•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

Rolf-Detlef Treede, Chair of Neurophysiology, CBTM, Medical Faculty Mannheim, Heidelberg University

Neuronal Mechanisms of Pain

Disclosures (2009-2015):Employment: Heidelberg UniversityAdvisor: Astellas, Astra-Zeneca, Boehringer Ingelheim, Galderma, Glaxo Smith Kline, Grünenthal, Lilly, Merz, Merck-Sharpe &

Dohme, Pfizer, Sanofi, Schwarz-Pharma/UCBShareholder: noneHonoraria: lectures for Astellas, AWD, Boehringer Ingelheim, Dr. Kade, Nycomed, Grünenthal, Lilly, Mundipharma, Pfizer,

Schwarz-Pharma/UCBGrants: BMBF, DFG, EU, NIH, Dr. Kade, Boehringer Ingelheim, Astellas, AbbVieReviewer: several public funding sources

Rolf-Detlef TreedePresident of IASP

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

World Congress on PainSeptember 26 - 30, 2016

www.iasp-pain.org

Ireland227 chapter members, 33 IASP members, 16 bothPain Medicine Specialization, EU presidency

IASP Chapters in 92 Countries

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 Recognition Participate 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.

IASP: for you

Look for upcoming

programme

World Congress on PainSeptember 26 - 30, 2016

www.iasp-pain.org

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, 2016Yokohama, Japan

September 12-16, 2018Boston, Massachusetts, USA

• 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 painImpact Factor: 5.836

Pain: Clinical UpdatesIASP’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

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

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 Right2005–06: Pain in Children2006–07: Pain in Older Persons2007–08: Pain in Women2008–09: Cancer Pain2009–10: Musculoskeletal Pain2010–11: Acute Pain2011–12: Headache2012–13: Visceral Pain2013-14: Orofacial Pain2014-15: Neuropathic Pain2016: Pain in the Joints2017: Pain after Surgery

See you at the IASP World Congress on Pain

September 26-30, 2016Yokohama, Japan

September 12-16, 2018Boston, Massachusetts, USA

Thank You!

Visit www.iasp-pain.org

Working together for pain relief throughout the world

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.

Emotional experience: Pain

Loeser JD, Treede RD (2008) The Kyoto protocol of IASP Basic Pain Terminology. Pain 137: 473–477

IASP definition of nociception:

The neural processes of encoding and processing noxious stimuli.

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.

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

Wool fibers (50 µm diameter) activate nociceptors

„fabric evoked prickle“

„Cool Wool“: desigend not to activate nociceptorsCSIRO Division of Textile & Fibre Technology

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.

Nociceptive brain areas

from Apkarian et al. 2005

A B

SISII, insulaACC, MCC, PFC

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

Pain and nociception

Nociception Pain

Third-person perspective First-person perspective

Stimulus-related Perception-related

Sensory discrimination Suffering

Peripheral nociceptive neurons

Caterina, Schumacher, Tominaga, Rosen, Levine, Julius (1997) Nature 389: 816-824, Schwarz, Greffrath, Büsselberg, Treede (2000) J Physiol 528: 539-549

Transduction of noxious stimuli into generator potentíals

Greffrath, Schwarz, Büsselberg, Treede (2009) J Neurophysiol 102: 424–436

Transformation of generator potentials into action potentials

open

inactivatedclosed

Sodium channels:

Peripheral nociceptive neurons

Peripheral sensitization, presynaptic transmitter release

Rezeptoren

Aus: Schmidt, Thews, Lang: Physiologie des Menschen, Abb. 14-3

Peripheral nociceptive neurons

peripheral terminal dorsal root ganglion central terminal

bradykininprostaglandins GABA

opioidscannabinoids

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)

Aus: Egle, Hoffmann, Lehmann, Nix: Handbuch chronischer Schmerz, Abb. 2.3.2.-3

HT: high threshold (small RF), WDR: wide dynamic range (large RF)

Central nociceptive neurons

Coding of stimulus intensity

Aus: Zenz, Jurna: Lehrbuch der Schmerztherapie, Kapitel A3, Abb. 5

Central nociceptive neurons

Noxious range

Stimulus intensity

Ne

uro

na

l re

spo

nse

Woolf (1983) Nature 306: 686-688

Hindlimb flexion reflex thresholds in 8 decerebrate rats following an adjacent burn injury (75° for 60 s)

Central sensitization following injury

Klein T, Magerl W, Treede RD (2006) Journal of Neurophysiology 96(6):3551-3555.

Perceptual LTP lasts for several hours after single HFSPerceptual LTP is reversible within a day

Static mechanical hyperalgesia to punctate probes after HFS (100 Hz, 5 x 1 s)

Long-term potentiation in the nociceptive 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

Nociceptive signal processing in the central nervous system

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

Rottmann, Jung, Ellrich (2008) Clinical Neurophysiology 119: 1895–1904

Long-term depression (LTD)

LTD by low-frequency electrical stimulation (1 Hz, 1200 pulses, Aδ)

Test stimuli (0.125 Hz = every 8 s)

LFS

Diffuse Noxious Inhibitory Controls (DNIC)

D. Le Bars / Brain Research Reviews 40 (2002) 29–44

Discharges evoked by glutamate, Inhibition via heterotopic noxious stimulation

Fibromyalgia: normal gate control, but deficient DNIC

Kosek E, Hansson P (1997) Pain 70: 41–51

Gate control: vibration of left forearm increases pressure pain threshold only homotopicallyDNIC: Ischemic muscle pain increases pressure pain threshold heterotopically

(pressure pain thresholds in kPa, 1 cm² probe diameter)

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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?

Endogenous pain control

Cervero and Laird (1991) NIPS 6: 268-273

Activation synaptic transmission descending control

Modulation peripheral and central sensitization

Modification degeneration regeneration

Three phases of pain mechanisms

Peripheral sensitization

Benrath, Gillardon, Zimmermann (2001) Eur J Pain 5: 155-167

Heat hyperalgesia following sunburn

Pinprick hyperalgesia following capsaicin injection

Central sensitization

Baumann et al. (1991) J Neurophysiol 66: 212-227, Simone et al. (1991) J Neurophysiol 66: 228-246

Enhanced responses to suprathreshold stimuli (225mN von Frey filament)after intradermal capsaicin injection

Sensitisation of central nociceptive neurons but not primary afferents to mechanical stimuli

• 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)

Plasticity of the nociceptive system

Heat hyperalgesia: predominantly peripheral sensitization

Dynamic mechanical allodynia: central sensitization

Pinprick hyperalgesia: predominantly central sensitization

Cold hyperalgesia and hyperalgesia to blunt pressure: unknown

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

Neuronal Mechanisms of Pain

http://www.umm.uni-heidelberg.de/inst/cbtm/nphys/

Binzen, Caspani, Greffrath, Hoheisel, Schäfer

Baumgärtner, Klein, Kroll, Magerl, Pfau, Schuh-Hofer

Thanks to:

See you in Yokohama!September 26 - 30, 2016