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  1. Book: Nervous system plasticity and chronic pain

    Sandkühler, Jürgen

    (Progress in brain research ; 129)

    2000  

    Author's details ed. by J. Sandkühler
    Series title Progress in brain research ; 129
    Collection
    Keywords Nervensystem ; Plastizität ; Chronischer Schmerz ; Neurobiologie
    Subject Schmerzsyndrom ; Schmerzkrankheit ; Verformbarkeit ; Systema nervosum ; NS
    Language English
    Size XVI, 543 S. : Ill., graph. Darst.
    Edition 1. ed.
    Publisher Elsevier
    Publishing place Amsterdam u.a.
    Publishing country Netherlands
    Document type Book
    HBZ-ID HT012869824
    ISBN 0-444-50509-1 ; 978-0-444-50509-5
    Database Catalogue ZB MED Medicine, Health

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  2. Article: Differential activation of spinal and parabrachial glial cells in a neuropathic pain model.

    Mussetto, Valeria / Moen, Aurora / Trofimova, Lidia / Sandkühler, Jürgen / Hogri, Roni

    Frontiers in cellular neuroscience

    2023  Volume 17, Page(s) 1163171

    Abstract: The clinical burden faced by chronic pain patients is compounded by affective comorbidities, such as depression and anxiety disorders. Emerging evidence suggests that reactive glial cells in the spinal cord dorsal horn play a key role in the ... ...

    Abstract The clinical burden faced by chronic pain patients is compounded by affective comorbidities, such as depression and anxiety disorders. Emerging evidence suggests that reactive glial cells in the spinal cord dorsal horn play a key role in the chronification of pain, while supraspinal glia are important for psychological aspects of chronic pain. The lateral parabrachial nucleus (LPBN) in the brainstem is a key node in the ascending pain system, and is crucial for the emotional dimension of pain. Yet, whether astrocytes and microglia in the LPBN are activated during chronic pain is unknown. Here, we evaluated the occurrence of glial activation in the LPBN of male Sprague-Dawley rats 1, 4, and 7 weeks after inducing a chronic constriction injury (CCI) of the sciatic nerve, a prevalent neuropathic pain model. CCI animals developed mechanical and thermal hypersensitivity that persisted for at least 4 weeks, and was mostly reversed after 7 weeks. Using immunohistochemical staining and confocal imaging, we found that CCI caused a strong increase in the expression of the astrocytic marker GFAP and the microglial marker Iba1 in the ipsilateral spinal dorsal horn, with peak expression observed 1 week post-injury. Moreover, morphology analysis revealed changes in microglial phenotype, indicative of microglia activation. In contrast, CCI did not induce any detectable changes in either astrocytes or microglia in the LPBN, at any time point. Thus, our results indicate that while neuropathic pain induces a robust glial reaction in the spinal dorsal horn, it fails to activate glial cells in the LPBN.
    Language English
    Publishing date 2023-04-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2023.1163171
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  3. Article ; Online: Translating synaptic plasticity into sensation.

    Sandkühler, Jürgen

    Brain : a journal of neurology

    2015  Volume 138, Issue Pt 9, Page(s) 2463–2464

    MeSH term(s) Capsaicin/pharmacology ; Humans ; Long-Term Potentiation/drug effects ; Male ; Nerve Fibers/drug effects ; Nociceptors/drug effects ; Pain/pathology ; Sensory System Agents/pharmacology
    Chemical Substances Sensory System Agents ; Capsaicin (S07O44R1ZM)
    Language English
    Publishing date 2015-09
    Publishing country England
    Document type Comment ; Journal Article
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awv193
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  4. Article ; Online: Anti-Nociceptive and Anti-Aversive Drugs Differentially Modulate Distinct Inputs to the Rat Lateral Parabrachial Nucleus.

    Teuchmann, Hannah Luise / Hogri, Roni / Heinke, Bernhard / Sandkühler, Jürgen

    The journal of pain

    2022  Volume 23, Issue 8, Page(s) 1410–1426

    Abstract: The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial dorsal horn and forms reciprocal connections with the periaqueductal grey matter (PAG), ... ...

    Abstract The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial dorsal horn and forms reciprocal connections with the periaqueductal grey matter (PAG), which is critical for adaptive behaviour and the modulation of pain processing. Here, using in situ hybridization and optogenetics combined with in vitro electrophysiology, we characterized the spinal- and PAG-LPBN circuits of rats. We found spinoparabrachial projections to be strictly glutamatergic, while PAG neurons send glutamatergic and GABAergic projections to the LPBN. We next investigated the effects of drugs with anti-aversive and/or anti-nociceptive properties on these synapses: The µ-opioid receptor agonist DAMGO (10 µM) reduced spinal and PAG synaptic inputs onto LPBN neurons, and the excitability of LPBN neurons receiving these inputs. The benzodiazepine receptor agonist diazepam (5 µM) strongly enhanced GABAergic action at inhibitory PAG-LPBN synapses. The cannabinoid receptor agonist WIN 55,212-2 (5 µM) led to a reduction in inhibitory and excitatory PAG-LPBN synaptic transmission, without affecting excitatory spinoparabrachial synaptic transmission. Our study reveals that opioid, cannabinoid and benzodiazepine receptor agonists differentially affect distinct LPBN synapses. These findings may support the efforts to develop pinpointed therapies for pain patients. PERSPECTIVE: The LPBN is an important brain region for the control of pain aversion versus recuperation, and as such constitutes a promising target for developing new strategies for pain management. We show that clinically-relevant drugs have complex and pathway-specific effects on LPBN processing of putative nociceptive and aversive inputs.
    MeSH term(s) Analgesics, Opioid/pharmacology ; Animals ; Pain ; Parabrachial Nucleus/physiology ; Periaqueductal Gray ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A
    Chemical Substances Analgesics, Opioid ; Receptors, GABA-A
    Language English
    Publishing date 2022-03-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2018789-0
    ISSN 1528-8447 ; 1526-5900
    ISSN (online) 1528-8447
    ISSN 1526-5900
    DOI 10.1016/j.jpain.2022.03.234
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  5. Article ; Online: Interferon-γ facilitates the synaptic transmission between primary afferent C-fibres and lamina I neurons in the rat spinal dorsal horn via microglia activation.

    Reischer, Gerda / Heinke, Bernhard / Sandkühler, Jürgen

    Molecular pain

    2020  Volume 16, Page(s) 1744806920917249

    MeSH term(s) Animals ; Inflammation ; Interferon-gamma/metabolism ; Male ; Microglia/metabolism ; Nerve Fibers, Unmyelinated/metabolism ; Neurons/metabolism ; Neurons, Afferent/metabolism ; Patch-Clamp Techniques ; Posterior Horn Cells/metabolism ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/metabolism ; Spinal Cord/metabolism ; Spinal Cord Dorsal Horn/metabolism ; Spine/metabolism ; Synapses/metabolism ; Synaptic Potentials ; Synaptic Transmission
    Chemical Substances Recombinant Proteins ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2020-04-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2174252-2
    ISSN 1744-8069 ; 1744-8069
    ISSN (online) 1744-8069
    ISSN 1744-8069
    DOI 10.1177/1744806920917249
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  6. Article ; Online: GABAergic CaMKIIα+ Amygdala Output Attenuates Pain and Modulates Emotional-Motivational Behavior via Parabrachial Inhibition.

    Hogri, Roni / Teuchmann, Hannah Luise / Heinke, Bernhard / Holzinger, Raphael / Trofimova, Lidia / Sandkühler, Jürgen

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2022  Volume 42, Issue 27, Page(s) 5373–5388

    Abstract: Pain and emotion are strongly regulated by neurons in the central nucleus of the amygdala (CeA), a major output of the limbic system; yet, the neuronal signaling pathways underlying this modulation are incompletely understood. Here, we characterized a ... ...

    Abstract Pain and emotion are strongly regulated by neurons in the central nucleus of the amygdala (CeA), a major output of the limbic system; yet, the neuronal signaling pathways underlying this modulation are incompletely understood. Here, we characterized a subpopulation of CeA neurons that express the CaMKIIα gene (CeA
    MeSH term(s) Amygdala/physiology ; Animals ; Emotions ; Male ; Neural Pathways/physiology ; Pain ; Parabrachial Nucleus/physiology ; Rats ; Rats, Sprague-Dawley
    Language English
    Publishing date 2022-06-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.2067-21.2022
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  7. Book ; Thesis: Untersuchungen zur Hemmung von nociceptiven Rückenmarksneuronen durch Morphinmikroinjektion und fokale elektrische Stimulation im Hirnstamm der Katze

    Sandkühler, Jürgen

    1984  

    Size 47 S. : graph. Darst.
    Document type Book ; Thesis
    Thesis / German Habilitation thesis Heidelberg, Univ., Diss., 1984
    HBZ-ID HT003252872
    Database Catalogue ZB MED Medicine, Health

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  8. Article ; Online: Central sensitization versus synaptic long-term potentiation (LTP): a critical comment.

    Sandkühler, Jürgen

    The journal of pain

    2010  Volume 11, Issue 8, Page(s) 798–800

    MeSH term(s) Cerebral Cortex/physiology ; Humans ; Neuronal Plasticity/physiology ; Neurons/physiology ; Synapses/physiology ; Synaptic Transmission/physiology
    Language English
    Publishing date 2010-07-30
    Publishing country United States
    Document type Comment ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2018789-0
    ISSN 1528-8447 ; 1526-5900
    ISSN (online) 1528-8447
    ISSN 1526-5900
    DOI 10.1016/j.jpain.2010.05.002
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  9. Article ; Online: Probing pain aversion in rats with the "Heat Escape Threshold" paradigm.

    Hogri, Roni / Baltov, Bozhidar / Drdla-Schutting, Ruth / Mussetto, Valeria / Raphael, Holzinger / Trofimova, Lidia / Sandkühler, Jürgen

    Molecular pain

    2023  Volume 19, Page(s) 17448069231156657

    Abstract: The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of novel methods focusing on affective-motivational behaviour in pain model animals. The ... ...

    Abstract The aversive aspect of pain constitutes a major burden faced by pain patients. This has been recognized by the pain research community, leading to the development of novel methods focusing on affective-motivational behaviour in pain model animals. The most common tests used to assess pain aversion in animals require cognitive processes, such as associative learning, complicating the interpretation of results. To overcome this issue, studies in recent years have utilized unconditioned escape as a measure of aversion. However, the vast majority of these studies quantify jumping - a common escape behaviour in mice, but not in adult rats, thus limiting its use. Here, we present the "Heat Escape Threshold" (HET) paradigm for assessing heat aversion in rats. We demonstrate that this method can robustly and reproducibly detect the localized effects of an inflammatory pain model (intraplantar carrageenan) in male and female Sprague-Dawley rats. In males, a temperature that evoked unconditioned escape following carrageenan treatment also induced real-time place avoidance (RTPA). Systemic morphine more potently alleviated carrageenan-induced heat aversion (as measured by the HET and RTPA methods), as compared to reflexive responses to heat (as measured by the Hargreaves test), supporting previous findings. Next, we examined how blocking of excitatory transmission to the lateral parabrachial nucleus (LPBN), a key node in the ascending pain system, affects pain behaviour. Using the HET and Hargreaves tests, we show that intra-LPBN application of glutamate antagonists reverses the effects of carrageenan on both affective and reflexive pain behaviour, respectively. Finally, we employed the HET paradigm in a generalized opioid-withdrawal pain model. Withdrawal from a brief systemic administration of remifentanil resulted in a long-lasting and robust increase in heat aversion, but no change in reflexive responses to heat. Taken together, these data demonstrate the utility of the HET paradigm as a novel tool in preclinical pain research.
    MeSH term(s) Rats ; Male ; Female ; Animals ; Mice ; Rats, Sprague-Dawley ; Carrageenan/adverse effects ; Hot Temperature ; Avoidance Learning ; Pain/drug therapy ; Morphine/pharmacology ; Pain Threshold
    Chemical Substances Carrageenan (9000-07-1) ; Morphine (76I7G6D29C)
    Language English
    Publishing date 2023-01-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2174252-2
    ISSN 1744-8069 ; 1744-8069
    ISSN (online) 1744-8069
    ISSN 1744-8069
    DOI 10.1177/17448069231156657
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  10. Article ; Online: Opioids Induce Bidirectional Synaptic Plasticity in a Brainstem Pain Center in the Rat.

    Mussetto, Valeria / Teuchmann, Hannah Luise / Heinke, Bernhard / Trofimova, Lidia / Sandkühler, Jürgen / Drdla-Schutting, Ruth / Hogri, Roni

    The journal of pain

    2023  Volume 24, Issue 9, Page(s) 1664–1680

    Abstract: Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately drive severe side effects, such as pain hypersensitivity and strong aversion during ... ...

    Abstract Opioids are powerful analgesics commonly used in pain management. However, opioids can induce complex neuroadaptations, including synaptic plasticity, that ultimately drive severe side effects, such as pain hypersensitivity and strong aversion during prolonged administration or upon drug withdrawal, even following a single, brief administration. The lateral parabrachial nucleus (LPBN) in the brainstem plays a key role in pain and emotional processing; yet, the effects of opioids on synaptic plasticity in this area remain unexplored. Using patch-clamp recordings in acute brainstem slices from male and female Sprague Dawley rats, we demonstrate a concentration-dependent, bimodal effect of opioids on excitatory synaptic transmission in the LPBN. While a lower concentration of DAMGO (0.5 µM) induced a long-term depression of synaptic strength (low-DAMGO LTD), abrupt termination of a higher concentration (10 µM) induced a long-term potentiation (high-DAMGO LTP) in a subpopulation of cells. LTD involved a metabotropic glutamate receptor (mGluR)-dependent mechanism; in contrast, LTP required astrocytes and N-methyl-D-aspartate receptor (NMDAR) activation. Selective optogenetic activation of spinal and periaqueductal gray matter (PAG) inputs to the LPBN revealed that, while LTD was expressed at all parabrachial synapses tested, LTP was restricted to spino-parabrachial synapses. Thus, we uncovered previously unknown forms of opioid-induced long-term plasticity in the parabrachial nucleus that potentially modulate some adverse effects of opioids. PERSPECTIVE: We found a previously unrecognized site of opioid-induced plasticity in the lateral parabrachial nucleus, a key region for pain and emotional processing. Unraveling opioid-induced adaptations in parabrachial function might facilitate the identification of new therapeutic measures for addressing adverse effects of opioid discontinuation such as hyperalgesia and aversion.
    MeSH term(s) Rats ; Male ; Female ; Animals ; Analgesics, Opioid/pharmacology ; Rats, Sprague-Dawley ; Pain Clinics ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology ; Neuronal Plasticity/physiology ; Brain Stem ; Pain
    Chemical Substances Analgesics, Opioid ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (100929-53-1)
    Language English
    Publishing date 2023-05-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2018789-0
    ISSN 1528-8447 ; 1526-5900
    ISSN (online) 1528-8447
    ISSN 1526-5900
    DOI 10.1016/j.jpain.2023.05.001
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