Long range afferents in rat spinal cord. III. Failure of impulse transmission in axons and relief of the failure after rhizotomy of dorsal roots

1994 ◽  
Vol 343 (1304) ◽  
pp. 211-223 ◽  
Keyword(s):  
Spinal Cord ◽  
Action Potential ◽  
Dorsal Horn ◽  
Long Range ◽  
Control Mechanism ◽  
Dorsal Roots ◽  
Large Numbers ◽  
Anatomical Finding ◽  
Dorsal Root Afferents ◽  
Presynaptic Control

Dorsal root afferents entering the spinal cord form a T-junction with a caudal branch descending m any segments and giving off side branches terminating in the dorsal horn. This anatomical finding contrasts with the physiological observation that the postsynaptic effects of arriving afferents in the dorsal horn are limited to a few segments on either side of the root carrying the input. This paper explores the possibility that one explanation for this paradox is that orthodromic impulse conduction fails to penetrate the long range parts of the caudal branch. The experiments show that when all roots are intact, very few fibres can be detected carrying orthodromic impulses as far as 20 mm caudal to the entry point. After section of neighbouring dorsal roots, however, large numbers of conducting fibres can be recorded at that point. Signs of orthodromic conduction begin 7 days after root section. These results were confirmed by another method which com pared the relative refractory period of the membrane of the descending branch produced either after a local stimulus had evoked an action potential or after a rostral distant stimulus had produced an orthodromic action potential. Again, in the intact cord, the results indicate that impulses fail to penetrate long distances into the descending branches but that, as soon as 2 days after rhizotomy in the area of suspected conduction failure, orthodromic conduction is restored. It is proposed that the failure and release of conduction may depend on the control of membrane potential in the primary afferents, which would form a pre-presynaptic control mechanism.

GABA-Receptor–Independent Dorsal Root Afferents Depolarization in the Neonatal Rat Spinal Cord

1998 ◽  
Vol 79 (5) ◽  
pp. 2581-2592 ◽  
Author(s):  
E. Kremer ◽  
A. Lev-Tov
Keyword(s):  
Spinal Cord ◽  
Dorsal Root ◽  
Gaba Receptor ◽  
Neonatal Rat ◽  
Extracellular Potassium ◽  
Rat Spinal Cord ◽  
Extracellular Potassium Concentration ◽  
Dorsal Roots ◽  
Intact Brain ◽  
Dorsal Root Afferents

Kremer, E. and A. Lev-Tov. GABA-receptor–independent dorsal root afferents depolarization in the neonatal rat spinal cord. J. Neurophysiol. 79: 2581–2592, 1998. Dorsal root afferent depolarization and antidromic firing were studied in isolated spinal cords of neonatal rats. Spontaneous firing accompanied by occasional bursts could be recorded from most dorsal roots in the majority of the cords. The afferent bursts were enhanced after elevation of the extracellular potassium concentration ([K+]e) by 1–2 mM. More substantial afferent bursts were produced when the cords were isolated with intact brain stems. Rhythmic afferent bursts could be recorded from dorsal roots in some of the cords during motor rhythm induced by bath-applied serotonin and N-methyl-d-aspartate (NMDA). Bilaterally synchronous afferent bursts were produced in pairs of dorsal roots after replacing the NaCl in the perfusate with sodium-2-hydroxyethansulfonate or after application of the γ-aminobutyric acid-A (GABAA) receptor antagonist bicuculline with or without serotonin (5-HT) and NMDA. Antidromic afferent bursts also could be elicited under these conditions by stimulation of adjacent dorsal roots, ventrolateral funiculus axons, or ventral white commissural (VWC) fibers. The antidromic bursts were superimposed on prolonged dorsal root potentials (DRPs) and accompanied by a prolonged increase in intraspinal afferent excitability. Surgical manipulations of the cord revealed that afferent firing in the presence of bicuculline persisted in the hemicords after hemisection and still was observed after removal of their ventral horns. Cutting the VWC throughout its length did not perturb the bilateral synchronicity of the discharge. These findings suggest that the activity of dorsal horn neurons is sufficient to produce the discharge and that the bilateral synchronicity can be maintained by cross connectivity that is relayed from side to side dorsal to the VWC. Antagonists of GABAB, 5-HT2/5-HT1C, or glutamate metabotropic group II and III receptors could not abolish afferent depolarization in the presence of bicuculline. Depolarization comparable in amplitude to DRPs, could be produced in tetrodotoxin-treated cords by elevation of [K+]e to the levels reported to develop in the neonatal rat spinal cord in response to dorsal root stimulation. A mechanism involving potassium transients produced by neuronal activity therefore is suggested to be the major cause of the GABA-independent afferent depolarization reported in our study. Possible implications of potassium transients in the developing and the adult mammalian spinal cord are discussed.

Somatotopic organization in cat spinal cord segments with fused dorsal horns: caudal and thoracic levels

1985 ◽  
Vol 54 (5) ◽  
pp. 1167-1177 ◽  
Author(s):  
L. A. Ritz ◽  
J. L. Culberson ◽  
P. B. Brown
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Dorsal Root ◽  
Receptive Fields ◽  
Vertical Orientation ◽  
Dorsal Roots ◽  
Somatotopic Organization ◽  
Dorsal Horns ◽  
Spinal Cord Regions ◽  
Low Threshold

We have explored the somatotopic organization of the two cat spinal cord regions where the dorsal horns are fused (i.e., continuous across the midline): the caudal and thoracic segments. We have mapped the low-threshold component of dorsal horn cell receptive fields (RFs) in these segments and have charted the locations of dorsal root low-threshold mechanoreceptive dermatomes. We also have determined the projections of caudal and thoracic dorsal roots to laminae III and IV by using degeneration techniques. The dorsal skin of the tail or thorax is represented laterally, and ventral skin is represented at the midline, in the fused dorsal horns. Many caudal and thoracic dorsal horn units had RFs that crossed the dorsal or ventral midline of the skin; these units were encountered near the edges or the midline, respectively, of the fused dorsal horns. The tail is fully represented within dorsal root dermatomes S3 to Ca5. Roots more caudal than Ca5 represent progressively smaller skin areas of the distal tail. Adjacent dermatomes overlapped 15-65%. Thoracic dermatomes had a nearly vertical orientation; adjacent dermatomes overlapped by 30-75%. Dorsal roots in caudal and thoracic regions have crossed projections to the medial and lateral (but not middle) portions of the contralateral dorsal horn. These crossed projections are a possible anatomical substrate for RFs that cross the ventral or dorsal midline. The dorsal root projection patterns are consistent with those that would be predicted from the dorsal root dermatomes and dorsal horn cell somatotopy, assuming that the presynaptic terminals' somatotopy is in register with that of dorsal horn cells (the presynaptic somatotopy hypothesis; see Ref. 12).

Subthreshold components of the cutaneous mechanoreceptive fields of dorsal horn neurons in the rat lumbar spinal cord

1989 ◽  
Vol 62 (4) ◽  
pp. 907-916 ◽  
Author(s):  
C. J. Woolf ◽  
A. E. King
Keyword(s):  
Spinal Cord ◽  
Action Potential ◽  
Dorsal Horn ◽  
Receptive Fields ◽  
Firing Zone ◽  
Lumbar Spinal Cord ◽  
High Threshold ◽  
Mechanical Stimuli ◽  
Low Probability ◽  
Excitatory Responses

1. Intracellular recordings have been made from 76 neurons in the dorsal horn of the fourth and fifth lumbar segments of the spinal cord in decerebrate-spinal rats. The locations of the neurons were identified after horseradish peroxidase (HRP) ionophoresis (n = 18) or calculated from depth readings (n = 58). Sixty-nine of the neurons were found or estimated to lie within the deep dorsal horn (laminae III-V), with the remaining 7 in laminae I and II. 2. Background excitatory activity was present in all the neurons in the absence of peripheral mechanical stimuli. In 22 neurons, this consisted only of subthreshold excitatory postsynaptic potentials (EPSPs), but in 54, a proportion of the EPSPs reached threshold, producing a spontaneous spike discharge (frequency 0.2-50 Hz) that had a rhythmic component in six cells. Spontaneous hyperpolarizations occurred but were uncommon (n = 10). 3. All the neurons had excitatory cutaneous mechanoreceptive fields on the ipsilateral hindlimb. The receptive fields, defined in terms of action-potential discharge, could be subdivided into two areas: a high-probability "firing zone," where skin stimulation elicited an action-potential discharge above the mean + 1 SD of the background activity; and a low-probability firing fringe, where the stimulus elicited a distinct subthreshold depolarization, but the action-potential response fell within the variability of the background discharge. 4. Mechanical stimulation in the middle of the firing zone in all cells generated both supra- and subthreshold excitatory responses, with the former predominating. As the stimuli were applied progressively farther away from the center of the firing zone, the subthreshold component became relatively more prominent. 5. Fifty percent of the 15 neurons that were recorded from for sufficient time (greater than 30 min) to enable the presence, extent, and characteristics of subthreshold responses to be examined in detail were found to have a low-probability firing fringe to their receptive fields. The response to stimulation within this fringe typically consisted of high-frequency, low-amplitude PSPs riding on a sustained depolarization, with an action-potential discharge that could not readily be distinguished from the spontaneous activity. The size of the fringe ranged from a small area adjacent to the firing zone to almost the entire hindlimb. 6. The firing zones of 20 neurons were low-threshold only and in 5 cells were high-threshold only. The majority of neurons were multireceptive, responding both to low- and high-intensity stimuli (n = 51).(ABSTRACT TRUNCATED AT 400 WORDS)

Role of TTX-Sensitive and TTX-Resistant Sodium Channels in Aδ- and C-Fiber Conduction and Synaptic Transmission

2008 ◽  
Vol 99 (2) ◽  
pp. 617-628 ◽  
Author(s):  
Vitor Pinto ◽  
Victor A. Derkach ◽  
Boris V. Safronov
Keyword(s):  
Spinal Cord ◽  
Synaptic Transmission ◽  
Dorsal Horn ◽  
Conduction Velocity ◽  
Room Temperature ◽  
Dorsal Horn Neurons ◽  
Dorsal Roots ◽  
Relative Contribution ◽  
C Fibers ◽  
C Fiber

Thin afferent axons conduct nociceptive signals from the periphery to the spinal cord. Their somata express two classes of Na+ channels, TTX-sensitive (TTX-S) and TTX-resistant (TTX-R), but their relative contribution to axonal conduction and synaptic transmission is not well understood. We studied this contribution by comparing effects of nanomolar TTX concentrations on currents associated with compound action potentials in the peripheral and central branches of Aδ- and C-fiber axons as well as on the Aδ- and C-fiber-mediated excitatory postsynaptic currents (EPSCs) in spinal dorsal horn neurons of rat. At room temperature, TTX completely blocked Aδ-fibers (IC50, 5–7 nM) in dorsal roots (central branch) and spinal, sciatic, and sural nerves (peripheral branch). The C-fiber responses were blocked by 85–89% in the peripheral branch and by 65–66% in dorsal roots (IC50, 14–33 nM) with simultaneous threefold reduction in their conduction velocity. At physiological temperature, the degree of TTX block in dorsal roots increased to 93%. The Aδ- and C-fiber-mediated EPSCs in dorsal horn neurons were also sensitive to TTX. At room temperature, 30 nM blocked completely Aδ-input and 84% of the C-fiber input, which was completely suppressed at 300 nM TTX. We conclude that in mammals, the TTX-S Na+ channels dominate conduction in all thin primary afferents. It is the only type of functional Na+ channel in Aδ-fibers. In C-fibers, the TTX-S Na+ channels determine the physiological conduction velocity and control synaptic transmission. TTX-R Na+ channels could not provide propagation of full-amplitude spikes able to trigger synaptic release in the spinal cord.

scholarly journals Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 864
Author(s):  
Christopher L. Cioffi
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Therapeutic Potential ◽  
Opioid Analgesic ◽  
Critical Role ◽  
Analgesic Efficacy ◽  
Standard Of Care ◽  
Current Standard ◽  
Glycine Transporters ◽  
Pathological Pain

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na+/Cl−-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain.

scholarly journals SUR1, newly expressed in astrocytes, mediates neuropathic pain in a mouse model of peripheral nerve injury

2021 ◽  
Vol 17 ◽  
pp. 174480692110066
Author(s):  
Orest Tsymbalyuk ◽  
Volodymyr Gerzanich ◽  
Aaida Mumtaz ◽  
Sanketh Andhavarapu ◽  
Svetlana Ivanova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Thermal Sensitivity ◽  
Gradual Improvement ◽  
Pain Behaviors

Background Neuropathic pain following peripheral nerve injury (PNI) is linked to neuroinflammation in the spinal cord marked by astrocyte activation and upregulation of interleukin 6 (IL -6 ), chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-X-C motif) ligand 1 (CXCL1), with inhibition of each individually being beneficial in pain models. Methods Wild type (WT) mice and mice with global or pGfap-cre- or pGFAP-cre/ERT2-driven Abcc8/SUR1 deletion or global Trpm4 deletion underwent unilateral sciatic nerve cuffing. WT mice received prophylactic (starting on post-operative day [pod]-0) or therapeutic (starting on pod-21) administration of the SUR1 antagonist, glibenclamide (10 µg IP) daily. We measured mechanical and thermal sensitivity using von Frey filaments and an automated Hargreaves method. Spinal cord tissues were evaluated for SUR1-TRPM4, IL-6, CCL2 and CXCL1. Results Sciatic nerve cuffing in WT mice resulted in pain behaviors (mechanical allodynia, thermal hyperalgesia) and newly upregulated SUR1-TRPM4 in dorsal horn astrocytes. Global and pGfap-cre-driven Abcc8 deletion and global Trpm4 deletion prevented development of pain behaviors. In mice with Abcc8 deletion regulated by pGFAP-cre/ERT2, after pain behaviors were established, delayed silencing of Abcc8 by tamoxifen resulted in gradual improvement over the next 14 days. After PNI, leakage of the blood-spinal barrier allowed entry of glibenclamide into the affected dorsal horn. Daily repeated administration of glibenclamide, both prophylactically and after allodynia was established, prevented or reduced allodynia. The salutary effects of glibenclamide on pain behaviors correlated with reduced expression of IL-6, CCL2 and CXCL1 by dorsal horn astrocytes. Conclusion SUR1-TRPM4 may represent a novel non-addicting target for neuropathic pain.

scholarly journals Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal Horn

Neuron ◽  
2014 ◽  
Vol 81 (6) ◽  
pp. 1443 ◽  
Author(s):  
Rita Bardoni ◽  
Vivianne L. Tawfik ◽  
Dong Wang ◽  
Amaury François ◽  
Carlos Solorzano ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Opioid Receptors ◽  
Spinal Cord Dorsal Horn ◽  
Mechanosensory Neuron ◽  
Delta Opioid Receptors ◽  
Spinal Cord Dorsal
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