A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins

François, Amaury; Low, Sarah; Sypek, Elizabeth I.; Christensen, Amelia J.; Sotoudeh, Chaudy; Beier, Kevin T.; Ramakrishnan, Charu; Ritola, Kimberly; Sharif‐Naeini, Reza; Deisseroth, Karl; Delp, Scott L.; Malenka, Robert C.; Luo, Liqun; Hantman, Adam W.; Scherrer, Grégory

doi:10.1016/j.neuron.2017.01.008

Cited by 275 publications

(249 citation statements)

References 96 publications

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“…These data are consistent with prior studies showing regular exercise produces analgesia through endogenous opioid systems in the RVM and spinal cord [6,39,60]. Since mu-opioid receptors are purported to be ON-cells and facilitate nociception [17,24], these data suggest that there is less descending facilitation from the RVM in physically active mice.…”

Section: Discussionsupporting

confidence: 91%

Regular physical activity reduces the percentage of spinally projecting neurons that express mu-opioid receptors from the RVM

Sluka

Kolker

Danielson

et al. 2020

Preprint

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Regular physical activity/exercise is an effective non-pharmacological treatment for individuals with chronic pain. Central inhibitory mechanisms, involving serotonin and opioids, are critical to analgesia produced by regular physical activity. The RVM sends projections to the spinal cord to inhibit or facilitate nociceptive neurons and plays a key role in exercise-induced analgesia. The goal of these studies was to examine if regular physical activity modifies RVM-spinal cord circuitry. Male and female mice received Fluoro-Gold placed on the spinal cord to identify spinally projecting neurons from the rostral ventromedial medulla (RVM) and the nucleus raphe obscuris/nucleus raphe pallidus (NRO/NRP), dermorphin-488 into caudal medulla to identify mu-opioid receptors, and were immunohistochemically stained for either phosphorylated-N-methyl-D-aspartate subunit NR1 (p-NR1) to identify excitatory neurons or tryptophan hydroxylase (TPH) to identify serotonin neurons. The percentage of dermorphin-488positive cells that stained for p-NR1 (or TPH), and the percentage of dermorphin-488positive cells that stained for p-NR1 (or TPH) and Fluoro-Gold was calculated. Physically active animals were provided running wheels in their cages for 8 weeks and compared to sedentary animals without running wheels. Animals with chronic muscle pain, induced by two intramuscular injections of pH 4.0, were compared to sham controls (pH 7.2). Physically active animals had less mu-opioid expressing neurons projecting to the spinal cord when compared to sedentary animals in the RVM, but not the NRO/NRP. No changes were observed for TPH. These data suggest that regular exercise alters central facilitation so that there is less descending facilitation to result in a net increase in inhibition. Summary Statement: Physically active animals has less mu-opioid expressing neurons projecting to the spinal cord in the RVM, but not the NRO/NRP, when compared to sedentary animals.

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Section: Discussionsupporting

confidence: 91%

Regular physical activity reduces the percentage of spinally projecting neurons that express mu-opioid receptors from the RVM

Sluka

Kolker

Danielson

et al. 2020

Preprint

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“…Here, inhibition exercises state-dependent control of sensory thresholds, for example suppressing nociceptive transmission during acute stress [23], and prevents sensorimotor reflexes from interfering with stable performance of motor acts such as reaching or locomotion [24,25]. Similarly, prepulse inhibition shares characteristics of both state- and task-dependent sensory gating.…”

Section: Discussionmentioning

confidence: 99%

Presynaptic Inhibition Selectively Gates Auditory Transmission to the Brainstem Startle Circuit

et al. 2018

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Filtering mechanisms prevent a continuous stream of sensory information from swamping perception, leading to diminished focal attention and cognitive processing. Mechanisms for sensory gating are commonly studied using prepulse inhibition, a paradigm that measures the regulated transmission of auditory information to the startle circuit; however, the underlying neuronal pathways are unresolved. Using large-scale calcium imaging, optogenetics, and laser ablations, we reveal a cluster of 30 morphologically identified neurons in zebrafish that suppress the transmission of auditory signals during prepulse inhibition. These neurons project to a key sensorimotor interface in the startle circuit-the termination zone of auditory afferents on the dendrite of a startle command neuron. Direct measurement of auditory nerve neurotransmitter release revealed selective presynaptic inhibition of sensory transmission to the startle circuit, sparing signaling to other brain regions. Our results provide the first cellular resolution circuit for prepulse inhibition in a vertebrate, revealing a central role for presynaptic gating of sensory information to a brainstem motor circuit.

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“…As a control for antibody specificity, pre-absorption of the Met-Enk and NT antibody with an excess of the native peptide resulted in the complete absence of immunolabeling for NT. Method specificity controls for Met-Enk or NT immunocytochemistry, performed by omitting the primary antibody at either of the two successive incubation steps, also failed to reveal immunolabeling for the respective antigens (Emson, Goedert, Williams, Ninkovic, & Hunt, 1982;Woulfe & Beaudet, 1992;François et al, 2017).…”

Section: Anti-met-enk and Anti-neurotensin (Nt)mentioning

confidence: 99%

Characterization of McDonald's intermediate part of the Central nucleus of the amygdala in the rat

Barbier

Fellmann

Risold

2018

J of Comparative Neurology

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The actual organization of the central nucleus of the amygdala (CEA) in the rat is mostly based on cytoarchitecture and the distribution of several cell types, as described by McDonald in 1982. Four divisions were identified by this author. However, since this original work, one of these divisions, the intermediate part, has not been consistently recognized based on Nissl-stained material. In the present study, we observed that a compact condensation of retrogradely labeled cells is found in the CEA after fluorogold injection in the anterior region of the tuberal lateral hypothalamic area (LHA) in the rat. We then searched for neurochemical markers of this cell condensation and found that it is quite specifically labeled for calbindin (Cb), but also contains calretinin (Cr), tyrosine hydroxylase (TH) and methionine-enkephalin (Met-Enk) immunohistochemical signals. These neurochemical features are specific to this cell group which, therefore, is distinct from the other parts of the CEA. We then performed cholera toxin injections in the mouse LHA to identify this cell group in this species. We found that neurons exist in the medial and rostral CEAl that project into the LHA but they have a less tight organization than in the rat.

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A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins

Cited by 275 publications

References 96 publications

Regular physical activity reduces the percentage of spinally projecting neurons that express mu-opioid receptors from the RVM

Regular physical activity reduces the percentage of spinally projecting neurons that express mu-opioid receptors from the RVM

Presynaptic Inhibition Selectively Gates Auditory Transmission to the Brainstem Startle Circuit

Characterization of McDonald's intermediate part of the Central nucleus of the amygdala in the rat

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