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22 POTENTIAL TARGETS AND NOVEL STRATEGIES FOR NOCICEPTIVE-SPECIFIC INHIBITION OF Na+ CHANNELS
European Journal of Pain Supplements 5 (2011) 1, 5–14
Contents lists available at ScienceDirect
European Journal of Pain journal homepage: www.EuropeanJournalPain.com
TOPICAL SEMINAR SUMMARIES 21 CANNABINOIDS IN PAIN MANAGEMENT: A DOUBLE-EDGED SWORD? H.G. Kress1 *, B. Kraft1 , A.S.C. Rice2 , H.U. Zeilhofer3 . 1 Dept. Special Anaesthesia and Pain Therapy, Medical University / AKH Vienna, Vienna, Austria; 2 Dept. of Surgery and Cancer, Imperial College London, London, UK; 3 Institute of Pharmacology and Toxicology, University of Z¨ urich, Zurich, Switzerland Based on clinical studies, the analgesic efficacy of exogenous cannabinoids, such as synthetic nabilone or plant-derived D9-tetrahydrocannabinol (THC, dronabinol) is still surprisingly controversial. In clinical settings, exogenous cannabinoids seem to be more effective in distinct chronic pain rather than acute pain conditions, presumably due to differences in the respective underlying pain mechanisms. In this Topical Seminar, the conflicting results from randomized, controlled clinical and from experimental studies will not only be reviewed and analysed, but – based on recent experimental and clinical data – also a tentative explanation will be discussed. In contrast to their anti-nociceptive and anti-hyperalgesic activity in experimental animal studies, exogenous cannabinoids often failed to produce significant in vivo analgesic and anti-hyperalgesic effects in human pain models. Despite inconsistent, weak analgesic effects, oral and inhaled cannabinoids often failed to reduce acute pain and hyperalgesia. Oral THC, nabilone and smoked cannabis have even induced acute hyperalgesia, indicating complex physiological mechanisms mediating the effects of cannabinoids and CB1 receptor stimulation. During the Topical Seminar, this complexity will be demonstrated at the spinal level: Besides the blockade of excitatory neurotransmission, CB1 receptor activation may also result in a reduction of inhibition by dorsal horn interneurons, which would be a plausible explanation of the hyperalgesic rather than antinociceptive effects of exogenous cannabinoids under certain conditions. The Topical Seminar will therefore increase the understanding of the complex actions of cannabinoids and CB1 receptors in vivo. Disclosure: HG Kress and B Kraft have received consultancy or speaker’s honoraria from Bionorica Ethics Austria.
22 POTENTIAL TARGETS AND NOVEL STRATEGIES FOR NOCICEPTIVE-SPECIFIC INHIBITION OF Na+ CHANNELS A. Leffler1 *, A. Lampert2 , C. Brenneis3 . 1 Anesthesiology and Intensive Care, Hannover Medical School, Hannover, 2 Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany; 3 F.M. Kirby Neurobiology Center, Children’s Hospital Boston, Boston, MA, USA An increased excitability of sensory neurons contribute to the development and maintenance of most types of pain. Accordingly, a considerable effort has been invested to identify molecular determinants for nociceptor-excitability. Voltage-gated Na+ channels are essential regulators of the action potential generation in nociceptors and are regarded as promising molecules in respect
to the development of novel analgesics. Several a-subunits of Na+ channels are expressed in sensory neurons, some of which display an almost selective expression in the nociceptive subpopulation. The subunits Nav1.7 and Nav1.8 have emerged as critical molecules for nociceptive-, inflammatory- and neuropathic pain. Thus both channels are targets for the development of new and subunitspecific pain killers. First reports on the analgesic properties of pre-clinical substances are promising. An alternative strategy to achieve a nociceptive-specific inhibition of Na+ channels is to induce a nociceptor-selective uptake of membrane-impermeable Na+ channel blockers. This approach was first demonstrated by the activation of the polymodal membrane receptors TRPV1 and TRPA1, whose pores are permeable for large molecules such as the lidocaine-derivative QX-314. The first pre-clinical studies with this approach delivered encouraging results. Beside of these hopeful perspectives, however, several less promising reports have questioned whether the above mentioned approaches are de facto “nociceptor-specific”. This workshop addresses recent findings on the potential utility of voltage-gated Na+ channels or TRP channels as possible targets for novel analgesics. Disclosure: None declared
23 “PAIN SOMATOTOPIES” – DO THEY EXIST AND ARE THEY SPECIFIC? 1 U. Baumgartner ¨ *, G. Iannetti2 , F. Mancini3 . 1 Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim (CBTM), Heidelberg University, Mannheim, Germany; 2 Department of Neuroscience, Physiology and Pharmacology, 3 Institute of Cognitive Neuroscience, University College London, London, UK The ability to discriminate sensory stimuli is necessary for orientation in our surrounding and survival. With respect to the somatosensory system, somatotopic representation as “body maps” is a prerequisite for spatial discrimination. Whereas abundant information is available on the somatotopic representation of nonnociceptive stimuli in the central nervous system (CNS), much less is known about “pain maps” of our body in the CNS. In this symposium, organization of the somatosensory system concerning somatotopy will be reviewed comparing representations of non-noxious and noxious stimuli. More emphasis will be put on the latter, since somatotopy in nociceptive cortical networks has remained largely unexplored till recent years. Important issues will be the current knowledge about resolution of the body maps and the question of specificity – is there a representation specific for nociceptive stimuli at all in the CNS? What information is still missing in the current picture? The first talk (Ulf Baumgartner) ¨ will focus on spinal and subcortical data and intracortical recordings in humans serving as introduction to the presentation of somatotopy data from neuroimaging studies (Giandomenico Iannetti). Finally, psychophysical evidence describing systematic distortions of perceptual maps of touch and pain will be discussed (Flavia Mancini). Disclosure: None declared
1090-3801 /$36.00 © 2011 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.
Contents lists available at ScienceDirect
European Journal of Pain journal homepage: www.EuropeanJournalPain.com
TOPICAL SEMINAR SUMMARIES 21 CANNABINOIDS IN PAIN MANAGEMENT: A DOUBLE-EDGED SWORD? H.G. Kress1 *, B. Kraft1 , A.S.C. Rice2 , H.U. Zeilhofer3 . 1 Dept. Special Anaesthesia and Pain Therapy, Medical University / AKH Vienna, Vienna, Austria; 2 Dept. of Surgery and Cancer, Imperial College London, London, UK; 3 Institute of Pharmacology and Toxicology, University of Z¨ urich, Zurich, Switzerland Based on clinical studies, the analgesic efficacy of exogenous cannabinoids, such as synthetic nabilone or plant-derived D9-tetrahydrocannabinol (THC, dronabinol) is still surprisingly controversial. In clinical settings, exogenous cannabinoids seem to be more effective in distinct chronic pain rather than acute pain conditions, presumably due to differences in the respective underlying pain mechanisms. In this Topical Seminar, the conflicting results from randomized, controlled clinical and from experimental studies will not only be reviewed and analysed, but – based on recent experimental and clinical data – also a tentative explanation will be discussed. In contrast to their anti-nociceptive and anti-hyperalgesic activity in experimental animal studies, exogenous cannabinoids often failed to produce significant in vivo analgesic and anti-hyperalgesic effects in human pain models. Despite inconsistent, weak analgesic effects, oral and inhaled cannabinoids often failed to reduce acute pain and hyperalgesia. Oral THC, nabilone and smoked cannabis have even induced acute hyperalgesia, indicating complex physiological mechanisms mediating the effects of cannabinoids and CB1 receptor stimulation. During the Topical Seminar, this complexity will be demonstrated at the spinal level: Besides the blockade of excitatory neurotransmission, CB1 receptor activation may also result in a reduction of inhibition by dorsal horn interneurons, which would be a plausible explanation of the hyperalgesic rather than antinociceptive effects of exogenous cannabinoids under certain conditions. The Topical Seminar will therefore increase the understanding of the complex actions of cannabinoids and CB1 receptors in vivo. Disclosure: HG Kress and B Kraft have received consultancy or speaker’s honoraria from Bionorica Ethics Austria.
22 POTENTIAL TARGETS AND NOVEL STRATEGIES FOR NOCICEPTIVE-SPECIFIC INHIBITION OF Na+ CHANNELS A. Leffler1 *, A. Lampert2 , C. Brenneis3 . 1 Anesthesiology and Intensive Care, Hannover Medical School, Hannover, 2 Physiology and Pathophysiology, University of Erlangen-Nuremberg, Erlangen, Germany; 3 F.M. Kirby Neurobiology Center, Children’s Hospital Boston, Boston, MA, USA An increased excitability of sensory neurons contribute to the development and maintenance of most types of pain. Accordingly, a considerable effort has been invested to identify molecular determinants for nociceptor-excitability. Voltage-gated Na+ channels are essential regulators of the action potential generation in nociceptors and are regarded as promising molecules in respect
to the development of novel analgesics. Several a-subunits of Na+ channels are expressed in sensory neurons, some of which display an almost selective expression in the nociceptive subpopulation. The subunits Nav1.7 and Nav1.8 have emerged as critical molecules for nociceptive-, inflammatory- and neuropathic pain. Thus both channels are targets for the development of new and subunitspecific pain killers. First reports on the analgesic properties of pre-clinical substances are promising. An alternative strategy to achieve a nociceptive-specific inhibition of Na+ channels is to induce a nociceptor-selective uptake of membrane-impermeable Na+ channel blockers. This approach was first demonstrated by the activation of the polymodal membrane receptors TRPV1 and TRPA1, whose pores are permeable for large molecules such as the lidocaine-derivative QX-314. The first pre-clinical studies with this approach delivered encouraging results. Beside of these hopeful perspectives, however, several less promising reports have questioned whether the above mentioned approaches are de facto “nociceptor-specific”. This workshop addresses recent findings on the potential utility of voltage-gated Na+ channels or TRP channels as possible targets for novel analgesics. Disclosure: None declared
23 “PAIN SOMATOTOPIES” – DO THEY EXIST AND ARE THEY SPECIFIC? 1 U. Baumgartner ¨ *, G. Iannetti2 , F. Mancini3 . 1 Neurophysiology, Centre for Biomedicine and Medical Technology Mannheim (CBTM), Heidelberg University, Mannheim, Germany; 2 Department of Neuroscience, Physiology and Pharmacology, 3 Institute of Cognitive Neuroscience, University College London, London, UK The ability to discriminate sensory stimuli is necessary for orientation in our surrounding and survival. With respect to the somatosensory system, somatotopic representation as “body maps” is a prerequisite for spatial discrimination. Whereas abundant information is available on the somatotopic representation of nonnociceptive stimuli in the central nervous system (CNS), much less is known about “pain maps” of our body in the CNS. In this symposium, organization of the somatosensory system concerning somatotopy will be reviewed comparing representations of non-noxious and noxious stimuli. More emphasis will be put on the latter, since somatotopy in nociceptive cortical networks has remained largely unexplored till recent years. Important issues will be the current knowledge about resolution of the body maps and the question of specificity – is there a representation specific for nociceptive stimuli at all in the CNS? What information is still missing in the current picture? The first talk (Ulf Baumgartner) ¨ will focus on spinal and subcortical data and intracortical recordings in humans serving as introduction to the presentation of somatotopy data from neuroimaging studies (Giandomenico Iannetti). Finally, psychophysical evidence describing systematic distortions of perceptual maps of touch and pain will be discussed (Flavia Mancini). Disclosure: None declared
1090-3801 /$36.00 © 2011 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.