Antinociception Following Implantation of AtT-20 and Genetically Modified AtT-20/hENK Cells in Rat Spinal Cord

AtT-20 cells, which produceß-endorphin, and AtT-20/hENK cells, which are AtT-20 cells transfected with a proenkephalin gene, were implanted in the rat spinal subarachnoid space in an effort to produce an antinociceptive effect. Host rats were tested for antinociceptive activity by standard nociceptive tests, tail flick and hot plate. Although cell implants had minimal effect on the basal response to thermal nociceptive stimuli, administration of theß2-adrenergic agonist isoproterenol produced antinociception in the cell-implanted group but not in the control group. The antinociceptive effect of isoproterenol was dose-related and could be blocked by the opioid antagonist naloxone. Immunohistochemical analysis of spinal cords revealed the presence of enkephalin-negative cells surrounding the spinal cord of rats receiving AtT-20 cell implants, and enkephalinpositive cells surrounding the spinal cord of rats. receiving AtT-20/hENK cell implants. These results suggest that opioid-releasing cells implanted around rat spinal cord can produce antinociception and may provide an alternative therapy for chronic pain.

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Antinociceptive Effect and Enzymatic Degradation of Endomorphin-1 in Newborn Rat Spinal Cord

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)30763-2 ◽

1999 ◽

Vol 81 (3) ◽

pp. 264-270

Author(s):

Azusa Sugimoto-Watanabe ◽

Kazufumi Kubota ◽

Kenji Fujibayashi ◽

Koji Saito

Keyword(s):

Spinal Cord ◽

Enzymatic Degradation ◽

Antinociceptive Effect ◽

Rat Spinal Cord ◽

Newborn Rat

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Roles of adenosine receptor subtypes on the antinociceptive effect of sildenafil in rat spinal cord

Neuroscience Letters ◽

10.1016/j.neulet.2010.06.025 ◽

2010 ◽

Vol 480 (3) ◽

pp. 182-185 ◽

Cited By ~ 11

Author(s):

Hyung Gon Lee ◽

Woong Mo Kim ◽

Jeong Il Choi ◽

Myung Ha Yoon

Keyword(s):

Spinal Cord ◽

Adenosine Receptor ◽

Antinociceptive Effect ◽

Receptor Subtypes ◽

Rat Spinal Cord

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Is Hippocampus Susceptible to Antinociceptive Tolerance to NSAIDs Like the Periaqueductal Grey?

Pain Research and Treatment ◽

10.1155/2014/654578 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Nana Tsiklauri ◽

Ivliane Nozadze ◽

Gulnazi Gurtskaia ◽

Merab G. Tsagareli

Keyword(s):

Dorsal Hippocampus ◽

Antinociceptive Effect ◽

Male Rats ◽

Opioid Antagonist ◽

Tail Flick ◽

Pain Models ◽

Inflammatory Drugs ◽

Antinociceptive Tolerance ◽

Undesirable Feature

Emotional distress is the most undesirable feature of painful experience. Numerous studies have demonstrated the important role of the limbic system in the affective-motivational component of pain. The purpose of this paper was to examine whether microinjection of nonsteroidal anti-inflammatory drugs (NSAIDs), Clodifen, Ketorolac, and Xefocam, into the dorsal hippocampus (DH) leads to the development of antinociceptive tolerance in male rats. We found that microinjection of these NSAIDs into the DH induces antinociception as revealed by a latency increase in the tail-flick (TF) and hot plate (HP) tests compared to controls treated with saline into the DH. Subsequent tests on consecutive three days, however, showed that the antinociceptive effect of NSAIDs progressively decreased, suggesting tolerance developed to this effect of NSAIDs. Both pretreatment and posttreatment with the opioid antagonist naloxone into the DH significantly reduced the antinociceptive effect of NSAIDs in both pain models. Our data indicate that microinjection of NSAIDs into the DH induces antinociception which is mediated via the opioid system and exhibits tolerance.

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Immunohistochemical Analysis of the Spinal Cord Ischemia– Effect of Remote Ischemic Preconditioning in a Porcine Model

The Heart Surgery Forum ◽

10.1532/hsf.1969 ◽

2018 ◽

Vol 21 (3) ◽

pp. 209 ◽

Cited By ~ 3

Author(s):

Henri Johannes Haapanen ◽

Johanna Herajärvi ◽

Hannu-Pekka Honkanen ◽

Caius Mustonen ◽

Hannu Tuominen ◽

...

Keyword(s):

Spinal Cord ◽

Ischemic Preconditioning ◽

Neuroprotective Effect ◽

Spinal Cord Ischemia ◽

Immunohistochemical Analysis ◽

Limb Ischemia ◽

Remote Ischemic Preconditioning ◽

Control Group ◽

Segmental Artery

Background: In experimental settings, remote ischemic preconditioning (RIPC) has shown a positive effect regarding spinal cord protection after local ischemia. In this study, we conducted spinal cord immunohistochemistry to demonstrate the protective effect of RIPC after 24 hours of the regional ischemia. Methods: Twenty piglets were randomized into an RIPC group (n = 10) and a control group (n = 10). The RIPC group underwent transient left hind limb ischemia before systematic left subclavian artery and segmental artery occlusion at the level of the diaphragm. Twenty-four hours later, the thoracic and lumbar spinal cords were harvested, and the oxidative stress markers were immunohistochemically analysed. Results: A total of 18 animals survived the 4-hour follow up (10 in the RIPC group, 8 in the control group) and 14 animals survived the 24-hour follow up (7 in each group). In the single sections of the spinal cord, the antioxidant pathway activation was seen in the RIPC group, as OGG1 and DJ-1/PARK7 activation was higher (P = .038 and P = .047, respectively). Conclusions: The results indicate that the neuroprotective effect of RIPC on the spinal cord after local ischemic insult remains controversial.

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Antinociceptive effects of intrathecally administered human β-endorphin in the rat and cat

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y78-120 ◽

1978 ◽

Vol 56 (5) ◽

pp. 754-759 ◽

Cited By ~ 57

Author(s):

Tony L. Yaksh ◽

James L. Henry

Keyword(s):

Subarachnoid Space ◽

Antinociceptive Effect ◽

Intrathecal Injection ◽

Opiate Receptor ◽

Tail Flick ◽

Dose Ratio ◽

Response Curves ◽

Indwelling Catheter ◽

Spinal Subarachnoid Space

Rats chronically implanted with intrathecal catheters displayed a dose-dependent increase in the hot-plate and tail-flick response latencies following the injection of human β-endorphin into the lumbar spinal subarachnoid space through the indwelling catheter. β-Endorphin was approximately 25 times more potent than morphine on a molar basis. Matching morphine and β-endorphin doses such that approximately equal submaximal effects occurred, it was observed that the antinociception produced by β-endorphin lasted approximately three times longer than that produced by morphine. Experiments with intrathecal injection of β-endorphin into the spinal subarachnoid space of cats fitted with intrathecal catheters also revealed a potent antinociceptive effect which was completely antagonized by naloxone. In the rats, naloxone administered systemically in doses of 10–100 μg/kg produced a parallel shift in the dose–response curves of both nociceptive measures suggesting a competitive antagonism. Using a dose ratio analysis, an in vivo pA2 of 7.1 for naloxone was obtained. These data and those derived from previous work based on the pA2 suggest that the interaction of morphine, certain pentapeptides, and β-endorphin is the same with regard to the spinal opiate receptor population mediating behavioraily defined analgesia.

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Dexmedetomidine Injection into the Locus Ceruleus Produces Antinociception

Anesthesiology ◽

10.1097/00000542-199604000-00015 ◽

1996 ◽

Vol 84 (4) ◽

pp. 873-881. ◽

Cited By ~ 175

Author(s):

Tian-Zhi Guo ◽

Jian-Yu Jiang ◽

Ann E. Buttermann ◽

Mervyn Maze

Keyword(s):

Spinal Cord ◽

Pertussis Toxin ◽

Antinociceptive Effect ◽

Intrathecal Injection ◽

Locus Ceruleus ◽

Tail Flick ◽

Sprague Dawley ◽

Tail Flick Latency ◽

Pharmacologically Active ◽

Sites Of Action

Background Alpha(2)-Adrenergic agonists such as clonidine and dexmedetomidine are known to produce sedation and analgesia in humans. The sedative effect of these agents is thought to occur through supraspinal pathways, involving the locus ceruleus (LC) and its projections in rats. While the antinociceptive response to alpha(2) agonists, given intrathecally, is mediated predominantly in the spinal cord, other sites of action have not been systematically studied. The authors examined whether alpha(2)-adrenergic receptors in the LC mediate an antinociceptive effect. Methods For administration of different drugs into the LC, guide cannulas were placed with their tips in the LC in male Sprague-Dawley rats. Dexmedetomidine (3.5 micrograms/0.2 microliter) was microinjected into the LC through the cannula, or given systemically by intraperitoneal injecton (50 micrograms/kg). The antinociceptive effect of dexmedetomidine was measured using the tail-flick latency response. To determine the sites through which dexmedetomidine injection into the LC produces antinociception, the authors examined whether this response could be perturbed by the specific alpha(2)-adrenergic antagonists atipamezole and L659,066 and pertussis toxin administered either into the LC or intrathecally before injection of dexmedetomidine systemically or directly into the LC. To eliminate the possibility that drug administered in one site (LC or intrathecal) could reach the other site, the dispositional characteristics of radiolabeled dexmedetomidine (LC) or atipamezole (intrathecal) were studied. Results Dexmedetomidine placed into the LC produces a dose-dependent increase in the tail-flick latency. This antinociceptive effect was blocked by pertussis toxin and by the alpha(2) antagonists atipamezole and L659,066 placed in the LC. Intrathecal administration of atipamezole and pertussis toxin also blocked the antinociceptive effect of dexmedetomidine placed in the LC. (3)H-dexmedetomidine introduced into the LC did not reach the spinal cord in pharmacologically active concentrations; also, intrathecally administered (3)H-atipamezole did not reach the LC in appreciable amounts. The systemic administration of dexmedetomidine produced an increase in tail-flick latency, and this effect was attenuated by the injection of atipamezole and L659,066 into the LC. Conclusions Part of the mechanism by which dexmedetomidine produces an antinociceptive effect is by an action directly on the LC, demonstrated by these studies in which antinociception produced by injection of this drug into the LC can be blocked by specific alpha(2) antagonists injected into the LC. Furthermore, the action of dexmedetomidine in the LC in turn may result in an increase in activation of alpha(2) adrenoceptors in the spinal cord, because the antinociceptive effect of LC dexmedetomidine injection also can be blocked by intrathecal injection of antipamezole and pertussis toxin.

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Electrophysiological evidence for an antinociceptive effect of ketamine in the rat spinal cord

Acta Anaesthesiologica Scandinavica ◽

10.1111/j.1399-6576.1998.tb05138.x ◽

1998 ◽

Vol 42 (4) ◽

pp. 435-441 ◽

Cited By ~ 10

Author(s):

J.-X. Hao ◽

B. H. Sjölund ◽

Z. Wiesenfeld-Hallin

Keyword(s):

Spinal Cord ◽

Antinociceptive Effect ◽

Rat Spinal Cord ◽

Electrophysiological Evidence

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Functional and anatomical characterization of corticotropin-releasing factor receptor subtypes of the rat spinal cord involved in somatic pain relief

10.21203/rs.3.rs-268281/v3 ◽

2021 ◽

Author(s):

Shaaban Mousa ◽

Mohammed Shaqura ◽

Baled khalefa ◽

Li Li ◽

Mohammed Al-madol ◽

...

Keyword(s):

Spinal Cord ◽

Opioid Receptor ◽

Radioligand Binding ◽

Corticotropin Releasing Factor ◽

Opioid Antagonist ◽

Receptor Subtypes ◽

Inhibitory Interneurons ◽

Rat Spinal Cord ◽

Nociceptive Neurons ◽

Somatic Pain

Abstract Corticotropin-releasing factor (CRF) orchestrates our body’s response to stressful stimuli. Pain is often stressful and counterbalanced by activation of CRF receptors along the nociceptive pathway although the involvement of the CRF receptor subtypes 1 and/or 2 (CRF-R1 and CRF-R2, respectively) in CRF-induced analgesia remains controversial. This study examined CRF-R1 and CRF-R2 expression within the spinal cord of rats with Freund’s complete adjuvant-induced hindpaw inflammation using reverse transcriptase polymerase chain reaction, Western blot, radioligand binding, and immunofluorescence confocal analysis. Moreover, paw pressure algesiometry examined antinociceptive effects of intrathecal (i.t.) CRF and their possible antagonism through CRF-R1 and/or CRF-R2 selective antagonists as well as the opioid receptor antagonist naloxone. Our results demonstrated predominantly CRF-R2 mRNA, protein, binding sites and immunoreactivity in the dorsal horn of the rat spinal cord. Consistently, CRF as well as CRF-R2 agonist elicited potent, dose-dependent anti-nociceptive effects which were antagonized selectively by i.t. CRF-R2 (K41498) antagonist but not by CRF-R1 (NBI35965) antagonist. Moreover, the opioid antagonist naloxone dose-dependently reversed the i.t. CRF- as well as CRF-R2 agonist-elicited inhibition of somatic pain. Supporting these findings, double immunofluorescence confocal microscopy showed CRF-R2 on enkephalin (ENK)-containing inhibitory interneurons in close opposition of incoming mu-opioid receptor-immunoreactive nociceptive neurons. CRF-R2 was, however, not seen on pre- or on postsynaptic sensory neurons of the spinal cord. Taken together, these findings suggest that i.t. CRF or CRF-R2 agonist inhibit inflammatory somatic pain, occurring predominantly through CRF-R2 receptors located on spinal enkephalinergic inhibitory interneurons, which results in endogenous opioid-mediated pain inhibition.

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Effect of Huangqi On Mesenchymal Stem Cells (MSC) Transplanted Therapy in Spinal Cord Injury: It Promotes the Neural Differentiation of MSC In Vivo.

Blood ◽

10.1182/blood.v114.22.4476.4476 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4476-4476

Author(s):

Qin Yu ◽

Yueshuang Bai ◽

Jie Lin ◽

Lixian Sheng ◽

Qin Dong ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Visual Field ◽

Sham Group ◽

Immunohistochemical Analysis ◽

Control Group ◽

Model Group ◽

Cord Injury ◽

Spinal Cord Injured

Abstract Abstract 4476 Introduction The therapeutic effects of using mesenchymal stem cells (MSCs) for transplantation in the treatment of spinal cord injury have been previously studied. Astragalus propinquus, also known as Huangqi, is a traditional Chinese herb commonly used to strengthen the immune system and protect neuron. However, the possibility of combining the beneficial effects of both MSC transplantation and Huangqi Injecta in treating spinal cord injury has not been addressed. Methods A total of 120 male, four-week-old, Wistar rats, were randomly divided into six groups: sham group, model group, phosphate buffered saline (PBS) solution control group (PBS group), Huangqi injection control group (Huangqi group), rMSCs transplantation group (rMSCs group), rMSCs and Huangqi injecta treated group (rMSCs + Huangqi group). There were 10 rats in the sham group and 22 rats in the other groups. In the PBS group, rats were injected 5 μl PBS into the cephalic site of spinal cord injured section three days after the operation; in the Huangqi group, rats were intraperitoneally injected with Huangqi Injecta at a dose of 1.2 ml per 100 g of body weight on day three after the operation; in the rMSCs group, 5 μl of rMSC suspension (2.5–5×105 cells) was injected into the cephalic site of the spinal cord injured part in rats on day three after the operation; in the rMSCs + Huangqi group, rats were injected Huangqi Injecta and 5 μl rMSC suspension (2.5–5×105 cells) following the methods mentioned in the Huangqi group and the rMSCs group. Six animals were randomly picked from each groups on day 7, 14, 21 and 28 to receive Basso-Beattie-Bresnahan (BBB) scale grading for motor function checking of the hind legs. HE staining is adopt for the histopathologic examination, and Dual-marked immunohistochemical analysis is applied for cell locating and differentiation determination. Results The average BBB score in the Huangqi group is higher than model group and PBS group, except on day 21. The score in rMSCs group and the rMSCs + Huangqi group is higher than that in the model group, PBS group and the Huangqi group. The rMSCs + Huangqi group has a higher score than the Huangqi group at each time point. Also, except on day 14, the score for the rMSCs + Huangqi group was higher than the rMSCs group, and the difference was significant. HE staining of the spinal cord paraffin sections showed that the degree of degeneration and necrosis in nerve cells was alleviated in the rMSCs and rMSCs + Huangqi groups, compared with the PBS and Huangqi groups. Edema and infiltration of inflammatory cells were obviously reduced, and the proliferation of glial cells and integrated nerve cells was detected in the rMSCs and rMSCs + Huangqi groups. Moreover, the proliferation of glial cells was more active in the rMSCs + Huangqi group than in the rMSCs group. Using immunohistochemical analysis, both in the rMSCs group and the rMSCs + Huangqi group, BrdU marked rMSCs survived in the spinal cord and accumulated in the gray matter more than in the white matter. GFAP + BrdU and BrdU+NF-M positive cells were detected from day 7 after transplantation. The quantity of BrdU + GFAP positive cells in the rMSCs group and rMSCs + Huangqi group is 6.35±1.14 and 8.75±1.16 per visual field relatively, while BrdU + NF-M positive cells in the rMSCs group and rMSCs + Huangqi group is 1.60±0.75 and 3.30±0.98 per visual field relatively. It indicated that the quantity of BrdU + GFAP and BrdU + NF-M positive cells per visual field observed in the spinal cord paraffin section of the rMSCs + Huangqi group, was significantly higher than that in the rMSCs group (P<0.05). Conclusions These findings indicated that MSCs transplantation has the capability of nerve restoration and recovery after spinal cord injury, and it could be enhanced by Huangqi Injecta. The strategy of combining Huangqi Injecta and MSCs, aimed to promote transplanted cell differentiation and their tissue repair capability, provided a simple yet effective way of optimizing cell transplantation therapy. Disclosures: No relevant conflicts of interest to declare.

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