Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo

Inflammation, trauma or nerve injury trigger low-level activity in C-fibres and may cause long-lasting hyperalgesia. Long-term potentiation (LTP) at synapses of primary afferent C-fibres is considered to underlie some forms of hyperalgesia. In previous studies, high- but not low-frequency conditioning stimulation of C-fibres has, however, been used to induce LTP in pain pathways. Recently we could show that also conditioning low-frequency stimulation (LFS) at C-fibre intensity induces LTP in vitro as well as in the intact animal, i.e. with tonic descending inhibition fully active. In the slice preparation, this form of LTP requires a rise in postsynaptic Ca2+-concentration and activation of Ca2+-dependent signalling pathways. Here, we investigated the signalling mechanisms underlying this novel form of LTP in vivo. We found that the signal transduction pathways causing LFS-induced LTP in vivo include activation of neurokinin 1 and N-methyl-D-aspartate receptors, rise of [Ca2+]i from intracellular stores and via T-type voltage-dependent Ca2+ channels, activation of phospholipase C, protein kinase C and Ca2+-calmodulin dependent kinase II. These pathways match those leading to hyperalgesia in behaving animals and humans. We thus propose that LTP induced by low-level activity in C-fibres may underlie some forms of hyperalgesia

Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy

Long-term potentiation (LTP) in nociceptive spinal pathways shares several features with hyperalgesia and has been proposed to be a cellular mechanism of pain amplification in acute and chronic pain states. Spinal LTP is typically induced by noxious input and has therefore been hypothesized to contribute to acute postoperative pain and to forms of chronic pain that develop from an initial painful event, peripheral inflammation or neuropathy. Under this assumption, preventing LTP induction may help to prevent the development of exaggerated postoperative pain and reversing established LTP may help to treat patients who have an LTP component to their chronic pain. Spinal LTP is also induced by abrupt opioid withdrawal, making it a possible mechanism of some forms of opioid-induced hyperalgesia. Here, we give an overview of targets for preventing LTP induction and modifying established LTP as identified in animal studies. We discuss which of the various symptoms of human experimental and clinical pain may be manifestations of spinal LTP, review the pharmacology of these possible human LTP manifestations and compare it to the pharmacology of spinal LTP in rodents

Central nervous system mast cells in peripheral inflammatory nociception

<p>Abstract</p> <p>Background</p> <p>Functional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. Little is known about the functional role of spinal cord dural mast cells. In this study, we examine their potential involvement in nociception and synaptic plasticity in superficial spinal dorsal horn. Changes of lower spinal cord dura mast cells and their contribution to hyperalgesia are examined in animal models of peripheral neurogenic and non-neurogenic inflammation.</p> <p>Results</p> <p>Spinal application of supernatant from activated cultured mast cells induces significant mechanical hyperalgesia and long-term potentiation (LTP) at spinal synapses of C-fibers. Lumbar, thoracic and thalamic preparations are then examined for mast cell number and degranulation status after intraplantar capsaicin and carrageenan. Intradermal capsaicin induces a significant percent increase of lumbar dural mast cells at 3 hours post-administration. Peripheral carrageenan in female rats significantly increases mast cell density in the lumbar dura, but not in thoracic dura or thalamus. Intrathecal administration of the mast cell stabilizer sodium cromoglycate or the spleen tyrosine kinase (Syk) inhibitor BAY-613606 reduce the increased percent degranulation and degranulated cell density of lumbar dural mast cells after capsaicin and carrageenan respectively, without affecting hyperalgesia.</p> <p>Conclusion</p> <p>The results suggest that lumbar dural mast cells may be sufficient but are not necessary for capsaicin or carrageenan-induced hyperalgesia.</p

Induction and reversal of long-term potentiation in the spinal cord dorsal horn in vivo

Chronic pain is still a major problem in modern medicine. Enhanced sensitivity to pain may persist long after the disappearance of the initial cause for pain. Then, pain is no longer a symptom but rather a disease on its own. Hyperalgesia (enhanced pain sensitivity to noxious stimuli) and allodynia (pain in response to normally innocuous stimuli) may persist for long periods of time due to altered processing of nociceptive information at the spinal cord level. In the spinal cord, nociceptive information is dynamically modulated by various mechanisms on a cellular or network level. This neuronal plasticity comprises a key feature of the nociceptive system. An intensively studied model of neuronal plasticity is synaptic long-term potentiation (LTP), defined as an increase in synaptic transmission efficacy lasting for days to months but at least 30 min. It has been suggested that LTP at synapses between primary afferent fibres and second order neurons in the superficial laminae of the spinal cord dorsal horn represents a model for some forms of afferent induced hyperalgesia. This hypothesis has been challenged, as LTP was experimentally induced with high-frequency, burst-like discharges at virtually all synapses studied so far. Nociceptive C-fibres, however, typically discharge at low frequencies. In the present study, it is demonstrated using C-fibre evoked field potential recordings in spinal laminae I/II of deeply anaesthetized rats that LTP is induced by electrical low-frequency stimulation of afferent fibres as well as by natural noxious stimulation. Examination of signal transduction pathways underlying the induction of LFS-induced LTP revealed that pain pathways activated during this process are of striking similarity to those known to be activated during hyperalgesia. This is consistent with a role of LTP at spinal synapses of C-fibres for pain amplification. Opioids are the mainstays for the treatment of moderate to severe pain. A growing body of evidence suggests, however, that opioids may also elicit hyperalgesia. Here, we discovered two novel effects of the -opioid receptor agonist remifentanil on spinal nociception. We show that remifentanil exerts a bidirectional effect on spinal nociception depending on the functional state of the spinal cord. C-fibre evoked field potentials were again recorded from deeply anaesthetized animals. In the normal animal, wash-out of remifentanil after i.v. administration led to potentiation of field potentials. This may represent a cellular model for the phenomenon of opioid-induced hyperalgesia. In contrast, remifentanil administered after LTP had been induced by different stimuli, led to depotentiation of LTP. This novel opioid action also had a behavioural correlate as enhanced nociceptive reflexes were normalised after a brief application of remifentanil. As opioids are widely used in clinical routine, the exploration of mechanisms of both opioid effects done in the present study and the possible translation of this knowledge into clinical applications might greatly improve the use of opioids for more targeted treatment of various causes of pain. The potential of opioids to reverse established LTP could accomplish a causal therapy for some forms of enhanced pain sensitivity in patients. Parts of this study have been published in Science, 2006, 312(5780):1659-62 and Molecular Pain, 2008, 4(1):18.Chronischer Schmerz stellt ein großes Problem in der modernen Medizin dar. Wenn eine erhöhte Schmerzempfindlichkeit lange nach dem Verschwinden des ursprünglichen Schmerzauslösers bestehen bleibt, kann Schmerz zu einer eigenen Krankheit werden. Die Symptome der Hyperalgesie (verstärktes Schmerzempfinden auf schmerzhafte Reize) und Allodynie (Schmerz als Antwort auf einen normalerweise nicht schmerzhaften Stimulus) können auf eine veränderte Verarbeitung der nozizeptiven Information im Rückenmark zurückzuführen sein. Nozizeptive Informationen unterliegen einer dynamischen Modulation durch unterschiedlichste Mechanismen auf Rückenmarksebene. Diese neuronale Plastizität stellt ein wichtiges Charakteristikum des nozizeptiven Systems dar. Ein intensiv untersuchtes Modell neuronaler Plastizität ist die synaptische Langzeitpotenzierung (LTP). Darunter versteht man einen Anstieg der synaptischen Übertragungsstärke für Tage oder Monate, jedoch mehr als 30 min. Die Hypothese, dass LTP an Synapsen zwischen primären Afferenzen und Neuronen zweiter Ordnung im oberflächlichen Hinterhorn des Rückenmarks ein Modell für manche Formen der Hyperalgesie darstellt, wurde kürzlich hinterfragt. Ein Grund dafür ist, dass LTP experimentell bislang an fast allen untersuchten Synapsen durch hochfrequente Entladungen ausgelöst wurde. Nozizeptive C-Fasern zeigen jedoch typischerweise eine niederfrequente Entladungsrate. In der vorliegenden Arbeit konnte gezeigt werden, dass LTP an Synapsen im oberflächlichen Dorsalhorn des Rückenmarks auch durch niederfrequente Stimulation afferenter Nervenfasern sowie durch Applikation natürlicher noxischer Stimuli ausgelöst werden kann. Dazu wurden C-Faser evozierte Feldpotentiale im Rückenmark tief anästhesierter Ratten abgeleitet. Die Signaltransduktionswege, die zur Induktion der LTP durch LFS führen, zeigen eine hohe Ähnlichkeit mit jenen bekannten Wegen, die zur Ausbildung einer Hyperalgesie führen. Dies unterstützt die Rolle der LTP an C-Fasersynapsen im Rückenmark bei der Schmerzverstärkung. Opioide sind das Mittel der Wahl zur Behandlung moderater bis starker akuter und chronischer Schmerzen. Immer mehr Studien haben jedoch gezeigt, dass Opioide auch zur Aktivierung pronozizeptiver Systeme und zur Hyperalgesie führen können. In der vorliegenden Arbeit werden zwei bislang unbekannte Effekte des -Opioidrezeptor Agonisten Remifentanil auf die spinale Nozizeption beschrieben. Es konnte gezeigt werden, dass Remifentanil gegensätzliche Effekte auf die spinale Nozizeption abhängig vom funktionellen Zustand des Rückenmarks aufweist. Erneut wurden C-Faser evozierte Feldpotentiale im Hinterhorn des Rückenmarks abgeleitet. Im naiven Tier führte eine i.v. Remifentanilapplikation zu einer Potenzierung der C-Faser evozierten Feldpotentialen nach dem Auswaschen. Diese Potenzierung stellt einen möglichen Mechanismus der Opioid-induzierten Hyperalgesie dar. Eine i.v. Infusion von Remifentanil nach LTP Induktion durch verschiedene Stimuli führte zu einer Depotenzierung nach Auswaschen des Opioids. Diese neue Opioidwirkung konnte auch im Verhalten von Ratten bestätigt werden. Opioide werden standardmäßig in der Klinik eingesetzt. Die in dieser Studie durchgeführten Untersuchungen der Mechanismen der beiden beschriebenen Opioideffekte und deren mögliche Umsetzung im klinischen Bereich könnten zur Entwicklung einer kausalen Therapie für manche chronische Schmerzpatienten führen. Teile dieser Arbeit wurden in Science, 2006, 312(5780):1659-62 und Molecular Pain, 2008, 4(1):18 publiziert.submitted by Ruth DrdlaAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersWien, Med. Univ., Diss., 2008OeBB(VLID)171418

Selective activation of microglia facilitates synaptic strength

Synaptic plasticity is thought to be initiated by neurons only, with the prevailing view assigning glial cells mere specify supportive functions for synaptic transmission and plasticity. We now demonstrate that glial cells can control synaptic strength independent of neuronal activity. Here we show that selective activation of microglia in the rat is sufficient to rapidly facilitate synaptic strength between primary afferent C-fibers and lamina I neurons, the first synaptic relay in the nociceptive pathway. Specifically, the activation of the CX3CR1 receptor by fractalkine induces the release of interleukin-1β from microglia, which modulates NMDA signaling in postsynaptic neurons, leading to the release of an eicosanoid messenger, which ultimately enhances presynaptic neurotransmitter release. In contrast to the conventional view, this form of plasticity does not require enhanced neuronal activity to trigger the events leading to synaptic facilitation. Augmentation of synaptic strength in nociceptive pathways represents a cellular model of pain amplification. The present data thus suggest that, under chronic pain states, CX3CR1-mediated activation of microglia drives the facilitation of excitatory synaptic transmission in the dorsal horn, which contributes to pain hypersensitivity in chronic pain states