Effects of 3-aminobenzamide (3-AB) on the alterations in primary afferent and spinal neurons induced by spinal nerve injury in rats..
0
Citation
0
Reference
20
Related Paper
Keywords:
Nerve Injury
Spinal injury
Spinal nerve
Cite
Capsaicin
Nociceptor
Premovement neuronal activity
Cite
Citations (2)
Nerve injury-induced central sensitization can manifest as an increase in excitatory synaptic transmission and/or as a decrease in inhibitory synaptic transmission in spinal dorsal horn neurons. Cytokines such as tumor necrosis factor-α (TNF-α) are induced in the spinal cord under various injury conditions and contribute to neuropathic pain. In this study we examined the effect of TNF-α in modulating excitatory and inhibitory synaptic input to spinal substantia gelatinosa (SG) neurons over time in mice following chronic constriction injury (CCI) of the sciatic nerve. Whole cell patch-clamp studies from SG neurons showed that TNF-α enhanced overall excitability of the spinal cord early in time following nerve injury 3 days after CCI compared with that in sham control mice. In contrast, the effects of TNF were blunted 14 days after CCI in nerve-injured mice compared with sham surgery mice. Immunohistochemical staining showed that the expression of TNF-α receptor 1 (TNFR1) was increased at 3 days but decreased at 14 days following CCI in the ipsilateral vs. the contralateral spinal cord dorsal horn. These results suggest that TNF-α acting at TNFR1 is important in the development of neuropathic pain by facilitating excitatory synaptic signaling in the acute phases after nerve injury but has a reduced effect on spinal neuron signaling in the later phases of nerve injury-induced pain. Failure of the facilatory effects of TNF-α on excitatory synaptic signaling in the dorsal horn to resolve following nerve injury may be an important component in the transition between acute and chronic pain conditions.
Nerve Injury
Peripheral nerve injury
Cite
Citations (39)
Cite
Citations (0)
Chronic pain caused by insults to the CNS (central neuropathic pain) is widely assumed to be maintained exclusively by central mechanisms. However, chronic hyperexcitablility occurs in primary nociceptors after spinal cord injury (SCI), suggesting that SCI pain also depends upon continuing activity of peripheral sensory neurons. The present study in rats (Rattus norvegicus) found persistent upregulation after SCI of protein, but not mRNA, for a voltage-gated Na+ channel, Nav1.8, that is expressed almost exclusively in primary afferent neurons. Selectively knocking down Nav1.8 after SCI suppressed spontaneous activity in dissociated dorsal root ganglion neurons, reversed hypersensitivity of hindlimb withdrawal reflexes, and reduced ongoing pain assessed by a conditioned place preference test. These results show that activity in primary afferent neurons contributes to ongoing SCI pain.
Premovement neuronal activity
Cite
Citations (137)
Abstract We investigated the therapeutic potential of mouse ESC-derived gamma-amino butyric acid (GABA)ergic neurons (∼74% of total neurons in vitro) to reduce neuropathic pain following spinal cord injury (SCI) in rats. Spinal cord hemisection at the T13 segment, which is used as a rat SCI pain model, induced tactile hypersensitivity of the hind paw, as evidenced by decreased paw withdrawal thresholds in response to von Frey filaments, and also induced hyperexcitability of wide dynamic range neurons in the lumbar spinal cord in response to natural cutaneous stimuli. At 2 weeks posthemisection, GABAergic neurons (500,000 cells) were transplanted into the subarachnoid space of the spinal lumbar enlargement via a modified lumbar puncture technique. The transplantation of GABAergic neurons led to long-term attenuation of hemisection-induced tactile hypersensitivity and neuronal hyperexcitability as compared with vehicle-treated controls. These attenuations were reversed by the application of bicuculline and CGP52432, GABA-A and GABA-B receptor antagonists, respectively, but not by application of the serotonergic receptor antagonist methylsergide, indicating a specific restoration of spinal GABAergic inhibition. Histological data from sections of the lumbar cord in grafts demonstrated that 43.5% of surviving engrafted cells were neurons and located densely in the lower-medial portion of the dorsal funiculi in the spinal white matter. Among the observed neurons, 26.2% were GABAergic. The results suggest that subarachnoid transplantation of ESC-derived GABAergic neurons appear to restore spinal GABAergic inhibitory tone and can be a promising strategy to treat SCI-induced pain.
Lumbar Spinal Cord
GABA receptor antagonist
Cite
Citations (31)
You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Neurogenic Voiding Dysfunction1 Apr 20131707 INCREASED EXCITABILITY OF BLADDER AFFERENT NEURONS ASSOCIATED WITH REDUCED EXPRESSION OF KV1.4 α-SUBUNIT IN RATS WITH SPINAL CORD INJURY Ryosuke Takahashi, Takakazu Yunoki, Seiji Naito, and Naoki Yoshimura Ryosuke TakahashiRyosuke Takahashi Fukuoka, Japan More articles by this author , Takakazu YunokiTakakazu Yunoki Fukuoka, Japan More articles by this author , Seiji NaitoSeiji Naito Fukuoka, Japan More articles by this author , and Naoki YoshimuraNaoki Yoshimura Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2953AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hyperexcitability of C-fiber bladder afferent pathways has been proposed as an important pathophysiological basis of neurogenic detrusor overactivity with spinal cord injury (SCI). However, the molecular mechanisms inducing hyperexcitability of C-fiber bladder afferent neurons (B-AN) after SCI are not fully elucidated. We therefore examined changes in electrophysiological properties of B-AN obtained from SCI rats, especially focusing on voltage-gated potassium channels and the expression levels of α?subunits, which can form A-type K+ (KA) channels. METHODS Fresh dissociated L6-S1 dorsal root ganglia (DRG) neurons were prepared from female spinal intact and SCI (T9-T10 transection) SD rats. Whole cell patch-clamp recordings were performed on individual B-AN, which were labeled by retrograde axonal transport of a fluorescent dye, Fast Blue (FB) injected into the bladder wall 7 days prior the dissociation. Since the majority (80%) of C-fibre bladder afferent neurons are known to be sensitive to capsaicin, capsaicin-sensitive neurons were selected for evaluation. The expression levels of Kv1.2 and 1.4 α-subunits were evaluated using immunohistochemical methods. RESULTS Capsaicin-sensitive B-AN from SCI rats exhibited increased cell excitability evidenced by lower thresholds for spike activation (-26.4±1.3mV) and the increased number of action potentials (4.7±0.7 spikes) during a 800 msec depolarizing pulse compare to control rats (-21.8±0.9mV and 1.3±0.1 spikes). The peak density of KA currents during membrane depolarizations to 0mV in capsaicin-sensitive B-AN of SCI rats was significantly smaller (38.1±4.6 pA/pF) than that from control rats (68.6±6.3 pA/pF), and the inactivation curve of the KA current was displaced to more hyperpolarized levels by ∼10mV after SCI. On the other hand, the sustained delayed-rectifier K+ current density was not altered after SCI. The expression of Kv1.4 α?subunits, which can form KA channels, was reduced in B-AN from SCI rats compared to control rats. CONCLUSIONS These results indicate that the excitability of capsaicin-sensitive C-fiber B-AN is increased in association with reductions in KA current size and Kv1.4 α-subunit expression in SCI rats. Thus, the Kv1.4 α-subunit could be a potential molecular target for treating OAB due to neurogenic detrusor overactivity. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e702-e703 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ryosuke Takahashi Fukuoka, Japan More articles by this author Takakazu Yunoki Fukuoka, Japan More articles by this author Seiji Naito Fukuoka, Japan More articles by this author Naoki Yoshimura Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
Pathophysiology
Cite
Citations (0)
Peripheral nerve injury
Cite
Citations (23)
You have accessJournal of UrologyBladder & Urethra: Anatomy, Physiology & Pharmacology I1 Apr 2017MP42-03 EFFECTS OF NERVE GROWTH FACTOR NEUTRALIZATION ON HYPEREXCITABILITY OF CAPSAICIN SENSITIVE BLADDER AFFERENT NEURONS IN MICE WITH SPINAL CORD INJURY Takahiro Shimizu, Tsuyoshi Majima, Takahisa Suzuki, Nobutaka Shimizu, Naoki Wada, Shun Takai, Eiichiro Takaoka, Joonbeom Kwon, Pradeep Tyagi, Motoaki Saito, and Naoki Yoshimura Takahiro ShimizuTakahiro Shimizu More articles by this author , Tsuyoshi MajimaTsuyoshi Majima More articles by this author , Takahisa SuzukiTakahisa Suzuki More articles by this author , Nobutaka ShimizuNobutaka Shimizu More articles by this author , Naoki WadaNaoki Wada More articles by this author , Shun TakaiShun Takai More articles by this author , Eiichiro TakaokaEiichiro Takaoka More articles by this author , Joonbeom KwonJoonbeom Kwon More articles by this author , Pradeep TyagiPradeep Tyagi More articles by this author , Motoaki SaitoMotoaki Saito More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1292AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nerve growth factor (NGF) has been implicated as an important mediator to induce C-fiber bladder afferent hyperexcitability, which contributes to the emergence of neurogenic detrusor overactivity (NDO) following spinal cord injury (SCI). In this study, we examined whether NGF neutralization using anti-NGF antibody normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fiber bladder afferent neurons in the mouse model. METHODS In female C57BL/6 mice, the spinal cord was transected at the Th8/9 level. Two weeks later, an osmotic pump was placed subcutaneously to administer anti-NGF antibody at 10 µg/kg/h for 2 weeks. Bladder afferent neurons were labeled with axonal transport of Fast Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared. Whole cell patch clamp recordings were then performed in FB-labeled bladder afferent neurons, and the data were compared between SCI and spinal intact (SI) mice. After recording action potentials (AP) or voltage-gated K+ (Kv) currents, the sensitivity of each neuron to capsaicin was evaluated. RESULTS In capsaicin-sensitive bladder afferent neurons, the resting membrane potentials and the peak and duration of AP did not changed by SCI. On the other hand, the threshold for eliciting AP was significantly reduced in SCI vs. SI mice. Also, SCI increased the number of AP during 800 ms membrane depolarization. These SCI induced changes were reversed by NGF neutralization. SCI induced significant increases in the diameter and cell input capacitance of capsaicin-sensitive bladder afferent neurons, which were not reversed by NGF neutralization. Densities of slow decaying KA and sustained KDR currents evoked by depolarization to 0 mV were significantly reduced by SCI. NGF neutralization reversed the SCI-induced reduction in the KA current density. CONCLUSIONS In SCI mice, NGF plays an important role in hyperexcitability of capsaicin sensitive C-fiber bladder afferent neurons due to KA current reduction. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and NDO in SCI. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e544-e545 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takahiro Shimizu More articles by this author Tsuyoshi Majima More articles by this author Takahisa Suzuki More articles by this author Nobutaka Shimizu More articles by this author Naoki Wada More articles by this author Shun Takai More articles by this author Eiichiro Takaoka More articles by this author Joonbeom Kwon More articles by this author Pradeep Tyagi More articles by this author Motoaki Saito More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...
Capsaicin
Cite
Citations (0)
Background: We have previously demonstrated that different spinal transmissions are involved in the nociceptive behavior caused by electrical stimulation of Aβ-, Aδ- or C-fibers using a Neurometer® in naïve mice. In this study, we attempted to pharmacologically characterize the alteration in spinal transmission induced by partial sciatic nerve injury in terms of nociceptive behavior and phosphorylation of extracellular signal-regulated kinase (pERK) in the spinal dorsal horn. Results: Aβ-fiber responses (2000-Hz), which were selectively blocked by the AMPA/kainate antagonist CNQX in naïve mice, were hypersensitized but blocked by the NMDA receptor antagonists MK-801 and AP-5 in injured mice in an electrical stimulation-induced paw withdrawal (EPW) test. Although Aδ-fiber responses (250-Hz) were also hypersensitized by nerve injury, there was no change in the pharmacological characteristics of Aδ-fiber responses through NMDA receptors. On the contrary, C-fiber responses (5-Hz) were hyposensitized by nerve injury. Moreover, Aδ- and C-, but not Aβ-fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horns of naïve mice, and corresponding antagonists used in the EPW test inhibited this increase. In mice with nerve injury, Aβ- as well as Aδ-fiber stimulations significantly increased the number of pERK-positive neurons in the superficial spinal dorsal horn, whereas C-fiber stimulation decreased this number. The nerve injury-specific pERK increase induced by Aβ-stimulation was inhibited by MK-801 and AP-5, but not by CNQX. However, Aβ- and Aδ-stimulations did not affect the number or size of pERK-positive neurons in the dorsal root ganglion, whereas C-fiber-stimulation selectively decreased the number of pERK-positive neurons. Conclusion: These results suggest that Aβ-fiber perception is newly transmitted to spinal neurons, which originally receive only Aδ- and C-fiber-mediated pain transmission, through NMDA receptor-mediated mechanisms, in animals with nerve injury. This pharmacological switch in Aβ-fiber spinal transmission could be a mechanism underlying neuropathic allodynia.
CNQX
Sciatic nerve injury
Nerve Injury
Kainate receptor
Cite
Citations (50)
Pharmacological evidence suggests a functional role for spinal nitric oxide (NO) in the modulation of thermal and/or inflammatory hyperalgesia. To assess the role of NO in nerve injury-induced tactile allodynia, we examined neuronal NO synthase (nNOS) expression in the spinal cord and dorsal root ganglia (DRG) of rats with tactile allodynia because of either tight ligation of the left fifth and sixth lumbar spinal nerves or streptozotocin-induced diabetic neuropathy. RNase protection assays indicated that nNOS mRNA (1) was upregulated in DRG, but not spinal cord, neurons on the injury side beginning 1 d after nerve ligation, (2) peaked (approximately 10-fold increase) at 2 d, and (3) remained elevated for at least 13 weeks. A corresponding increase in DRG nNOS protein was also observed and localized principally to small and occasionally medium-size sensory neurons. In rats with diabetic neuropathy, there was no significant change in DRG nNOS mRNA. However, similar increases in DRG nNOS mRNA were observed in rats that did not develop allodynia after nerve ligation and in rats fully recovered from allodynia 3 months after the nerve ligation. Systemic treatment with a specific pharmacological inhibitor of nNOS failed to prevent or reverse allodynia in nerve-injured rats. Thus, regulation of nNOS may contribute to the development of neuronal plasticity after specific types of peripheral nerve injury. However, upregulation of nNOS is not responsible for the development and/or maintenance of allodynia after nerve injury.
Allodynia
Nerve Injury
Peripheral nerve injury
Spinal nerve
Cite
Citations (89)