Transcript Folie 1 - Irish Pain Society

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
Rolf-Detlef Treede
President of IASP
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
www.iasp-pain.org
IASP Chapters in 92 Countries
Ireland
227 chapter members, 33 IASP members, 16 both
Pain Medicine Specialization, EU presidency
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Yokohama, Japan
September 12-16, 2018
Boston, Massachusetts, USA
Visit www.iasp-pain.org
Working together for
pain relief throughout
the world
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.
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
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
„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.
Nociceptive brain areas
B
A
SI
SII, insula
ACC, MCC, PFC
from Apkarian et al. 2005
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
Nociception
Pain
Third-person perspective
Stimulus-related
Sensory discrimination
First-person perspective
Perception-related
Suffering
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
Peripheral nociceptive neurons
Transformation of generator potentials into action potentials
Sodium channels:
open
closed
Greffrath, Schwarz, Büsselberg, Treede (2009) J Neurophysiol 102: 424–436
inactivated
Peripheral nociceptive neurons
Peripheral sensitization, presynaptic transmitter release
peripheral terminal
dorsal root ganglion
central terminal
Rezeptoren
bradykinin
prostaglandins
Aus: Schmidt, Thews, Lang: Physiologie des Menschen, Abb. 14-3
GABA
opioids
cannabinoids
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)
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
Central nociceptive neurons
Coding of stimulus intensity
Neuronal response
Noxious range
Stimulus intensity
Aus: Zenz, Jurna: Lehrbuch der Schmerztherapie, Kapitel A3, Abb. 5
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
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.
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
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
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
Diffuse Noxious Inhibitory Controls (DNIC)
Discharges evoked by glutamate, Inhibition via heterotopic noxious stimulation
D. Le Bars / Brain Research Reviews 40 (2002) 29–44
Fibromyalgia:
normal gate control, but deficient DNIC
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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
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?
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
Peripheral sensitization
Heat hyperalgesia following sunburn
Benrath, Gillardon, Zimmermann (2001) Eur J Pain 5: 155-167
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
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
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
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