scholarly journals Colonic afferent input and dorsal horn neuron activation differs between the thoracolumbar and lumbosacral spinal cord

2019 ◽  
Vol 317 (3) ◽  
pp. G285-G303 ◽  
Author(s):  
Andrea M. Harrington ◽  
Sonia Garcia Caraballo ◽  
Jessica E. Maddern ◽  
Luke Grundy ◽  
Joel Castro ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Afferent Input ◽  
Dorsal Horn Neuron ◽  
Neuronal Activation ◽  
Colorectal Distension ◽  
Central Projections ◽  
Colon Wall ◽  
Lumbosacral Spinal Cord

The distal colon is innervated by the splanchnic and pelvic nerves, which relay into the thoracolumbar and lumbosacral spinal cord, respectively. Although the peripheral properties of the colonic afferent nerves within these pathways are well studied, their input into the spinal cord remain ill defined. The use of dual retrograde tracing from the colon wall and lumen, in conjunction with in vivo colorectal distension and spinal neuronal activation labeling with phosphorylated MAPK ERK 1/2 (pERK), allowed us to identify thoracolumbar and lumbosacral spinal cord circuits processing colonic afferent input. In the thoracolumbar dorsal horn, central projections of colonic afferents were primarily labeled from the wall of the colon and localized in laminae I and V. In contrast, lumbosacral projections were identified from both lumen and wall tracing, present within various dorsal horn laminae, collateral tracts, and the dorsal gray commissure. Nonnoxious in vivo colorectal distension evoked significant neuronal activation (pERK-immunoreactivity) within the lumbosacral dorsal horn but not in thoracolumbar regions. However, noxious in vivo colorectal distension evoked significant neuronal activation in both the thoracolumbar and lumbosacral dorsal horn, with the distribution of activated neurons correlating to the pattern of traced projections. Dorsal horn neurons activated by colorectal distension were identified as possible populations of projection neurons or excitatory and inhibitory interneurons based on their neurochemistry. Our findings demonstrate how colonic afferents in splanchnic and pelvic pathways differentially relay mechanosensory information into the spinal cord and contribute to the recruitment of spinal cord pathways processing non-noxious and noxious stimuli. NEW & NOTEWORTHY In mice, retrograde tracing from the colon wall and lumen was used to identify unique populations of afferent neurons and central projections within the spinal cord dorsal horn. We show that there are pronounced differences between the spinal cord regions in the distribution pattern of colonic afferent central projections and the pattern of dorsal horn neuron activation evoked by colorectal distension. These findings demonstrate how colonic afferent input influences spinal processing of colonic mechanosensation.

Developmental Changes in the Fidelity and Short-Term Plasticity of GABAergic Synapses in the Neonatal Rat Dorsal Horn

2008 ◽  
Vol 99 (6) ◽  
pp. 3144-3150 ◽  
Author(s):  
Rachel A. Ingram ◽  
Maria Fitzgerald ◽  
Mark L. Baccei
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Receptive Fields ◽  
Neuronal Firing ◽  
Neonatal Rat ◽  
Superficial Dorsal Horn ◽  
Short Term ◽  
Dorsal Horn Neurons ◽  
Gabaergic Synapses

The lower thresholds and increased excitability of dorsal horn neurons in the neonatal rat suggest that inhibitory processing is less efficient in the immature spinal cord. This is unlikely to be explained by an absence of functional GABAergic inhibition because antagonism of γ-aminobutyric acid (GABA) type A receptors augments neuronal firing in vivo from the first days of life. However, it is possible that more subtle deficits in GABAergic signaling exist in the neonate, such as decreased reliability of transmission or greater depression during repetitive stimulation, both of which could influence the relative excitability of the immature spinal cord. To address this issue we examined monosynaptic GABAergic inputs onto superficial dorsal horn neurons using whole cell patch-clamp recordings made in spinal cord slices at a range of postnatal ages (P3, P10, and P21). The amplitudes of evoked inhibitory postsynaptic currents (IPSCs) were significantly lower and showed greater variability in younger animals, suggesting a lower fidelity of GABAergic signaling at early postnatal ages. Paired-pulse ratios were similar throughout the postnatal period, whereas trains of stimuli (1, 5, 10, and 20 Hz) revealed frequency-dependent short-term depression (STD) of IPSCs at all ages. Although the magnitude of STD did not differ between ages, the recovery from depression was significantly slower at immature GABAergic synapses. These properties may affect the integration of synaptic inputs within developing superficial dorsal horn neurons and thus contribute to their larger receptive fields and enhanced afterdischarge.

scholarly journals Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

2020 ◽  
Vol 21 (7) ◽  
pp. 2390
Author(s):  
Masamichi Shinoda ◽  
Satoshi Fujita ◽  
Shiori Sugawara ◽  
Sayaka Asano ◽  
Ryo Koyama ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Electrical Stimulation ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Spinal Cord Stimulation ◽  
Microglial Activation ◽  
In Vivo Optical Imaging ◽  
Stimulation Of

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

Recording Temperature Affects the Excitability of Mouse Superficial Dorsal Horn Neurons, In Vitro

2008 ◽  
Vol 99 (5) ◽  
pp. 2048-2059 ◽  
Author(s):  
B. A. Graham ◽  
A. M. Brichta ◽  
R. J. Callister
Keyword(s):  
Spinal Cord ◽  
Elevated Temperature ◽  
Dorsal Horn ◽  
Current Injection ◽  
Resting Membrane Potential ◽  
Temperature Sensitive ◽  
Superficial Dorsal Horn ◽  
Pain Mechanisms

Superficial dorsal horn (SDH) neurons in laminae I–II of the spinal cord play an important role in processing noxious stimuli. These neurons represent a heterogeneous population and are divided into various categories according to their action potential (AP) discharge during depolarizing current injection. We recently developed an in vivo mouse preparation to examine functional aspects of nociceptive processing and AP discharge in SDH neurons and to extend investigation of pain mechanisms to the genetic level of analysis. Not surprisingly, some in vivo data obtained at body temperature (37°C) differed from those generated at room temperature (22°C) in spinal cord slices. In the current study we examine how temperature influences SDH neuron properties by making recordings at 22 and 32°C in transverse spinal cord slices prepared from L3–L5 segments of adult mice (C57Bl/6). Patch-clamp recordings (KCH3SO4 internal) were made from visualized SDH neurons. At elevated temperature all SDH neurons had reduced input resistance and smaller, briefer APs. Resting membrane potential and AP afterhyperpolarization amplitude were temperature sensitive only in subsets of the SDH population. Notably, elevated temperature increased the prevalence of neurons that did not discharge APs during current injection. These reluctant firing neurons expressed a rapid A-type potassium current, which is enhanced at higher temperatures and thus restrains AP discharge. When compared with previously published whole cell recordings obtained in vivo (37°C) our results suggest that, on balance, in vitro data collected at elevated temperature more closely resemble data collected under in vivo conditions.

In vivo characterization of colorectal and cutaneous inputs to lumbosacral dorsal horn neurons in the mouse spinal cord

Neuroscience ◽  
2016 ◽  
Vol 316 ◽  
pp. 13-25 ◽  
Author(s):  
K.E. Farrell ◽  
M.M. Rank ◽  
S. Keely ◽  
A.M. Brichta ◽  
B.A. Graham ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Mouse Spinal Cord ◽  
Dorsal Horn Neurons ◽  
In Vivo Characterization

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.

scholarly journals Role of spinal α1-adrenoceptor subtypes in the bladder reflex in anesthetized rats

2001 ◽  
Vol 280 (5) ◽  
pp. R1414-R1419 ◽  
Author(s):  
Mitsuharu Yoshiyama ◽  
William C. De Groat
Keyword(s):  
Spinal Cord ◽  
Afferent Input ◽  
Bladder Pressure ◽  
Contraction Amplitude ◽  
Lumbosacral Spinal Cord ◽  
Anesthetized Rats ◽  
Bladder Contraction ◽  
Transurethral Catheter ◽  
Bladder Activity

The contribution of different subtypes of α1-adrenoceptors in the lumbosacral spinal cord to the control of the urinary bladder was examined in urethane-anesthetized rats. Bladder pressure was recorded via a transurethral catheter under isovolumetric conditions. Drugs were administered intrathecally at the L6-S1segmental level of spinal cord. RS-100329 (an α1A-antagonist) in doses of 25, 50, and 100 nmol significantly decreased bladder-contraction amplitude by 38%, 52%, and 95%, respectively, whereas (+)-cyclazosin (an α1B-antagonist) significantly decreased bladder-contraction amplitude (48% reduction) only in a 50-nmol but not a 100-nmol dose. Fifty nanomoles of RS-100329 and (+)-cyclazosin increased bladder-contraction frequency by 54% and 44%, respectively. BMY7378 (an α1D-antagonist), in doses of 25, 50, and 100 nmol, did not change bladder activity. These studies suggest that reflex-bladder activity is modulated by two types of spinal α1-adrenergic mechanisms: 1) α1A- or α1B-inhibitory control of the frequency of voiding reflexes presumably mediated by an alteration in the processing of bladder afferent input and 2) α1A-facilitatory modulation of the descending efferent limb of the micturition-reflex pathway. Spinal α1D-adrenoceptors do not appear to have a significant role at either site.

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