1. Neuroscience
Download icon

Identification of a novel spinal nociceptive-motor gate control for Aδ pain stimuli in rats

  1. Dvir Blivis  Is a corresponding author
  2. Gal Haspel
  3. Philip Z Mannes
  4. Michael James O'Donovan
  5. Michael J Iadarola
  1. National Institutes of Health, United States
Research Article
  • Cited 13
  • Views 1,320
  • Annotations
Cite this article as: eLife 2017;6:e23584 doi: 10.7554/eLife.23584

Abstract

Physiological responses to nociceptive stimuli are initiated within tens of milliseconds, but the corresponding sub-second behavioral responses have not been adequately explored in awake, unrestrained animals. A detailed understanding of these responses is crucial for progress in pain neurobiology. Here, high-speed videography during nociceptive Aδ fiber stimulation demonstrated engagement of a multi-segmental motor program coincident with, or even preceding, withdrawal of the stimulated paw. The motor program included early head orientation and adjustments of the torso and un-stimulated paws. Moreover, we observed a remarkably potent gating mechanism when the animal was standing on its hindlimbs and which was partially dependent on the endogenous opioid system. These data reveal a profound, immediate and precise integration of nociceptive inputs with ongoing motor activities leading to the initiation of complex, yet behaviorally appropriate, response patterns and the mobilization of a new type of analgesic mechanism within this early temporal nociceptive window.

Article and author information

Author details

  1. Dvir Blivis

    Developmental Neurobiology Section, Laboratory of Neural Control, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
    For correspondence
    blivisd@ninds.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6203-7325
  2. Gal Haspel

    Developmental Neurobiology Section, Laboratory of Neural Control, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Philip Z Mannes

    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael James O'Donovan

    Developmental Neurobiology Section, Laboratory of Neural Control, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2487-7547
  5. Michael J Iadarola

    Department of Perioperative Medicine, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7188-9810

Funding

National Institute of Neurological Disorders and Stroke (Intramural Research Program)

  • Dvir Blivis
  • Gal Haspel
  • Michael James O'Donovan

National Institutes of Health (Clinical Center Intramural Research Program)

  • Michael J Iadarola

National Institute of Dental and Craniofacial Research (Intramural Research Program)

  • Philip Z Mannes
  • Michael J Iadarola

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled and procedures conducted according to approved animal care and use committee (ACUC) protocol (#10-555).

Reviewing Editor

  1. Peggy Mason, University of Chicago, United States

Publication history

  1. Received: November 23, 2016
  2. Accepted: May 22, 2017
  3. Accepted Manuscript published: May 24, 2017 (version 1)
  4. Accepted Manuscript updated: May 26, 2017 (version 2)
  5. Accepted Manuscript updated: June 6, 2017 (version 3)
  6. Version of Record published: June 14, 2017 (version 4)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Metrics

  • 1,320
    Page views
  • 245
    Downloads
  • 13
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Neuroscience
    Rawan AlSubaie et al.
    Research Article Updated

    Projections from the basal amygdala (BA) to the ventral hippocampus (vH) are proposed to provide information about the rewarding or threatening nature of learned associations to support appropriate goal-directed and anxiety-like behaviour. Such behaviour occurs via the differential activity of multiple, parallel populations of pyramidal neurons in vH that project to distinct downstream targets, but the nature of BA input and how it connects with these populations is unclear. Using channelrhodopsin-2-assisted circuit mapping in mice, we show that BA input to vH consists of both excitatory and inhibitory projections. Excitatory input specifically targets BA- and nucleus accumbens-projecting vH neurons and avoids prefrontal cortex-projecting vH neurons, while inhibitory input preferentially targets BA-projecting neurons. Through this specific connectivity, BA inhibitory projections gate place-value associations by controlling the activity of nucleus accumbens-projecting vH neurons. Our results define a parallel excitatory and inhibitory projection from BA to vH that can support goal-directed behaviour.

    1. Cell Biology
    2. Neuroscience
    Angela Kim et al.
    Research Article Updated

    Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.