1. A novel role for opioids: the reversal of established hyperalgesia and chronic pain by synaptic depotentiation Jürgen Sandkühler, Ruth Drdla-Schutting, Burkhard Gustorff LS07-040

2. Project-team Univ.-Prof. Dr. Jürgen Sandkühler Ass.-Prof. Mag. Ruth Drdla-Schutting, PhD Univ. –Prof. Dr. Burkhard Gustorff, DEAA

3. A synaptic amplifier of pain at the spinal level Noxious stimulus

4. Opioid receptors at the spinal relay for nociception µ-Opioid receptor IR Spinal dorsal horn

5. A brief, high-dose opioid application persistently reverses LTP Drdla-Schutting et al., Science 335 (2012) 235

6. A brief, high-dose opioid application persistently reverses LTP Drdla-Schutting et al., Science 335 (2012) 235

7. Mechanisms of LTP reversal by opioids Drdla-Schutting et al., Science 335 (2012) 235

8. Opioids reverse hyperalgesia in behaving animals High-dose opioid Capsaicin Drdla-Schutting et al., Science 335 (2012) 235

9. Brief high-dose opioid treatment persistently reduces pain ratings in patients

10. Summary and Impact Novel opioid mechanism: Single, high-dose opioid application reverses established LTP at nociceptive synapses Hyperalgesia pain ratings in patients with post-herpetic neuralgia Immediate and effective pain treatment Forms of chronic pain involving LTP might benefit Causal therapy for some forms of enhanced pain sensitivity

11. Output of the project Drdla R, Sandkühler J (2008) Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo. Mol Pain 4:18.2008 Sandkühler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707-758.2009 Heinke B, Gingl E, Sandkühler J (2011) Multiple targets of µ-opioid receptor mediated presynaptic inhibition at primary afferent Aδ- and C-fibers. J Neurosci 31:1313-1322. 2011 Heinl C, Drdla R, Xanthos DN, Sandkühler J (2011) Distinct mechanisms underlying pronociceptive effects of opioids. J Neurosci 36 (46):16748-16756 2011 Ruscheweyh R, Wilder-Smith O, Drdla R, Liu X-G, Sandkühler J (2011) Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol Pain 7:20. 2011 Gustorff B, Hauer D, Thaler J, Seis A, Draxler J (2011) Antihyperalgesic efficacy of 5% lidocaine medicated plaster in capsaicin and sunburn pain models - two randomized, double-blinded, placebo-controlled crossover trials in healthy volunteers. Expert Opin Pharmacother 12(18):2781-90. 2011 Sandkühler,J. & Gruber-Schoffnegger,D. Hyperalgesia by synaptic long-term potentiation (LTP): an update. Curr. Opin. Pharmacol. 12, 18-27 (2011). 2011 Drdla-Schutting R, Benrath J, Wunderbaldinger G, Sandkühler J (2012) Erasure of spinal memory traces of pain by a brief, high- dose opioid administration. Science 13;335(6065):235-8 2012 Ortner C, Womastek I, Margeta K, Schulz M, Gustorff B (2012) Dose Response of Tramadol and its Combination with Acetaminophen in UVB induced Hyperalgesia. Eur J Pain 16(4): 562-73 2012 Sandkühler J, Lee J (2013) How to erase memory traces of pain and fear Trends Neurosci., doi: 10.1016/j.tins.2013.03.0042013 Gustorff B, Sycha T, Lieba-Samal D, Rolke R, Treede RD, Magerl W (2013).The pattern and time course of somatosensory changes in the human UVB sunburn model reveal the presence of peripheral and central sensitization. Pain 154(4):586-97 2013 Drdla-Schutting R, Benrath J, Wunderbaldinger G, Sandkühler J (2012) Erasure of spinal memory traces of pain by a brief, high-dose opioid administration. Science 13;335(6065):235-8 Drdla-Schutting R, Benrath J, Wunderbaldinger G, Sandkühler J (2012) Erasure of spinal memory traces of pain by a brief, high-dose opioid administration. Science 13;335(6065):235-8 Prof. Burkhard Gustorff: Head of Department Anaesthesiology, Wilhelminenspital – Chief physician (2009) Ruth Drdla-Schutting: Assistant Professor, Medical University of Vienna, CBR (2011)

12. A novel role for opioids: the reversal of established hyperalgesia and chronic pain by synaptic depotentiation Jürgen Sandkühler, Ruth Drdla-Schutting, Burkhard Gustorff Thank you for your attention!