Adiponectin regulates electroacupuncture-produced analgesic effects in association with a crosstalk between the peripheral circulation and the spinal cord

The demonstration of depolarization-induced release of substance P, Met- and Leu-enkephalin, somatostatin, neurotensin, vasoactive intestinal polypeptide and cholecystokinin-like material from various regions of rat brain in vitro supports the hypothesis that these and other neuropeptides may act as neurotransmitters. In each case the stimulusevoked release, but not the basal release, of peptide was dependent on the presence of calcium ions in the external medium. The stimulus-evoked release of substance P from nerve terminals in rat substantia nigra may be regulated by presynaptic γ -aminobutyric acid (GABA) receptors. The possible existence of presynaptic opiate receptors on substance P-containing sensory nerve terminals may offer an explanation for the analgesic effects of opiates at spinal cord level, and for the existence of enkephalin neurons in substantia gelatinosa. Capsaicin releases substance P from spinal cord nerve terminals and may impair their function, while having no effect on substance P neurons in supraspinal regions. The possibility of cosecretion of peptide and amine products from the same cells is discussed.

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Levo-Tetrahydropalmatine Attenuates Bone Cancer Pain by Inhibiting Microglial Cells Activation

Mediators of Inflammation ◽

10.1155/2015/752512 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Mao-yin Zhang ◽

Yue-peng Liu ◽

Lian-yi Zhang ◽

Dong-mei Yue ◽

Dun-yi Qi ◽

...

Keyword(s):

Spinal Cord ◽

Cancer Pain ◽

Mechanical Allodynia ◽

Thermal Hyperalgesia ◽

Bone Cancer ◽

Microglial Cells ◽

Bone Cancer Pain ◽

Enzyme Linked Immunosorbent Assay ◽

Analgesic Effects ◽

Before And After

Objective. The present study is to investigate the analgesic roles of L-THP in rats with bone cancer pain caused by tumor cell implantation (TCI).Methods. Thermal hyperalgesia and mechanical allodynia were measured at different time points before and after operation. L-THP (20, 40, and 60 mg/kg) were administrated intragastrically at early phase of postoperation (before pain appearance) and later phase of postoperation (after pain appearance), respectively. The concentrations of TNF-α, IL-1β, and IL-18 in spinal cord were measured by enzyme-linked immunosorbent assay. Western blot was used to test the activation of astrocytes and microglial cells in spinal cord after TCI treatment.Results. TCI treatment induced significant thermal hyperalgesia and mechanical allodynia. Administration of L-THP at high doses significantly prevented and/or reversed bone cancer-related pain behaviors. Besides, TCI-induced activation of microglial cells and the increased levels of TNF-αand IL-18 were inhibited by L-THP administration. However, L-THP failed to affect TCI-induced astrocytes activation and IL-1βincrease.Conclusion. This study suggests the possible clinical utility of L-THP in the treatment of bone cancer pain. The analgesic effects of L-THP on bone cancer pain maybe underlying the inhibition of microglial cells activation and proinflammatory cytokines increase.

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Sexual Dimorphism of Pain Control: Analgesic Effects of Pioglitazone and Azithromycin in Chronic Spinal Cord Injury

Journal of Neurotrauma ◽

10.1089/neu.2018.6207 ◽

2019 ◽

Vol 36 (15) ◽

pp. 2372-2376 ◽

Cited By ~ 6

Author(s):

John C. Gensel ◽

Renée R. Donahue ◽

William M. Bailey ◽

Bradley K. Taylor

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Sexual Dimorphism ◽

Pain Control ◽

Chronic Spinal Cord Injury ◽

Analgesic Effects ◽

Cord Injury

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Dexmedetomidine Enhances Analgesic Action of Nitrous Oxide

Anesthesiology ◽

10.1097/00000542-200404000-00020 ◽

2004 ◽

Vol 100 (4) ◽

pp. 894-904 ◽

Cited By ~ 23

Author(s):

Cecilia Dawson ◽

Daqing Ma ◽

Andre Chow ◽

Mervyn Maze

Keyword(s):

Spinal Cord ◽

Nitrous Oxide ◽

Neuronal Activity ◽

Locus Ceruleus ◽

Tail Flick ◽

Receptor Subtypes ◽

Dental Surgery ◽

Analgesic Effects ◽

Adrenoceptor Antagonist ◽

Tail Flick Latency

Background Nitrous oxide and dexmedetomidine are thought to mediate analgesia (antinociception in a noncommunicative organism) via alpha 2B- and alpha 2A-adrenergic receptor subtypes within the spinal cord, respectively. Nitrous oxide and dexmedetomidine exert diametrically opposite effects on neuronal activity within the locus ceruleus, a pivotal site for modulation of analgesia. Because of these differences, the authors explored whether the two analgesics in combination would provide satisfactory analgesia. Methods The analgesic effects of nitrous oxide and dexmedetomidine given both intraperitoneally and intrathecally were evaluated using the tail-flick latency test in rats. For investigation of the interaction, rats were pretreated with dexmedetomidine, either intraperitoneally or intrathecally, immediately before nitrous oxide exposure such that peak antinociceptive effects of each drug coincided. For assessment of the effect on tolerance, dexmedetomidine was administered as tolerance to nitrous oxide developed. Expression of c-Fos was used to assess neuronal activity in the locus ceruleus. Results Nitrous oxide and dexmedetomidine increased tail-flick latency with an ED50 (mean +/- SEM) of 55.0 +/- 2.2% atm for nitrous oxide, 27.6 +/- 5.1 for microg/kg intraperitoneal dexmedetomidine, and 2.9 +/- 0.1 microg for intrathecal dexmedetomidine. Combinations of systemically administered dexmedetomidine and nitrous oxide produced an additive analgesic interaction; however, neuraxially administered dexmedetomidine interacted synergistically with nitrous oxide. Tolerance to nitrous oxide was reversed by coadministration of dexmedetomidine. Prazosin, the alpha 1-/alpha 2B-adrenoceptor antagonist, attenuated the analgesic effect of nitrous oxide and prevented dexmedetomidine-induced reversal of tolerance to nitrous oxide. Nitrous oxide-induced increase of neuronal activity in the locus ceruleus was reversed by dexmedetomidine. Conclusion The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedetomidine is administered systemically in the pretolerant state. After tolerance to nitrous oxide develops, supraspinal functional antagonism no longer obtains exposing the synergistic action at the level of the spinal cord, which expresses itself as a reversal of the tolerant state. The authors speculate that the addition of dexmedetomidine to nitrous oxide is likely to provide enhanced and more durable analgesia in settings in which nitrous oxide is currently used alone (e.g., labor and dental surgery).

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Intrathecal injection of bone marrow stromal cells attenuates neuropathic pain via inhibition of P2X4R in spinal cord microglia

Journal of Neuroinflammation ◽

10.1186/s12974-019-1631-0 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 7

Author(s):

Yongbo Teng ◽

Yang Zhang ◽

Shouwei Yue ◽

Huanwen Chen ◽

Yujuan Qu ◽

...

Keyword(s):

Spinal Cord ◽

Bone Marrow ◽

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Purinergic Receptor ◽

Intrathecal Injection ◽

Transient Receptor Potential Vanilloid ◽

Drg Neurons ◽

Analgesic Effects

Abstract Background Neuropathic pain is one of the most debilitating of all chronic pain syndromes. Intrathecal (i.t.) bone marrow stromal cell (BMSC) injections have a favorable safety profile; however, results have been inconsistent, and complete understanding of how BMSCs affect neuropathic pain remains elusive. Methods We evaluated the analgesic effect of BMSCs on neuropathic pain in a chronic compression of the dorsal root ganglion (CCD) model. We analyzed the effect of BMSCs on microglia reactivity and expression of purinergic receptor P2X4 (P2X4R). Furthermore, we assessed the effect of BMSCs on the expression of transient receptor potential vanilloid 4 (TRPV4), a key molecule in the pathogenesis of neuropathic pain, in dorsal root ganglion (DRG) neurons. Results I.t. BMSC transiently but significantly ameliorated neuropathic pain behavior (37.6% reduction for 2 days). We found no evidence of BMSC infiltration into the spinal cord parenchyma or DRGs, and we also demonstrated that intrathecal injection of BMSC-lysates provides similar relief. These findings suggest that the analgesic effects of i.t. BMSC were largely due to the release of BMSC-derived factors into the intrathecal space. Mechanistically, we found that while i.t. BMSCs did not change TRPV4 expression in DRG neurons, there was a significant reduction of P2X4R expression in the spinal cord microglia. BMSC-lysate also reduced P2X4R expression in activated microglia in vitro. Coadministration of additional pharmacological interventions targeting P2X4R confirmed that modulation of P2X4R might be a key mechanism for the analgesic effects of i.t. BMSC. Conclusion Altogether, our results suggest that i.t. BMSC is an effective and safe treatment of neuropathic pain and provides novel evidence that BMSC’s analgesic effects are largely mediated by the release of BMSC-derived factors resulting in microglial P2X4R downregulation.

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Repairing and Analgesic Effects of Umbilical Cord Mesenchymal Stem Cell Transplantation in Mice with Spinal Cord Injury

BioMed Research International ◽

10.1155/2020/7650354 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Ling-ling Wu ◽

Xiao-ming Pan ◽

Hao-hao Chen ◽

Xiao-yan Fu ◽

Jinzhan Jiang ◽

...

Keyword(s):

Spinal Cord ◽

Treatment Group ◽

Pain Threshold ◽

Inflammatory Factors ◽

Histological Evaluation ◽

Spinal Cord Tissue ◽

Model Group ◽

Analgesic Effects ◽

Cord Injury ◽

Over Time

Transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) into spinal cord injury (SCI) may alleviate neuropathic pain and promote functional recovery. The underlying mechanism likely involves activation of glial cells and regulation of inflammatory factors but requires further validation. SCI was induced in 16 ICR mice using an SCI compression model, followed by injection of lentiviral vector-mediated green fluorescent protein- (GFP-) labeled hUC-MSCs 1 week later. Behavioral tests, histological evaluation, and inflammatory factor detection were performed in the treatment (SCI+hUC-MSCs) and model (SCI) groups. Histological evaluation revealed GFP expression in the spinal cord tissue of the treatment group, implying that the injected MSCs successfully migrated to the SCI. The Basso, Beattie, and Bresnahan (BBB) scores showed that motor function gradually recovered over time in both groups, but recovery speed was significantly higher in the treatment group than in the model group. The pain threshold in mice decreased after SCI but gradually increased over time owing to the self-repair function of the body. The corresponding pain threshold of the treatment group was significantly higher than that of the model group, indicating the therapeutic and analgesic effects of hUC-MSCs. Expression of IL-6 and TNF-α in the spinal cord tissue of the treated group decreased, whereas glial cell line-derived neurotrophic factor (GDNF) expression along with ED1 expression increased compared with those in the model group, suggesting that SCI activated ED1 inflammatory macrophages/microglia, which were subsequently reduced by hUC-MSC transplantation. hUC-MSCs are speculated to enhance the repair of the injured spinal cord tissue and exert an analgesic effect by reducing the secretion of inflammatory factors IL-6 and TNF-α and upregulating the expression of GDNF.

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Do Microencapsulated Bovine Adrenal Medullary Chromaffin Cells Transplanted in Rats' Spinal Cord Produce Analgesic Effects?

Korean Journal of Anesthesiology ◽

10.4097/kjae.2003.44.1.116 ◽

2003 ◽

Vol 44 (1) ◽

pp. 116

Author(s):

Chi Hong Ahn ◽

Young Hoon Jeon ◽

Kyu Ho Lee ◽

Guang Chun Jin ◽

Yu Mi Kim ◽

...

Keyword(s):

Spinal Cord ◽

Chromaffin Cells ◽

Analgesic Effects

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Rib soft fixation produces better analgesic effects and is associated with cytokine changes within the spinal cord in a rat rib fracture model

Molecular Pain ◽

10.1177/1744806919855204 ◽

2019 ◽

Vol 15 ◽

pp. 174480691985520

Author(s):

Yuan-Yuarn Liu ◽

Jeffrey Chi-Fei Wang ◽

Ya-Chi Lin ◽

Hung-Tsung Hsiao ◽

Yen-Chin Liu

Keyword(s):

Spinal Cord ◽

Rib Fracture ◽

Fracture Model ◽

Analgesic Effects

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Intrathecal Grafting of Porcine Chromaffin Cells Reduces Formalin-Evoked c-Fos Expression in the Rat Spinal Cord

Cell Transplantation ◽

10.3727/000000005783982963 ◽

2005 ◽

Vol 14 (6) ◽

pp. 353-365 ◽

Cited By ~ 12

Author(s):

J. C. Sol ◽

R. Y. Li ◽

B. Sallerin ◽

S. Jozan ◽

H. Zhou ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Chromaffin Cells ◽

Formalin Injection ◽

Adrenal Chromaffin Cells ◽

Nociceptive Neurons ◽

Analgesic Effects ◽

Bovine Chromaffin Cells ◽

Fos Expression ◽

Adrenal Chromaffin

Chromaffin cells from the adrenal gland secrete a combination of neuroactive compounds including catecholamines, opioid peptides, and growth factors that have strong analgesic effects, especially when administered intrathecally. Preclinical studies of intrathecal implantation with xenogeneic bovine chromaffin cells in rats have provided conflicting data with regard to analgesic effects, and recent concern over risk of prion transmission has precluded their use in human clinical trials. We previously developed a new, safer source of adult adrenal chromaffin cells of porcine origin and demonstrated an in vivo antinociceptive effect in the formalin test, a rodent model of tonic pain. The goal of the present study was to confirm porcine chromaffin cell analgesic effects at the molecular level by evaluating neural activity as reflected by spinal cord c-Fos protein expression. To this end, the expression of c-Fos in response to intraplantar formalin injection was evaluated in animals following intrathecal grafting of 106 porcine or bovine chromaffin cells. For the two species, adrenal chromaffin cells significantly reduced the tonic phases of the formalin response. Similarly, c-Fos-like immunoreactive neurons were markedly reduced in the dorsal horns of animals that had received injections of xenogeneic chromaffin cells. This reduction was observed in both the superficial (I—II) and deep (V—VI) lamina of the dorsal horn. The present study demonstrates that both xenogeneic porcine and bovine chromaffin cells transplanted into the spinal subarachnoid space of the rat can suppress formalin-evoked c-Fos expression equally, in parallel with suppression of nociceptive behaviors in the tonic phase of the test. These findings confirm previous reports that adrenal chromaffin cells may produce antinociception by inhibiting activation of nociceptive neurons in the spinal dorsal horn. Taken together these results support the concept that porcine chromaffin cells may offer an alternative xenogeneic cell source for transplants delivering pain-reducing neuroactive substances.

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Pre-Injury Administration of Morphine Prevents Development of Neuropathic Hyperalgesia through Activation of Descending Monoaminergic Mechanisms in the Spinal Cord in Mice

Molecular Pain ◽

10.1186/1744-8069-1-19 ◽

2005 ◽

Vol 1 ◽

pp. 1744-8069-1-19 ◽

Cited By ~ 7

Author(s):

Md Harunor Rashid ◽

Hiroshi Ueda

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Nerve Injury ◽

Adrenergic Agonist ◽

Analgesic Effects ◽

Spinal Dorsal ◽

Serotonin Uptake Inhibitor ◽

Kinase C ◽

Inhibitory Pathways ◽

Monoaminergic Mechanisms

The present study examined whether pre-injury administration of morphine can prevent partial sciatic nerve injury-induced neuropathic pain in mice. We observed that pre-injury administration of subcutaneous (s.c.) and intracerebroventricular (i.c.v.) morphine dose-dependently prevented the development of both thermal and mechanical hyperalgesia at 7 days following nerve injury in mice. The pre-injury morphine (s.c.)-induced analgesia was significantly blocked by pretreatment with naloxone injected s.c. or i.c.v., but not i.t., suggesting that systemic morphine produced the pre-emptying effects mainly by acting at the supra-spinal sites. Since it is believed that activation of descending monoaminergic mechanisms in spinal cord largely contributes to the supra-spinal analgesic effects of morphine, we investigated the involvement of serotonergic and noradrenergic mechanisms in spinal cord in the pre-injury morphine-induced analgesic effects. We found that pre-injury s.c. morphine-induced analgesic effect was significantly blocked by i.t. pretreatment with serotonergic antagonist, methysergide and noradrenergic antagonist, phentolamine. In addition, pre-injury i.t. injection of serotonin uptake inhibitor, fluoxetine and α2-adrenergic agonist, clonidine significantly prevented the neuropathic hyperalgesia. We next examined whether pre-injury morphine prevented the expression of neuronal hyperactivity markers such as c-Fos and protein kinase C γ (PKCγ) in the spinal dorsal horn. We found that pre-injury administration of s.c. morphine prevented increased expressions of both c-Fos and PKCγ observed following nerve injury. Similar results were obtained with i.t. fluoxetine and clonidine. Altogether these results suggest that pre-injury administration of morphine might prevent the development of neuropathic pain through activation of descending monoaminergic pain inhibitory pathways.

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