiol 102: 424–436

  19. Peripheral nociceptive neurons Peripheral sensitization, presynaptic transmitter release peripheral terminal dorsal root ganglion central terminal Rezeptoren bradykinin prostaglandins GABA opioids cannabinoids Aus: Schmidt, Thews, Lang: Physiologie des Menschen, Abb. 14-3

  20. Nociceptive signal processing in the peripheral nervous system • Transduction (capsaicin) • Peripheral sensitization (NSAID) • Transformation (local anaesthetics) • Impulse conduction (local anaesthetics) • Presynaptic transmitter release (Gabapentinoids, Opioids, Cannabinoids)

  21. Central nociceptive neurons HT: high threshold (small RF), WDR: wide dynamic range (large RF) Aus: Egle, Hoffmann, Lehmann, Nix: Handbuch chronischer Schmerz, Abb. 2.3.2.-3

  22. Central nociceptive neurons Coding of stimulus intensity Noxious range Neuronal response Stimulus intensity Aus: Zenz, Jurna: Lehrbuch der Schmerztherapie, Kapitel A3, Abb. 5

  23. Central sensitization following injury Hindlimb flexion reflex thresholds in 8 decerebrate rats following an adjacent burn injury (75° for 60 s) Woolf (1983) Nature 306: 686-688

  24. Long-term potentiation in the nociceptive system Perceptual LTP lasts for several hours after single HFS Perceptual LTP is reversible within a day Static mechanical hyperalgesia to punctate probes after HFS (100 Hz, 5 x 1 s) Klein T, Magerl W, Treede RD (2006) Journal of Neurophysiology 96(6):3551-3555.

  25. Nociceptive signal processing in the central nervous system • HT and WDR-neurons • spatial and intensity coding in separate channels? • central sensitization (NMDA-R? NK1-R?) • long-term potentiation for about one day

  26. Descending controls PAG, periaqueductal grey; NTS, nucleus tractus solitarii; PBN, parabrachial nucleus; DRT, dorsoreticular nucleus; RVM, rostroventral medulla; NA, noradrenaline; perikarya 5-HT, serotonergic perikarya; PAF, primary afferent fibre DRG, dorsal root ganglion. Millan MJ (2002) Descending control of pain. Progress in Neurobiology 66: 355-474

  27. Long-term depression (LTD) LFS LTD by low-frequency electrical stimulation (1 Hz, 1200 pulses, Aδ) Test stimuli (0.125 Hz = every 8 s) Rottmann, Jung, Ellrich (2008) Clinical Neurophysiology 119: 1895–1904

  28. Diffuse Noxious Inhibitory Controls (DNIC) Discharges evoked by glutamate, Inhibition via heterotopic noxious stimulation D. Le Bars / Brain Research Reviews 40 (2002) 29–44

  29. Fibromyalgia: normal gate control, but deficient DNIC *** *** *** Gate control: vibration of left forearm increases pressure pain threshold only homotopically DNIC: Ischemic muscle pain increases pressure pain threshold heterotopically (pressure pain thresholds in kPa, 1 cm² probe diameter) Kosek E, Hansson P (1997) Pain 70: 41–51

  30. Endogenous pain control • Gate control theory (Aß fibers): localized effects • Long-term depression (Aδ and C fibers): localized effects • Brainstem pain inhibition (e.g. DNIC): widespread effects • Cortical pain inhibition (via brainstem): widespread effects? • Cortical pain inhibition (intracortical): localized effects?

  31. Three phases of pain mechanisms Activation synaptic transmission descending control Modulation peripheral and central sensitization Modification degeneration regeneration Cervero and Laird (1991) NIPS 6: 268-273

  32. Peripheral sensitization Heat hyperalgesia following sunburn Benrath, Gillardon, Zimmermann (2001) Eur J Pain 5: 155-167

  33. Central sensitization Pinprick hyperalgesia following capsaicin injection Sensitisation of central nociceptive neurons but not primary afferents to mechanical stimuli Enhanced responses to suprathreshold stimuli (225mN von Frey filament) after intradermal capsaicin injection Baumann et al. (1991) J Neurophysiol 66: 212-227, Simone et al. (1991) J Neurophysiol 66: 228-246

  34. Plasticity of the nociceptive system • Peripheral sensitization following injury leads to heat hyperalgesia at the site of injury (primary hyperalgesia) • Central sensitization following injury leads to pinprick hyperalgesia adjacent to the site of injury (secondary hyperalgesia) Heat hyperalgesia: predominantly peripheral sensitization Dynamic mechanical allodynia: central sensitization Pinprick hyperalgesia: predominantly central sensitization Cold hyperalgesia and hyperalgesia to blunt pressure: unknown

  35. Neuronal Mechanisms of Pain Rolf-Detlef Treede, Chair of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University • Pain: result of network activity in nociceptive system • Peripheral encoding and central processing • Short-term plasticity in acute pain • Clinical assessment of pain: ask the patient • Clinical assessment of nociception: sensory examination

  36. Thanks to: Binzen, Caspani, Greffrath, Hoheisel, Schäfer Baumgärtner, Klein, Kroll, Magerl, Pfau, Schuh-Hofer http://www.umm.uni-heidelberg.de/inst/cbtm/nphys/ See you in Yokohama! September 26 - 30, 2016

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