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Identification and Validation of Targets for Chronic Pain Treatment Hanns Ulrich Zeilhofer Institute of Pharmaceutical Sciences ETH Zurich Institute of Pharmacology University of Zurich Prevalence of Chronic Pain 19% of the European

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Identification and Validation of Targets for Chronic Pain Treatment

Hanns Ulrich Zeilhofer Institute of Pharmaceutical Sciences ETH Zurich Institute of Pharmacology University of Zurich

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Prevalence of Chronic Pain

19% of the European population suffer from chronic pain (VAS ≥ 5, range 0 ... 10) 33% of these patients report strong pain (VAS ≥ 8 - 10) In 59% of these patients pain lasted for at least 5 years.

* Telephone interviews with 46’392 persons from 15 European countries and from Israel ** longer than 6 months, VAS (0-10): ≥ 5 *** VAS (0-10): 8-10

Breivik et al., Eur J Pain 2006

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Insufficient pain relief

Breivik et al., Eur J Pain 2006

Satisfaction with Pain Medication

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Patients Concerns about Pain Medication

Breivik et al., Eur J Pain 2006

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Inflammation
Nerve damage
Trauma

Examples for Sources of Chronic Pain

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amputation rheumatoid arthritis chronic regional pain syndrome

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Acute Pain - Chronic Pain

Acute Pain

Evoked by adequate stimuli, e.g. mechanical stress noxious heat acidosis Correlates with intensity and duration of the stimulus

Chronic Pain

Evoked by in-adequate stimuli hyperalgesia allodynia spontaneous pain Outlasts peripheral stimulation (inflammation or tissue repair)

Chronic pain is a form of maladaptive CNS plasticity

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secondary (central) hyperalgesia allodynia spontaneous pain primary (peripheral) hyperalgesia

Peripheral and Central Pain Sensitization

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Patch-Clamp Recordings from Neurons in a Transverse Rat Spinal Cord Slice Preparation

Patch- Clamp Amplifier Upright Microscope Synaptic Stimulation

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Biologically Active Prostanoids

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Ahmadi et al., Nat. Neurosci., 2002

PGE2

Do Prostaglandins Affect Dorsal Horn Synapses?

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Ahmadi et al., Nat. Neurosci., 2002

PGE2

Do Prostaglandins Affect Dorsal Horn Synapses?

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wild-type Harvey et al., Science 2004 Reinold et al., J. Clin. Invest. 2005

Spinal Neuroplasticity and Pain: Disinhibition

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EP2 and GlyRα3 Mediate the Central Component of Inflammatory Pain

Harvey et al., Science 2004 Reinold et al., J. Clin. Invest. 2005

paw withdrawal latency (s) time (h) paw withdrawal latency (s) time (d)

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COX-2 / mPGES1 PGE2 Inflammation Pain

Dis-Inhibition in Inflammatory Pain

Coxibs mPGES1 inhibitors

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mPGES-1 Inhibition in Inflammatory Pain

Xu et al., JPET, 2008

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The Dorsal Horn Pain Filter: Impairment and Repair

Pain

Inflammation PGE2 COX-2 Neuropathy Microglia BDNF

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Gate-Control Theory of Pain

Melzack & Wall, Science 1965

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Facilitation of GABAergic Inhibition Reverses Hyperalgesia

CCI

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Subtype-Selective “Benzodiazepines“: L-838,417

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GABAA Receptor Subtypes and Spinal Analgesia - Inflammatory Pain

Withdrawal latency (s)

time (h)

Katharina Hösl & Heiko Reinold in Knabl et al., Nature 2008

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Subtype-Selective “Benzodiazepines“: L-838,417

L-838,417

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L-838,417 versus Morphine

Knabl et al., Nature 2008

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L-838‘417: fMRI in Hyperalgesic Rats

Andreas Hess in: Knabl et al., Nature, 2008

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Pain Control by Inhibitory Interneurons

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Generation of BAC Transgenic Mice Expressing EGFP in Neuronal Subpopulations

GlyT2 gene

Zeilhofer et al., J. Comp. Neurol.,

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Inhibitory Neurons in the Spinal Dorsal Horn

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Transcriptom of dorsal horn inhibitory cells GlyT2-EGFP GAD67-EGFP ppN/OFQ-EGFP Inhibitory interneuron-specific gene deletion GlyT2-cre GAD67-cre Association studies postoperative hyperalgesia migraine