Spinal Antinociceptive Action of Na+-K+Pump Inhibitor Ouabain and Its Interaction with Morphine and Lidocaine in Rats 

1999 ◽  
Vol 90 (2) ◽  
pp. 500-508 ◽  
Author(s):  
Weian Zeng ◽  
Shuji Dohi ◽  
Hiroyuki Shimonaka ◽  
Toshio Asano
Keyword(s):  
Enzyme System ◽  
Antinociceptive Effect ◽  
Processing System ◽  
Cell Types ◽  
Potential Interaction ◽  
Tail Flick ◽  
Isobolographic Analysis ◽  
Tail Flick Latency ◽  
Ion Gradient ◽  
The Central Nervous System

Background The Na+,K+-adenosine triphosphatase is a ubiquitous enzyme system that maintains the ion gradient across the plasma membrane of a variety of cell types, including cells in the central nervous system. We investigated the antinociceptive effect of intrathecally administered ouabain and examined its potential interaction with spinal morphine and lidocaine. Methods Using rats chronically implanted with lumbar intrathecal catheters, the ability of intrathecally administered ouabain, morphine, and lidocaine and of mixtures of ouabain-morphine and ouabain-lidocaine to alter tail-flick latency was examined. To characterize any interactions, isobolographic analysis was performed. The effects of pretreatment with intrathecally administered atropine or naloxone also were tested. Results Intrathecally administered ouabain (0.1-5.0 microg), morphine (0.2-10.0 microg), and lidocaine (25-300 microg) given alone produced significant dose- and time-dependent antinociception, but systemic administration of ouabain did not produce such an effect. The median effective dose (ED50) values for intrathecally administered ouabain, morphine, and lidocaine were 2.3, 5.0, and 227.0 microg, respectively. Isobolographic analysis exhibited a synergistic interaction after the coadministration of ouabain and morphine. With ouabain and lidocaine, there was no such evidence of synergism. Intrathecally administered atropine, but not naloxone, completely blocked the antinociceptive effect of ouabain and attenuated its interaction with spinally administered morphine. Conclusions Intrathecally administered ouabain produces antinociception, at least in part, via an enhancement of cholinergic transmission in the spinal nociceptive processing system. The results of the interaction of ouabain with morphine and lidocaine suggest that modulation of Na+-,K+-electrochemical gradients and thus subsequent release of neurotransmitters in the spinal cord are likely to play important roles in the spinal antinociceptive effect of intrathecally administered ouabain.

Antinociceptive Interaction of Intrathecal α2-adrenergic Agonists, Tizanidine and Clonidine, with Lidocaine in Rats 

1997 ◽  
Vol 87 (2) ◽  
pp. 436-448 ◽  
Author(s):  
Tomoyuki Kawamata ◽  
Keiichi Omote ◽  
Mikito Kawamata ◽  
Hiroshi Iwasaki ◽  
Akiyoshi Namiki
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Motor Function ◽  
Antinociceptive Effect ◽  
Synergistic Interaction ◽  
Tail Flick ◽  
Adrenergic Agonist ◽  
Potency Ratio ◽  
Isobolographic Analysis ◽  
Tail Flick Latency

Background The intrathecal alpha2-adrenergic agonist, clonidine, has been shown to have considerable antinociceptive effect, although clonidine causes hypotension and bradycardia. The combination of intrathecal clonidine and local anesthetics enhances analgesic effects, whereas the combination may cause marked hypotension and motor blockade, which may limit the clinical application of the combination. Tizanidine, another alpha2-adrenergic agonist, has also provided antinociception without producing pronounced hemodynamic changes. This study was designed to evaluate the antinociceptive and hemodynamic interactions of tizanidine and clonidine with lidocaine. Methods Male Sprague Dawley rats were chronically implanted with lumbar intrathecal catheters. The tail-flick test was used to assess the thermal nociceptive threshold. The ability of intrathecal tizanidine, clonidine, lidocaine, or the combinations of alpha2-adrenergic agonist and lidocaine to alter the tail-flick latency was examined. To characterize the antinociceptive interaction, the isobolographic analysis was applied. Additionally, the motor function, blood pressure and heart rate after intrathecal administration of drugs and combinations were also monitored. Results Intrathecal tizanidine, clonidine, or the combinations increased the tail-flick latency in dose- and time-dependent fashion without affecting motor function. The order potencies (dose producing a 50% of peak effect, in microg) of tizanidine and clonidine were 1.8 and 0.75, respectively. With isobolographic analysis, tizanidine with lidocaine and clonidine with lidocaine showed significantly synergistic antinociceptive interaction. Potency ratio analysis and fractional analysis also confirmed the synergistic interaction. At the doses in the combinations showing comparable antinociception, tizanidine with lidocaine, unlike clonidine with lidocaine, did not affect motor function or blood pressure. Conclusion The authors' results show that intrathecal tizanidine and clonidine synergistically interact with lidocaine so that the degree of antinociception to somatic noxious stimuli are enhanced. The antinociceptive synergistic interaction between tizanidine and lidocaine may be useful in clinical practice without affecting blood pressure, heart rate, or motor function.

Low Concentrations of Halothane Increase Response to a Noxious Thermal Stimulus and Attenuate the Antinociceptive Effect of Intraventricular but Not Intrathecal Morphine

2001 ◽  
Vol 94 (2) ◽  
pp. 298-302 ◽  
Author(s):  
Kenneth Drasner
Keyword(s):  
Pain Perception ◽  
Intrathecal Morphine ◽  
Antinociceptive Effect ◽  
Maximum Effect ◽  
Tail Flick ◽  
Temperature Threshold ◽  
Thermal Stimulus ◽  
Descending Inhibition ◽  
Low Concentrations ◽  
Tail Flick Latency

Background Classically, the first plane of anesthesia is known as the stage of analgesia. Nonetheless, clinical evidence suggests that low doses of inhaled agents might enhance pain perception. The present experiments test the hypothesis that low concentrations of halothane increase response to a noxious thermal stimulus and attenuate the antinociceptive effect of intraventricular morphine via disruption of descending inhibition. Methods In the first experiment, the temperature at which rats withdraw their tails from a heat source was measured in animals breathing various concentrations of halothane. In the second experiment, the effect of intraventricular or intrathecal morphine on tail-flick latency was assessed in rats breathing either oxygen or 0.23% halothane. Results Low concentrations of halothane decreased the temperature threshold for tail-flick with a maximum effect at 0.06% atmospheres. Halothane attenuated the antinociceptive potency of intraventricular morphine but enhanced the efficacy of intrathecal morphine. Conclusions Subanesthetic concentrations of halothane may enhance response to a noxious stimulus. The differential effect on intraventricular and intrathecal morphine suggests that this enhancement results from disruption of descending inhibition.

Analgesia additive interaction between tadalafil and morphine in an experimental animal model

2020 ◽  
Vol 98 (11) ◽  
pp. 771-776
Author(s):  
Mohammed Mehanna ◽  
Souraya Domiati ◽  
Hania Nakkash Chmaisse ◽  
Ahmed El Mallah
Keyword(s):  
Central Nervous System ◽  
Side Effects ◽  
Tail Flick ◽  
Response Curves ◽  
Additive Interaction ◽  
Tail Flick Test ◽  
Isobolographic Analysis ◽  
Cgmp Pathway ◽  
The Central Nervous System ◽  
Total Fraction

Since both morphine and tadalafil have been proven to exert some of their analgesic activity through modulation of the NO–cGMP pathway, the aim of the current study is to evaluate the pharmacologic interaction between tadalafil and morphine to decrease the dose of morphine and subsequently its side effects. The assessment was carried out through isobolographic analysis relative to ED50s of both morphine and tadalafil obtained by tail-flick test on BALB/c mice. Morphine and tadalafil ED50s calculated from the dose–response curves were 8303 and 2080 μg/kg, respectively. The experimental ED50 values of morphine and tadalafil in their mixture were 4800 and 1210 μg/kg, respectively. Those results showed an additive interaction between morphine and tadalafil presented by a total fraction value for the mixture of 1160 μg/kg. This outcome can be interpreted by the fact that both drugs share common pathways, namely, NO–cGMP and opioid receptors. As a conclusion, the morphine and tadalafil combination showed an additive effect against acute pain, which is mediated through the central nervous system, thus providing a rationale for combining them to decrease morphine dose and thus minimizing its side effects.

Nitrous Oxide Produces Antinociceptive Response via α2Band/or α2CAdrenoceptor Subtypes in Mice 

1999 ◽  
Vol 90 (2) ◽  
pp. 470-476 ◽  
Author(s):  
Tian-Zhi Guo ◽  
Frances M. Davies ◽  
Wade S. Kingery ◽  
Andrew J. Patterson ◽  
Lee E. Limbird ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Transgenic Mice ◽  
Time Course ◽  
Antinociceptive Effect ◽  
Opiate Receptors ◽  
Opiate Receptor ◽  
Tail Flick ◽  
Wild Type ◽  
Tail Flick Latency ◽  
In The Wild

Background Opiate receptors in the periaqueductal gray region and alpha2 adrenoceptors in the spinal cord of the rat mediate the antinociceptive properties of nitrous oxide (N2O). The availability of genetically altered mice facilitates the detection of the precise protein species involved in the transduction pathway. In this study, the authors establish the similarity between rats and mice in the antinociceptive action of N2O and investigate which alpha2 adrenoceptor subtypes mediate this response. Methods After obtaining institutional approval, antinociceptive dose-response and time-course to N2O was measured in wild-type and transgenic mice (D79N), with a nonfunctional alpha2A adrenoceptor using tail-flick latency. The antinociceptive effect of N2O was tested after pretreatment systemically with yohimbine (nonselective alpha2 antagonist), naloxone (opiate antagonist), L659,066 (peripheral alpha2-antagonist) and prazosin (alpha2B- and alpha2C-selective antagonist). The tail-flick latency to dexmedetomidine (D-med), a nonselective alpha2 agonist, was tested in wild-type and transgenic mice. Results N2O produced antinociception in both D79N transgenic and wild-type litter mates, although the response was less pronounced in the transgenic mice. Antinociception from N2O decreased over time with continuing exposure, and the decrement was more pronounced in the transgenic mice. The antinociceptive response could be dose dependently antagonized by opiate receptor and selective alpha2B-/alpha2C-receptor antagonists but not by a central nervous system-impermeant alpha2 antagonist (L659,066). Whereas dexmedetomidine exhibited no antinociceptive response in the D79N mice, the robust antinociceptive response in the wild-type litter mates could not be blocked by a selective alpha2B-/alpha2C-receptor antagonist. Conclusion These data confirm that the antinociceptive response to an exogenous alpha2-agonist is mediated by an alpha2A adrenoceptor and that there appears to be a role for the alpha2B- or alpha2C-adrenoceptor subtypes, or both, in the analgesic response to N2O.

Dexmedetomidine Injection into the Locus Ceruleus Produces Antinociception

1996 ◽  
Vol 84 (4) ◽  
pp. 873-881. ◽  
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.

scholarly journals Neural Stem Cells: What Happens When They Go Viral?

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1468
Author(s):  
Yashika S. Kamte ◽  
Manisha N. Chandwani ◽  
Alexa C. Michaels ◽  
Lauren A. O’Donnell
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Viral Infections ◽  
Wide Spectrum ◽  
Cell Types ◽  
Developmental Abnormalities ◽  
Multipotent Progenitor Cells ◽  
The Central Nervous System ◽  
Simplex Virus ◽  
The Brain

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.

scholarly journals The Microbiota–Gut–Brain Axis and Alzheimer Disease. From Dysbiosis to Neurodegeneration: Focus on the Central Nervous System Glial Cells

2021 ◽  
Vol 10 (11) ◽  
pp. 2358
Author(s):  
Maria Grazia Giovannini ◽  
Daniele Lana ◽  
Chiara Traini ◽  
Maria Giuliana Vannucchi
Keyword(s):  
Alzheimer Disease ◽  
Glial Cells ◽  
Cell Types ◽  
The Past ◽  
The Central Nervous System ◽  
Diseased State ◽  
The Brain ◽  
Alzheimer Disease Pathogenesis ◽  
Brain Homeostasis

The microbiota–gut system can be thought of as a single unit that interacts with the brain via the “two-way” microbiota–gut–brain axis. Through this axis, a constant interplay mediated by the several products originating from the microbiota guarantees the physiological development and shaping of the gut and the brain. In the present review will be described the modalities through which the microbiota and gut control each other, and the main microbiota products conditioning both local and brain homeostasis. Much evidence has accumulated over the past decade in favor of a significant association between dysbiosis, neuroinflammation and neurodegeneration. Presently, the pathogenetic mechanisms triggered by molecules produced by the altered microbiota, also responsible for the onset and evolution of Alzheimer disease, will be described. Our attention will be focused on the role of astrocytes and microglia. Numerous studies have progressively demonstrated how these glial cells are important to ensure an adequate environment for neuronal activity in healthy conditions. Furthermore, it is becoming evident how both cell types can mediate the onset of neuroinflammation and lead to neurodegeneration when subjected to pathological stimuli. Based on this information, the role of the major microbiota products in shifting the activation profiles of astrocytes and microglia from a healthy to a diseased state will be discussed, focusing on Alzheimer disease pathogenesis.

scholarly journals Made to Measure: Patient-Tailored Treatment of Multiple Sclerosis Using Cell-Based Therapies

2021 ◽  
Vol 22 (14) ◽  
pp. 7536
Author(s):  
Inez Wens ◽  
Ibo Janssens ◽  
Judith Derdelinckx ◽  
Megha Meena ◽  
Barbara Willekens ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Autoimmune Diseases ◽  
Stromal Cells ◽  
Mononuclear Cells ◽  
Treatment Options ◽  
Cell Types ◽  
Peripheral Blood Mononuclear ◽  
Tailored Treatment ◽  
Key Issues ◽  
The Central Nervous System

Currently, there is still no cure for multiple sclerosis (MS), which is an autoimmune and neurodegenerative disease of the central nervous system. Treatment options predominantly consist of drugs that affect adaptive immunity and lead to a reduction of the inflammatory disease activity. A broad range of possible cell-based therapeutic options are being explored in the treatment of autoimmune diseases, including MS. This review aims to provide an overview of recent and future advances in the development of cell-based treatment options for the induction of tolerance in MS. Here, we will focus on haematopoietic stem cells, mesenchymal stromal cells, regulatory T cells and dendritic cells. We will also focus on less familiar cell types that are used in cell therapy, including B cells, natural killer cells and peripheral blood mononuclear cells. We will address key issues regarding the depicted therapies and highlight the major challenges that lie ahead to successfully reverse autoimmune diseases, such as MS, while minimising the side effects. Although cell-based therapies are well known and used in the treatment of several cancers, cell-based treatment options hold promise for the future treatment of autoimmune diseases in general, and MS in particular.

scholarly journals Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders

2021 ◽  
Author(s):  
George B. Stefano ◽  
Richard M. Kream
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Neurological Disorders ◽  
Nuclear Dna ◽  
Mitochondrial Dynamics ◽  
Cell Types ◽  
Tissue Specific ◽  
Copy Numbers ◽  
The Central Nervous System ◽  
Mitochondrial Dna Heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

scholarly journals Effects of Electroacupuncture on Pain Threshold of Laboring Rats and the Expression of Norepinephrine Transporter andα2 Adrenergic Receptor in the Central Nervous System

2016 ◽  
Vol 2016 ◽  
pp. 1-8
Author(s):  
Qianli Tang ◽  
Qiuyan Jiang ◽  
Suren R. Sooranna ◽  
Shike Lin ◽  
Yuanyuan Feng ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adrenergic Receptor ◽  
Pain Threshold ◽  
Norepinephrine Transporter ◽  
Control Group ◽  
Tail Flick ◽  
Pregnant Rats ◽  
Tail Flick Test ◽  
The Central Nervous System

To observe the effects of electroacupuncture on pain threshold of laboring rats and the expression of norepinephrine transporter andα2 adrenergic receptor in the central nervous system to determine the mechanism of the analgesic effect of labor. 120 pregnant rats were divided into 6 groups: a control group, 4 electroacupuncture groups, and a meperidine group. After interventions, the warm water tail-flick test was used to observe pain threshold. NE levels in serum, NET, andα2AR mRNA and protein expression levels in the central nervous system were measured. No difference in pain threshold was observed between the 6 groups before intervention. After intervention, increased pain thresholds were observed in all groups except the control group with a higher threshold seen in the electroacupuncture groups. Serum NE levels decreased in the electroacupuncture and MP groups. Increases in NET andα2AR expression in the cerebral cortex and decreases in enlarged segments of the spinal cord were seen. Acupuncture increases uptake of NE via cerebral NET and decreases its uptake by spinal NET. The levels ofα2AR are also increased and decreased, respectively, in both tissues. This results in a decrease in systemic NE levels and may be the mechanism for its analgesic effects.

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