Elimination of rat spinal neurons expressing neurokinin 1 receptors reduces bladder overactivity and spinal c-fos expression induced by bladder irritation

2005 ◽  
Vol 288 (3) ◽  
pp. F466-F473 ◽  
Author(s):  
Satoshi Seki ◽  
Kristin A. Erickson ◽  
Masako Seki ◽  
Osamu Nishizawa ◽  
Yasuhiko Igawa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Intrathecal Administration ◽  
Superficial Layer ◽  
Sprague Dawley ◽  
Intrathecal Catheter ◽  
Micturition Reflex ◽  
Nociceptive Responses ◽  
Fos Expression ◽  
Neurokinin 1

Substance P (SP) binding to neurokinin 1 receptors (NK1R) in the spinal cord reportedly plays an important role in the micturition reflex as well as in nociceptive responses. We therefore investigated the effect of ablation of NK1R-expressing neurons in the spinal cord using saporin, a ribosome-inactivating protein, conjugated with [Sar9, Met (O2)11]SP, a specific ligand of NK1R (SSP-saporin), on the micturition reflex in rats. In female Sprague-Dawley rats, SSP-saporin (1.0 or 1.5 μM) or saporin (1.5 μM) only was injected through an intrathecal catheter implanted at the L6-S1 level of the spinal cord. Three weeks after intrathecal administration of SSP-saporin, NK1R immunoreactivity in lamina I of the spinal cord was significantly reduced, but cystometric parameters in awake rats were not altered. Instillation of capsaicin (15 μM) into the bladder of normal rats induced bladder overactivity. This response to capsaicin was significantly suppressed in SSP-saporin-treated animals. SSP-saporin treatment also decreased c- fos expression in the dorsal horn of the spinal cord induced by instillation of capsaicin into the bladder. These data indicate that NK1R-expressing neurons in the superficial layer of the dorsal horn play an important role in transmission of nociceptive afferent information from the bladder to induce bladder overactivity and spinal c- fos expression elicited by bladder irritation. Toxin-induced damage of NK1R-expressing neurons in the lumbosacral spinal cord may provide an effective modality for treating overactivity and/or nociceptive responses in the bladder without affecting normal micturition.

scholarly journals Peripheral Glutamate Receptors Are Required for Hyperalgesia Induced by Capsaicin

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
You-Hong Jin ◽  
Motohide Takemura ◽  
Akira Furuyama ◽  
Norifumi Yonehara
Keyword(s):  
Spinal Cord ◽  
Glutamate Receptors ◽  
Dorsal Horn ◽  
Transient Receptor Potential ◽  
Small Diameter ◽  
Spinal Cord Dorsal Horn ◽  
Group I ◽  
Nociceptive Responses ◽  
Spinal Cord Dorsal ◽  
Fos Expression

Transient receptor potential vanilloid1 (TRPV1) and glutamate receptors (GluRs) are located in small diameter primary afferent neurons (nociceptors), and it was speculated that glutamate released in the peripheral tissue in response to activation of TRPV1 might activate nociceptors retrogradely. But, it was not clear which types of GluRs are functioning in the nociceptive sensory transmission. In the present study, we examined the c-Fos expression in spinal cord dorsal horn following injection of drugs associated with glutamate receptors with/without capsaicin into the hindpaw. The subcutaneous injection of capsaicin or glutamate remarkably evoked c-Fos expression in ipsilateral sides of spinal cord dorsal horn. This capsaicin evoked increase of c-Fos expression was significantly prevented by concomitant administration of MK801, CNQX, and CPCCOEt. On the other hand, there were not any significant changes in coinjection of capsaicin and MCCG or MSOP. These results reveal that the activation of iGluRs and group I mGluR in peripheral afferent nerves play an important role in mechanisms whereby capsaicin evokes/maintains nociceptive responses.

Comparison of the Effects of Treatment with Intrathecal Lidocaine Given before and after Formalin on Both Nociception and Fos Expression in the Spinal Cord Dorsal Horn 

1998 ◽  
Vol 88 (1) ◽  
pp. 157-164 ◽  
Author(s):  
Kiran Yashpal ◽  
Patrick Mason ◽  
John E. McKenna ◽  
Sushil K. Sharma ◽  
James L. Henry ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Intrathecal Injection ◽  
Post Treatment ◽  
Spinal Cord Dorsal Horn ◽  
Formalin Injection ◽  
Second Phase ◽  
Nociceptive Responses ◽  
Spinal Cord Dorsal ◽  
Fos Expression

Background It has been proposed that the measure of noxious stimulus-induced Fos (the protein product of the immediate early gene c-fos) expression in the spinal cord dorsal horn of laboratory animals may provide an estimate of the potential of specific treatments to produce preemptive analgesia. The present study examined this hypothesis by comparing the effects of intrathecal lidocaine given before and after hindpaw formalin injection on persistent nociceptive responses and Fos expression in spinal cord dorsal horn of rats. Methods Formalin-induced nociception and Fos expression in the spinal cord, in response to a 50-microl injection of 2.5% formalin into the hind paw, were assessed in rats given an intrathecal injection of 50 microl 2% lidocaine by lumbar puncture between the L5 and L6 vertebrae, either 3 min before (pretreatment) or 5 min after (post-treatment) formalin injection. Results Pain behaviors (hindpaw licking, elevation, and favoring) in the second phase of the formalin test were significantly reduced by pretreatment, but were unaffected by post-treatment. The number of immunocytochemically stained Fos-positive cells and the immunoprecipitation of the Fos antibodies were reduced by pretreatment, and were also reduced, to a lesser extent, by post-treatment. Conclusions The finding that persistent nociceptive behaviors and Fos expression were suppressed by intrathecal lidocaine pretreatment suggests that nociception in the second phase of the formalin test depends on increases in central hyperexcitability generated during the first phase. On the other hand, the finding that the intrathecal injection of lidocaine after formalin treatment reduced Fos expression but not nociceptive responses indicates an uncoupling of the behavioral and Fos protein responses to formalin and suggests that changes in Fos expression may not be a good predictor of the ability of agents to produce preemptive analgesia.

scholarly journals Effects of General Anesthetics on Substance P Release and c-Fos Expression in the Spinal Dorsal Horn

2013 ◽  
Vol 119 (2) ◽  
pp. 433-442 ◽  
Author(s):  
Toshifumi Takasusuki ◽  
Shigeki Yamaguchi ◽  
Shinsuke Hamaguchi ◽  
Tony L. Yaksh
Keyword(s):  
Nitrous Oxide ◽  
Substance P ◽  
Dorsal Horn ◽  
Receptor Internalization ◽  
General Anesthetics ◽  
Neurokinin 1 Receptor ◽  
P Release ◽  
Fos Expression ◽  
Neurokinin 1 ◽  
Substance P Release

Abstract Background: The authors examined in vivo the effects of general anesthetics on evoked substance P release (primary afferent excitability) and c-Fos expression (neuronal activation) in superficial dorsal horn. Methods: Rats received saline, propofol (100 mg/kg), pentobarbital (50 mg/kg), isoflurane (2 minimum alveolar concentration), nitrous oxide (66%), or fentanyl (30 μg/kg). During anesthesia, rats received intraplantar 5% formalin (50 μl) to left hind paw. Ten minutes later, rats underwent transcardial perfusion with 4% paraformaldehyde. Substance P release from small primary afferents was assessed by incidence of neurokinin 1 receptor internalization in the superficial dorsal horn. In separate studies, rats were sacrificed after 2 h and c-Fos expression measured. Results: Intraplantar formalin-induced robust neurokinin 1 receptor internalization in ipsilateral dorsal horn (ipsilateral: 54 ± 6% [mean ± SEM], contralateral: 12 ± 2%; P < 0.05; n = 4). Fentanyl, but not propofol, pentobarbital, isoflurane, nor nitrous oxide alone inhibited neurokinin 1 receptor internalization. However, 2 minimum alveolar concentration isoflurane + nitrous oxide reduced neurokinin 1 receptor internalization (27 ± 3%; P < 0.05; n = 5). All agents reduced c-Fos expression (control: 34 ± 4, fentanyl: 8 ± 2, isoflurane: 12 ± 3, nitrous oxide: 11 ± 2, isoflurane + nitrous oxide: 12 ± 1, pentobarbital: 11 ± 2, propofol: 13 ± 3; P < 0.05; n = 3). Conclusion: General anesthetics at anesthetic concentrations block spinal neuron activation through a mechanism that is independent of an effect on small primary afferent peptide release. The effect of fentanyl alone and the synergistic effect of isoflurane and nitrous oxide on substance P release suggest a correlative rationale for the therapeutic use of these anesthetic protocols by blocking nociceptive afferent transmitter release and preventing the initiation of cascade, which is immediately postsynaptic to the primary afferent.

scholarly journals Dorsal horn interneuron-derived Netrin-4 contributes to spinal sensitization in chronic pain via Unc5B

2016 ◽  
Vol 213 (13) ◽  
pp. 2949-2966 ◽  
Author(s):  
Yasufumi Hayano ◽  
Keiko Takasu ◽  
Yoshihisa Koyama ◽  
Moe Yamada ◽  
Koichi Ogawa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Dorsal Horn ◽  
Molecular Mechanisms ◽  
Tyrosine Phosphatase ◽  
Intrathecal Administration ◽  
Human Spinal Cord ◽  
Similar Expression Pattern ◽  
Subsequent Activation ◽  
Spinal Sensitization

Because of the incomplete understanding of the molecular mechanisms that underlie chronic pain, the currently available treatments for this type of pain remain inefficient. In this study, we show that Netrin-4, a member of the axon guidance molecule family, was expressed in dorsal horn inner lamina II excitatory interneurons in the rat spinal cord. A similar expression pattern for Netrin-4 was also observed in human spinal cord. Behavioral analysis revealed that tactile and heat hyperalgesia after peripheral nerve injury or inflammation were abolished in Netrin-4–mutant rats. Transient suppression of Netrin-4 or its receptor Unc5B after injury could also prevent allodynia. Conversely, intrathecal administration of Netrin-4 protein to naive rats enhanced excitatory synaptic transmission in the dorsal horn and induced allodynia, suggesting that Netrin-4 is involved in spinal sensitization. Furthermore, the Unc5B receptor and subsequent activation of the tyrosine phosphatase SHP2 mediated Netrin-4–induced pain signaling in the spinal cord. These results identify Netrin-4 as a novel protein regulating spinal sensitization leading to chronic pain. Our findings provide evidence for the function of Netrin in the adult nervous system, as well as a previously unknown function in inducing pain signals from dorsal horn interneurons.

scholarly journals Spinal Cord Glycine Transporter 2 Mediates Bilateral ST35 Acupoints Sensitization in Rats with Knee Osteoarthritis

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Fuhai Bai ◽  
Yongyuan Ma ◽  
Haiyun Guo ◽  
Yuheng Li ◽  
Feifei Xu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mast Cell ◽  
Knee Osteoarthritis ◽  
Dorsal Horn ◽  
Intrathecal Administration ◽  
Mast Cell Degranulation ◽  
Spinal Cord Dorsal Horn ◽  
Glycine Transporter ◽  
Mechanical Threshold ◽  
Glycine Transporter 2

The concept of “acupoint sensitization” refers to the functional status of acupoint switches from silent to active under pathological conditions. In clinic, acupoint sensitization provides important guidance for acupoints selection in different diseases. However, the mechanism behind this phenomenon remains unclear. We generated a model of knee osteoarthritis (KOA) by intra-articular injection of monosodium iodoacetate (MIA) into the left knee of rats. The paw withdrawal mechanical threshold (PWMT) and the total number of mast cells as well as mast cell degranulation rate (MCDR) of acupoint tissue were used to test whether the acupoints were sensitized. The results showed that KOA resulted in a reduced mechanical threshold and elevated total number of mast cell as well as mast cell degranulation rate at bilateral ST35 (Dubi) but not GB37 (Guangming) or nonacupoint area. The acupoint sensitization was accompanied by upregulation of glycine transporter 2 (GlyT2) and reduction of extracellular glycine levels in the bilateral dorsal horns of the spinal cord at L3-5. Selective inhibition of GlyT2 or intrathecal administration of glycine attenuated ST35 acupoint sensitization. The sensitization of bilateral ST35 was blocked after intraspinal GlyT2 short hairpin (sh) RNA (GlyT2-shRNA) microinjection to specifically downregulate GlyT2 expression in the left side (ipsilateral) L3-5 spinal cord dorsal horn before MIA injection. Moreover, electroacupuncture (EA) stimulation at ST35 ameliorated articular pathological lesions and improved KOA-related pain behaviors. GlyT2-shRNA injection reversed EA-induced pain relief but not EA-induced reduction of joint lesions. Overall, this study demonstrated that spinal GlyT2, especially elevated GlyT2 expression in the ipsilateral dorsal horn of the spinal cord, is a crucial mediator of ST35 acupoint sensitization in KOA rats.

scholarly journals Hyperalgesia and sensitization of dorsal horn neurons following activation of NK-1 receptors in the rostral ventromedial medulla

2017 ◽  
Vol 118 (5) ◽  
pp. 2727-2744 ◽  
Author(s):  
Sergey G. Khasabov ◽  
Patrick Malecha ◽  
Joseph Noack ◽  
Janneta Tabakov ◽  
Glenn J. Giesler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Receptor Activation ◽  
Rostral Ventromedial Medulla ◽  
Dorsal Horn Neurons ◽  
Descending Modulation ◽  
Ventromedial Medulla ◽  
Neurokinin 1 ◽  
Wdr Neurons

Neurons in the rostral ventromedial medulla (RVM) project to the spinal cord and are involved in descending modulation of pain. Several studies have shown that activation of neurokinin-1 (NK-1) receptors in the RVM produces hyperalgesia, although the underlying mechanisms are not clear. In parallel studies, we compared behavioral measures of hyperalgesia to electrophysiological responses of nociceptive dorsal horn neurons produced by activation of NK-1 receptors in the RVM. Injection of the selective NK-1 receptor agonist Sar9,Met(O2)11-substance P (SSP) into the RVM produced dose-dependent mechanical and heat hyperalgesia that was blocked by coadministration of the selective NK-1 receptor antagonist L-733,060. In electrophysiological studies, responses evoked by mechanical and heat stimuli were obtained from identified high-threshold (HT) and wide dynamic range (WDR) neurons. Injection of SSP into the RVM enhanced responses of WDR neurons, including identified neurons that project to the parabrachial area, to mechanical and heat stimuli. Since intraplantar injection of capsaicin produces robust hyperalgesia and sensitization of nociceptive spinal neurons, we examined whether this sensitization was dependent on NK-1 receptors in the RVM. Pretreatment with L-733,060 into the RVM blocked the sensitization of dorsal horn neurons produced by capsaicin. c-Fos labeling was used to determine the spatial distribution of dorsal horn neurons that were sensitized by NK-1 receptor activation in the RVM. Consistent with our electrophysiological results, administration of SSP into the RVM increased pinch-evoked c-Fos expression in the dorsal horn. It is suggested that targeting this descending pathway may be effective in reducing persistent pain. NEW & NOTEWORTHY It is known that activation of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM), a main output area for descending modulation of pain, produces hyperalgesia. Here we show that activation of NK-1 receptors produces hyperalgesia by sensitizing nociceptive dorsal horn neurons. Targeting this pathway at its origin or in the spinal cord may be an effective approach for pain management.

Are there long-term changes in the basal or evoked Fos expression in the dorsal horn of the spinal cord of the mononeuropathic rat?

Pain ◽  
1999 ◽  
Vol 80 (1) ◽  
pp. 347-357 ◽  
Author(s):  
Gwénaëlle Catheline ◽  
Stéphanie Le Guen ◽  
Prisca Honoré ◽  
Jean-Marie Besson
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Long Term Changes ◽  
Fos Expression

scholarly journals Pregabalin alleviates postherpetic neuralgia by downregulating spinal TRPV1 channel protein

2021 ◽  
Vol 20 (11) ◽  
pp. 2287-2292
Author(s):  
Zhenping Xiao ◽  
Mengjun Liao ◽  
Yunwu He ◽  
Yonglin Li ◽  
Wuzhou Yang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Postherpetic Neuralgia ◽  
New Drugs ◽  
Spinal Cord Tissue ◽  
Sprague Dawley ◽  
Trpv1 Channel ◽  
Channel Protein ◽  
Tnf Α ◽  
Prefrontal Lobe

Purpose: To determine the mechanism involved in pregabalin-induced alleviation of postherpetic neuralgia in a rat model.Methods: Ninety-sixty healthy Sprague-Dawley (SD) rats were assigned to sham, model andpregabalin groups (32 rats per group). A model of postherpetic neuralgia (PN) was established. The expressions of IL-1β and TNF-α in spinal cord tissue were determined 7 days after administration of treatments. The proportions of fluorescence areas in astrocytes in the dorsal horn, prefrontal lobe and hippocampus, and level of spinal cord TRPV1 channel protein in each group were evaluated.Results: Relative to model rats, IL-1β and TNF-α in spinal cord of pregabalin rats were significantly reduced (p < 0.05). The areas of fluorescence in astrocytes in dorsal horn of spinal cord, prefrontal lobe and hippocampus of model group were significantly increased, relative to sham, but were decreased in rats in pregabalin group (p < 0.05).Conclusion: Pregabalin significantly alleviates postherpetic neuralgia via mechanisms which may be related to the inflammatory response of spinal dorsal horn and downregulation of TRPV1 channel protein expression. This finding may be useful in developing new drugs for alleviating postherpetic neuralgia.

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