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43 THE FAST AND THE FURIOUS – DECISIVE ROLES FOR A-delta NOCICEPTORS IN HYPERALGESIA
TOPICAL SEMINAR SUMMARIES / European Journal of Pain Supplements 5 (2011) 5–14
pharmacological evidence, knock-down strategies and a nociceptorspecific knock-out mouse model suggest that the S1P1 receptor plays an essential but not exclusive role in this proalgesic action of S1P. In contrast, the role of S1P and S1P receptors in the central nervous system is still controversially discussed. S1P concentrations are decreased in cerebrospinal fluid in acute and inflammatory pain models. Pharmacological inhibition of S1P synthesis decreases basal pain thresholds and intrathecal application of S1P reduces pain-like behaviour in the formalin test. On the other hand, S1P is involved in counter-regulation of opioid analgesia. Chronic morphine treatment upregulates spinal S1P concentration, and co-administering morphine with intrathecally applied pharmacological S1P inhibitors blocks development of hypersensitivity and tolerance in rats. The role of particular S1PRs and signalling pathways are addressed for peripheral and spinal mechanisms of S1P in pain modulation. Disclosure: None declared
43 THE FAST AND THE FURIOUS – DECISIVE ROLES FOR A-delta NOCICEPTORS IN HYPERALGESIA W. Magerl1 *, S. Hunt2 , G. Iannetti3 . 1 Dept. of Neurophysiology, Center of Biomedicine and Medical Technology Univ Heidelberg, Mannheim, Germany; 2 Department of Cell and Developmental Biology, 3 Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK Neuropathic pain is notoriously difficult to control using current therapeutic approaches. The damage of peripheral nerves elicits a multitude of peripheral changes and central sensitization of their synaptic transmission to spinal nociceptive neurons. This symposium will focus on evidence that the fastest conducting (A-delta) nociceptors play a decisive role in animal models of neuropathic pain, experimentally-induced hyperalgesia in human volunteers, and neuropathic pain patients. Steve Hunt will present evidence in neuropathic animals that A-fibre nociceptors rather than C-fibre nociceptors represent an interesting target for therapeutic intervention. A-fibre nociceptors express the kinase mTOR (largely absent from C-nociceptors). Inhibition of mTOR locally, intrathecally or systemically alleviates neuropathic pain sensitivity in mice or rats by reducing the sensitivity of A-fibre-nociceptors, while C-fibre-mediated primary sensitization remains largely unimpaired Walter Magerl will present data from human surrogate models of neuropathic pain (secondary hyperalgesia, longterm potentiation of pain). Functional blockades in healthy volunteers dissect the specific roles of subsets of nociceptive primary afferents and their functional significance for induction (mediated by peptidergic capsaicin-sensitive C-fibre nociceptors) and signaling of hyperalgesia (mediated by capsaicin-insensitive A-fibre mechanonociceptors). Giandomenico Iannetti will present electrophysiological and imaging data on the specialization of subclasses of A-delta nociceptors in pain and hyperalgesia. He will present novel approaches to elicit electrocortical responses to stimulation of A-delta-mechanonociceptors representing specific and objective electrophysiological measures for central sensitization in neuropathic pain. These results will be discussed together with those obtained using metabolic functional neuroimaging techniques in experimental models and in patients with mechanical hyperalgesia. Disclosure: Walter Magerl receives royalties from the sales of sensory test devices (pin pricks) used for functional assessment of Adelta fiber function.
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44 BRAIN AND SPINAL TRPV1 RECEPTORS – A GOOD TARGET FOR PAIN THERAPY? J. Palecek1 *, I. Nagy2 , S. Maione3 . 1 Functional Morphology, Institute of Physiology AS CR, v.v.i., Prague, Czech Republic; 2 Imperial College London, London, UK; 3 Department of Experimental Medicine, Division of Pharmacology, The Second University of Naples, Italy, Naples, Italy Peripheral TRPV1 receptors have been recently identified as molecular integrators of noxious stimuli and are under intensive investigation both in academy and industry. As a result, numerous compounds have been developed and used in clinical trials to assess their analgesic efficacy and potency. However, in the clinical trials, these TRPV1 antagonists produced unexpected side effects such as hyperthermia and potentially dangerous increase of heat threshold. Recent finding suggested that TRPV1 antagonists with high permeability through the blood brain barrier are more potent in producing antinociception than those with low permeability. This suggests that TRPV1 receptors in the central nervous system play an important role in modulating nociceptive signaling. This topical seminar will provide information about the role of TRPV1 receptors in the spinal cord and brain, their possible endogenous ligands and their clinical relevance for potential pain therapy. The first lecture, by Dr. Istvan Nagy, will provide information about the distribution of TRPV1 receptors in the central nervous system and their activation by endogenous ligands. The following presentation, by Dr. Jiri Palecek, will cover the role of TRPV1 receptors in modulating nociceptive signaling in the spinal cord (based on results of both in vivo and in vitro experiments). The last lecture, by Prof. Sabatino Maione, will give an overview concerning the function of endovanilloids in cortical plasticity associated with neuropathic pain. Disclosure: None declared
45 TRANSLATIONAL STUDIES ON MYOFASCIAL TRIGGER POINTS – MODELS AND CLINICAL IMPLICATION T. Graven-Nielsen1 *, S. Mense2 , M.A. Giamberardino3 . 1 Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark; 2 CBTM, Neuroanatomie, Heidelberg University, Mannheim, Germany; 3 Department of Medicine and Science of Aging, ‘G. D’Annunzio’ University of Chieti, Chieti Scalo, Italy Musculoskeletal structures are significant sources of chronic pain. Especially the myofascial pain syndrome manifested as localized and hypersensitive trigger points in muscle has a high prevalence. Myofascial trigger points (MTrPs) in muscles are frequently associated with other chronic pain conditions such as osteoarthritis, headache, rheumatoid arthritis, chronic back pain, visceral pain and fibromyalgia. New models and systematic approaches to study mechanisms and manifestations of MTrPs are needed to improve diagnosis and therapy. MTrPs are localised spots of tenderness in palpable taut bands of muscle fibres which often give referred pain. The mechanisms involved in the development of MTrPs are not clear although increased activity of the motor endplate and release of sensitising substances have been suggested. Nonetheless, the initial factors important for development of an MTrP as well as the relative importance of the central nociceptive systems need clarification. Particularly the latent MTrPs are still enigmatic. Animal models mimicking the characteristics of clinical MTrPs have been developed and suggest involvement of central sensitisation manifested as additional hyperalgesia. Some of these manifestations can also be translated into experimental human studies and patient studies. Recently it was demonstrated that pain from MTrPs contribute to maintain widespread hyperalgesia due to central sensitisation in musculoskeletal pain patients. Translation of findings from animal models to human models and patients launch new ways to identify MTrP pathophysiology and open for
pharmacological evidence, knock-down strategies and a nociceptorspecific knock-out mouse model suggest that the S1P1 receptor plays an essential but not exclusive role in this proalgesic action of S1P. In contrast, the role of S1P and S1P receptors in the central nervous system is still controversially discussed. S1P concentrations are decreased in cerebrospinal fluid in acute and inflammatory pain models. Pharmacological inhibition of S1P synthesis decreases basal pain thresholds and intrathecal application of S1P reduces pain-like behaviour in the formalin test. On the other hand, S1P is involved in counter-regulation of opioid analgesia. Chronic morphine treatment upregulates spinal S1P concentration, and co-administering morphine with intrathecally applied pharmacological S1P inhibitors blocks development of hypersensitivity and tolerance in rats. The role of particular S1PRs and signalling pathways are addressed for peripheral and spinal mechanisms of S1P in pain modulation. Disclosure: None declared
43 THE FAST AND THE FURIOUS – DECISIVE ROLES FOR A-delta NOCICEPTORS IN HYPERALGESIA W. Magerl1 *, S. Hunt2 , G. Iannetti3 . 1 Dept. of Neurophysiology, Center of Biomedicine and Medical Technology Univ Heidelberg, Mannheim, Germany; 2 Department of Cell and Developmental Biology, 3 Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK Neuropathic pain is notoriously difficult to control using current therapeutic approaches. The damage of peripheral nerves elicits a multitude of peripheral changes and central sensitization of their synaptic transmission to spinal nociceptive neurons. This symposium will focus on evidence that the fastest conducting (A-delta) nociceptors play a decisive role in animal models of neuropathic pain, experimentally-induced hyperalgesia in human volunteers, and neuropathic pain patients. Steve Hunt will present evidence in neuropathic animals that A-fibre nociceptors rather than C-fibre nociceptors represent an interesting target for therapeutic intervention. A-fibre nociceptors express the kinase mTOR (largely absent from C-nociceptors). Inhibition of mTOR locally, intrathecally or systemically alleviates neuropathic pain sensitivity in mice or rats by reducing the sensitivity of A-fibre-nociceptors, while C-fibre-mediated primary sensitization remains largely unimpaired Walter Magerl will present data from human surrogate models of neuropathic pain (secondary hyperalgesia, longterm potentiation of pain). Functional blockades in healthy volunteers dissect the specific roles of subsets of nociceptive primary afferents and their functional significance for induction (mediated by peptidergic capsaicin-sensitive C-fibre nociceptors) and signaling of hyperalgesia (mediated by capsaicin-insensitive A-fibre mechanonociceptors). Giandomenico Iannetti will present electrophysiological and imaging data on the specialization of subclasses of A-delta nociceptors in pain and hyperalgesia. He will present novel approaches to elicit electrocortical responses to stimulation of A-delta-mechanonociceptors representing specific and objective electrophysiological measures for central sensitization in neuropathic pain. These results will be discussed together with those obtained using metabolic functional neuroimaging techniques in experimental models and in patients with mechanical hyperalgesia. Disclosure: Walter Magerl receives royalties from the sales of sensory test devices (pin pricks) used for functional assessment of Adelta fiber function.
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44 BRAIN AND SPINAL TRPV1 RECEPTORS – A GOOD TARGET FOR PAIN THERAPY? J. Palecek1 *, I. Nagy2 , S. Maione3 . 1 Functional Morphology, Institute of Physiology AS CR, v.v.i., Prague, Czech Republic; 2 Imperial College London, London, UK; 3 Department of Experimental Medicine, Division of Pharmacology, The Second University of Naples, Italy, Naples, Italy Peripheral TRPV1 receptors have been recently identified as molecular integrators of noxious stimuli and are under intensive investigation both in academy and industry. As a result, numerous compounds have been developed and used in clinical trials to assess their analgesic efficacy and potency. However, in the clinical trials, these TRPV1 antagonists produced unexpected side effects such as hyperthermia and potentially dangerous increase of heat threshold. Recent finding suggested that TRPV1 antagonists with high permeability through the blood brain barrier are more potent in producing antinociception than those with low permeability. This suggests that TRPV1 receptors in the central nervous system play an important role in modulating nociceptive signaling. This topical seminar will provide information about the role of TRPV1 receptors in the spinal cord and brain, their possible endogenous ligands and their clinical relevance for potential pain therapy. The first lecture, by Dr. Istvan Nagy, will provide information about the distribution of TRPV1 receptors in the central nervous system and their activation by endogenous ligands. The following presentation, by Dr. Jiri Palecek, will cover the role of TRPV1 receptors in modulating nociceptive signaling in the spinal cord (based on results of both in vivo and in vitro experiments). The last lecture, by Prof. Sabatino Maione, will give an overview concerning the function of endovanilloids in cortical plasticity associated with neuropathic pain. Disclosure: None declared
45 TRANSLATIONAL STUDIES ON MYOFASCIAL TRIGGER POINTS – MODELS AND CLINICAL IMPLICATION T. Graven-Nielsen1 *, S. Mense2 , M.A. Giamberardino3 . 1 Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark; 2 CBTM, Neuroanatomie, Heidelberg University, Mannheim, Germany; 3 Department of Medicine and Science of Aging, ‘G. D’Annunzio’ University of Chieti, Chieti Scalo, Italy Musculoskeletal structures are significant sources of chronic pain. Especially the myofascial pain syndrome manifested as localized and hypersensitive trigger points in muscle has a high prevalence. Myofascial trigger points (MTrPs) in muscles are frequently associated with other chronic pain conditions such as osteoarthritis, headache, rheumatoid arthritis, chronic back pain, visceral pain and fibromyalgia. New models and systematic approaches to study mechanisms and manifestations of MTrPs are needed to improve diagnosis and therapy. MTrPs are localised spots of tenderness in palpable taut bands of muscle fibres which often give referred pain. The mechanisms involved in the development of MTrPs are not clear although increased activity of the motor endplate and release of sensitising substances have been suggested. Nonetheless, the initial factors important for development of an MTrP as well as the relative importance of the central nociceptive systems need clarification. Particularly the latent MTrPs are still enigmatic. Animal models mimicking the characteristics of clinical MTrPs have been developed and suggest involvement of central sensitisation manifested as additional hyperalgesia. Some of these manifestations can also be translated into experimental human studies and patient studies. Recently it was demonstrated that pain from MTrPs contribute to maintain widespread hyperalgesia due to central sensitisation in musculoskeletal pain patients. Translation of findings from animal models to human models and patients launch new ways to identify MTrP pathophysiology and open for