scholarly journals Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kelly M Smith ◽  
Tyler J Browne ◽  
Olivia C Davis ◽  
A Coyle ◽  
Kieran A Boyle ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Calcium Binding ◽  
Spinal Cord Dorsal Horn ◽  
Projection Neurons ◽  
Spinal Interneurons ◽  
Nociceptive Information ◽  
Spinal Cord Dorsal ◽  
Pathological Pain

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.

scholarly journals Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

2019 ◽  
Author(s):  
KM Smith ◽  
TJ Browne ◽  
O Davis ◽  
A Coyle ◽  
KA Boyle ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Calcium Binding ◽  
Spinal Cord Dorsal Horn ◽  
Projection Neurons ◽  
Neuronal Circuits ◽  
Nociceptive Information ◽  
Spinal Cord Dorsal ◽  
Pathological Pain

AbstractThe passage of nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate neurons that contain the calcium-binding protein calretinin (CR). We show that CR+ interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relays signals to lamina I projection neurons. In vivo photoactivation of CR+ interneurons resulted in a significant nocifensive behavior that was morphine sensitive and cause a conditioned place aversion. Furthermore, halorhodopsin-mediated inhibition of CR+ interneurons elevated sensory thresholds. These results suggest that neuronal circuits in the superficial dorsal horn that involve excitatory CR+ neurons are important for the generation and amplification of pain, and identify these interneurons as a future analgesic target.

scholarly journals Chemokine CCL2 prevents opioid-induced inhibition of nociceptive synaptic transmission in spinal cord dorsal horn

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Mario Heles ◽  
Petra Mrozkova ◽  
Dominika Sulcova ◽  
Pavel Adamek ◽  
Diana Spicarova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Synaptic Transmission ◽  
Dorsal Horn ◽  
Transient Receptor Potential ◽  
Pain Treatment ◽  
Spinal Cord Dorsal Horn ◽  
Transient Receptor Potential Vanilloid ◽  
Trpv1 Receptors ◽  
Spinal Cord Dorsal

Abstract Background Opioid analgesics remain widely used for pain treatment despite the related serious side effects. Some of those, such as opioid tolerance and opioid-induced hyperalgesia may be at least partially due to modulation of opioid receptors (OR) function at nociceptive synapses in the spinal cord dorsal horn. It was suggested that increased release of different chemokines under pathological conditions may play a role in this process. The goal of this study was to investigate the crosstalk between the µOR, transient receptor potential vanilloid 1 (TRPV1) receptor and C–C motif ligand 2 (CCL2) chemokine and the involvement of spinal microglia in the modulation of opioid analgesia. Methods Patch-clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) and dorsal root evoked currents (eEPSC) in spinal cord slices superficial dorsal horn neurons were used to evaluate the effect of µOR agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO), CCL2, TRPV1 antagonist SB366791 and minocycline. Paw withdrawal test to thermal stimuli was combined with intrathecal (i.t.) delivery of CCL2 and DAMGO to investigate the modulation in vivo. Results Application of DAMGO induced a rapid decrease of mEPSC frequency and eEPSC amplitude, followed by a delayed increase of the eESPC amplitude, which was prevented by SB366791. Chemokine CCL2 treatment significantly diminished all the DAMGO-induced changes. Minocycline treatment prevented the CCL2 effects on the DAMGO-induced eEPSC depression, while mEPSC changes were unaffected. In behavioral experiments, i.t. injection of CCL2 completely blocked DAMGO-induced thermal hypoalgesia and intraperitoneal pre-treatment with minocycline prevented the CCL2 effect. Conclusions Our results indicate that opioid-induced inhibition of the excitatory synaptic transmission could be severely attenuated by increased CCL2 levels most likely through a microglia activation-dependent mechanism. Delayed potentiation of neurotransmission after µOR activation is dependent on TRPV1 receptors activation. Targeting CCL2 and its receptors and TRPV1 receptors in combination with opioid therapy could significantly improve the analgesic properties of opioids, especially during pathological states.

Ubiquitination and functional modification of GluN2B subunit–containing NMDA receptors by Cbl-b in the spinal cord dorsal horn

2020 ◽  
Vol 13 (638) ◽  
pp. eaaw1519 ◽  
Author(s):  
Zi-Yang Zhang ◽  
Hu-Hu Bai ◽  
Zhen Guo ◽  
Hu-Ling Li ◽  
Xin-Tong Diao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Critical Time ◽  
Brain Regions ◽  
Spinal Cord Dorsal Horn ◽  
Intraplantar Injection ◽  
Adult Mice ◽  
Spinal Cord Dorsal ◽  
Synapse Maturation

N-methyl-d-aspartate (NMDA) glutamate receptors (NMDARs) containing GluN2B subunits are prevalent early after birth in most brain regions in rodents. Upon synapse maturation, GluN2B is progressively removed from synapses, which affects NMDAR function and synaptic plasticity. Aberrant recruitment of GluN2B into mature synapses has been implicated in several neuropathologies that afflict adults. We found that the E3 ubiquitin ligase Cbl-b was enriched in the spinal cord dorsal horn neurons of mice and rats and suppressed GluN2B abundance during development and inflammatory pain. Cbl-b abundance increased from postnatal day 1 (P1) to P14, a critical time period for synapse maturation. Through its N-terminal tyrosine kinase binding domain, Cbl-b interacted with GluN2B. Ubiquitination of GluN2B by Cbl-b decreased the synaptic transmission mediated by GluN2B-containing NMDARs. Knocking down Cbl-b in vivo during P1 to P14 led to sustained retention of GluN2B at dorsal horn synapses, suggesting that Cbl-b limits the synaptic abundance of GluN2B in adult mice. However, peripheral inflammation induced by intraplantar injection of complete Freund’s adjuvant resulted in the dephosphorylation of Cbl-b at Tyr363, which impaired its binding to and ubiquitylation of GluN2B, enabling the reappearance of GluN2B-containing NMDARs at synapses. Expression of a phosphomimic Cbl-b mutant in the dorsal horn suppressed both GluN2B-mediated synaptic currents and manifestations of pain induced by inflammation. The findings indicate a ubiquitin-mediated developmental switch in NMDAR subunit composition that is dysregulated by inflammation, which can enhance nociception.

Peripheral axotomy influences the in vivo release of cholecystokinin in the spinal cord dorsal horn—possible involvement of cholecystokinin-B receptors

1998 ◽  
Vol 790 (1-2) ◽  
pp. 141-150 ◽  
Author(s):  
Henrik Gustafsson ◽  
Guilherme de Araújo Lucas ◽  
Eva Schött ◽  
Carl-Olav Stiller ◽  
Pawel Alster ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Spinal Cord Dorsal Horn ◽  
In Vivo Release ◽  
Spinal Cord Dorsal

scholarly journals Serotonergic Modulation of Nociceptive Circuits in Spinal Cord Dorsal Horn

2019 ◽  
Vol 17 (12) ◽  
pp. 1133-1145 ◽  
Author(s):  
Rita Bardoni
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Pain Modulation ◽  
Spinal Cord Dorsal Horn ◽  
Pain Transmission ◽  
Spinal Cord Dorsal ◽  
Spinal Cord Level ◽  
Serotonergic Modulation

Background: Despite the extensive number of studies performed in the last 50 years, aimed at describing the role of serotonin and its receptors in pain modulation at the spinal cord level, several aspects are still not entirely understood. The interpretation of these results is often complicated by the use of different pain models and animal species, together with the lack of highly selective agonists and antagonists binding to serotonin receptors. Method: In this review, a search has been conducted on studies investigating the modulatory action exerted by serotonin on specific neurons and circuits in the spinal cord dorsal horn. Particular attention has been paid to studies employing electrophysiological techniques, both in vivo and in vitro. Conclusion: The effects of serotonin on pain transmission in dorsal horn depend on several factors, including the type of receptors activated and the populations of neurons involved. Recently, studies performed by activating and/or recording from identified neurons have importantly contributed to the understanding of serotonergic modulation on dorsal horn circuits.

Antinociceptive actions of tramadol revealed by in vivo patch-clamp recordings in the spinal cord dorsal horn

2013 ◽  
Vol 30 ◽  
pp. 212-212
Author(s):  
H. Yamasaki ◽  
T. Mori ◽  
Y. Funai ◽  
T. Hamada ◽  
T. Yamada ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Patch Clamp ◽  
Dorsal Horn ◽  
Spinal Cord Dorsal Horn ◽  
Spinal Cord Dorsal
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