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1.
BACKGROUND AND PURPOSE
Methadone activates opioid receptors to increase a potassium conductance mediated by G-protein-coupled, inwardly rectifying, potassium (KIR3) channels. Methadone also blocks KIR3 channels and N-methyl-D-aspartic acid (NMDA) receptors. However, the concentration dependence and stereospecificity of receptor activation and channel blockade by methadone on single neurons has not been characterized.EXPERIMENTAL APPROACH
Intracellular and whole-cell recording were made from locus coeruleus neurons in brain slices and the activation of µ-opioid receptors and blockade of KIR3 and NMDA channels with l- and d-methadone was examined.KEY RESULTS
The potency of l-methadone, measured by the amplitude of hyperpolarization was 16.5-fold higher than with d-methadone. A maximum hyperpolarization was caused by both enantiomers (∼30 mV); however, the maximum outward current measured with whole-cell voltage-clamp recording was smaller than the current induced by [Met]5enkephalin. The KIR3 conductance induced by activation of α2-adrenoceptors was decreased with high concentrations of l- and d-methadone (10–30 µM). In addition, methadone blocked the resting inward rectifying conductance (KIR). Both l- and d-methadone blocked the NMDA receptor-dependent current. The block of NMDA receptor-dependent current was voltage-dependent suggesting that methadone acted as a channel blocker.CONCLUSIONS AND IMPLICATIONS
Methadone activated µ-opioid receptors at low concentrations in a stereospecific manner. KIR3 and NMDA receptor channel block was not stereospecific and required substantially higher concentrations. The separation in the concentration range suggests that the activation of µ-opioid receptors rather than the channel blocking properties mediate both the therapeutic and toxic actions of methadone. 相似文献2.
Summary In pontine slices of the rat brain, the frequency of spontaneous action potentials of locus coeruleus (LC) neurones was recorded extracellularly. Noradrenaline 0.1–100 mol/l, UK 14,304 0.01–100 nmol/l, [Met5]-enkephalin 1–10,000 nmol/l and [D-Ala2, D-Leu5]enkephalin 0.1–1,000 nmol/l, all depressed the firing rate. Rauwolscine 1 mol/l antagonized the effects of both noradrenaline and UK 14,304, but potentiated the effects of [Met']enkephalin and [D-Ala2, D-Leu5]enkephalin. Idazoxan 1 mol/l acted in a similar manner. Prazosin 1 mol/l did not change the effects of either noradrenaline or [Met5]enkephalin. Naloxone 0.1 mol/l antagonized both [Met']enkephalin and [D-Ala2, D-Leu5]enkephalin, but failed to alter the effects of either noradrenaline or UK 14,304. Rauwolscine, idazoxan and prazosin, all 1 mol/l, as well as naloxone 0.1 mol/l, did not influence the firing rate when given alone. Desipramine 1 mol/l inhibited the discharge of action potentials in a rauwolscine-antagonizable manner. Noradrenaline 10 mol/l produced the same depression of firing, both in the presence of noradrenaline 1 mol/l and [Met5]enkephalin 0.03 mol/l. Likewise, the effect of [Met5]enkephalin 0.3 mol/l was the same, irrespective of whether it was added to a medium containing [Met5]enkephalin 0.03 mol/l or noradrenaline 1 mol/l. The spontaneous activity of LC neurones is inhibited by somatic 2-adrenoceptors and opioid -receptors. We suggest that the two receptors interact with each other at a site located between themselves and not in the subsequent common signal transduction system.Send offprint requests to: P. Illes at the above address 相似文献
3.
Bruce A. Pappas George R. Breese Richard B. Mailman Robert A. Mueller 《Psychopharmacology》1980,69(2):163-171
The latency, duration, hindlimb kick frequency, and total activity components of the post-decapitation reflex (PDR) were measured in the rat using a movement-sensitive transducer. Reduction of brain and spinal cord norepinephrine (NE) caused by neonatal administration of 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine, which also reduced brain serotonin, decreased all components of the PDR. Depletion of serotonin or dopamine alone reduced the vigor of the reflex, suggesting that these pathways can influence the PDR but are not essential for the response. Lesions of neurons in the Locus coeruleus, made electrolytically or with 6-OHDA, decreased the intensity of the PDR, with the 6-OHDA-induced lesion being more effective. Depletion of forebrain NE terminals with 6-OHDA did not alter the PDR, consistent with a critical involvement of spinal noradrenergic fibers. The PDR was also decreased by phentolamine and prazosin, but not by propanolol, suggesting an involvement of -adrenergic receptors in the response. This hypothesis was further supported by the finding that the efficacy of a variety of drugs (such as tricyclic antidepressants, phenothiazines, and antihypertensive compounds) for blocking the reflex was apparently related to their affinity for -adrenergic receptors. Thus, the PDR is dependent on noradrenergic fibers in the spinal cord and may provide a simple screen for drugs with suspected -adrenergic blocking properties or for agents that disrupt the function of central noradrenergic fibers.Bruce A. Pappas was a visiting Professor on sabbatical leave from the Department of Psychology, Carleton University, Ottawa, Canada K1S 5B6 相似文献
4.
Carl Dahlöf Göran Engberg Torgny H. Svensson 《Naunyn-Schmiedeberg's archives of pharmacology》1981,317(1):26-30
Summary Acute i.v. administration of the non-selective -adrenoceptor antagonist dl-propranolol given in incremental doses (<40 mg/kg) did not affect the firing rate of locus coeruleus (LC) neurones in the rat, as revealed by single cell recording techniques. Furthermore, no effect was seen 4 h after a single i.p. dose of this -blocker (10 mg/kg). However, repeated treatment with dl-propranolol (1, 5, 10 or 20 mg/kg i.p., twice daily for 4 days) produced a significant, dose-dependent decrease of the average LC neuronal firing rate in comparison to controls. The dextro isomer of propranolol, which has negligible -blocking activity but the same local anaesthetic potency as the racemate, had no corresponding effect. The non-selective -adrenoceptor antagonist sotalol, which is one of the most hydrophilic -blockers, had much less inhibitory effect on LC neurones than dl-propranolol. The 1-selective antagonist metoprolol did not change the firing of noradrenergic neurones in the LC after similar treatment for 4 days. However, when the rats were subjected to oral treatment for 28 days, metoprolol was found to produce a slight inhibitory effect although much less than dl-propranolol.In view of these findings we propose a stimulatory and mainly 2-adrenoceptor-mediated control mechanism for the noradrencrgic neurones in the LC. This mechanism seems to be characterized by a delayed responsiveness. 相似文献
5.
6.
A Jayamanne H J Jeong C I Schroeder R J Lewis M J Christie C W Vaughan 《British journal of pharmacology》2013,170(2):245-254
BACKGROUND AND PURPOSE
Antagonists of the N-type voltage gated calcium channel (VGCC), Cav2.2, have a potentially important role in the treatment of chronic neuropathic pain. ω-conotoxins, such MVIIA and CVID are effective in neuropathic pain models. CVID is reported to have a greater therapeutic index than MVIIA in neuropathic pain models, and it has been suggested that this is due to faster reversibility of binding, but it is not known whether this can be improved further.EXPERIMENTAL APPROACH
We examined the potency of CVID, MVIIA and two intermediate hybrids ([K10R]CVID and [R10K]MVIIA) to reverse signs of neuropathic pain in a rat nerve ligation model in parallel with production of side effects. We also examined the potency and reversibility to inhibit primary afferent synaptic neurotransmission in rat spinal cord slices.KEY RESULTS
All ω-conotoxins produced dose-dependent reduction in mechanical allodynia. They also produced side effects on the rotarod test and in a visual side-effect score. CVID displayed a marginally better therapeutic index than MVIIA. The hybrids had a lesser effect in the rotarod test than either of their parent peptides. Finally, the conotoxins all presynaptically inhibited excitatory synaptic neurotransmission into the dorsal horn and displayed recovery that was largely dependent upon the magnitude of inhibition and not the conotoxin type.CONCLUSIONS AND IMPLICATIONS
These findings indicate that CVID provides only a marginal improvement over MVIIA in a preclinical model of neuropathic pain, which appears to be unrelated to reversibility from binding. Hybrids of these conotoxins might provide viable alternative treatments. 相似文献7.
Mahsa Sadeghi Thomas M Tzschentke MacDonald J Christie 《British journal of pharmacology》2015,172(2):460-468
BACKGROUND AND PURPOSE
Tapentadol is a novel analgesic that combines moderate μ-opioid receptor agonism and noradrenaline reuptake inhibition in a single molecule. Both mechanisms of action are involved in producing analgesia; however, the potency and efficacy of tapentadol in individual neurons has not been characterized.EXPERIMENTAL APPROACH
Whole-cell patch-clamp recordings of G-protein-coupled inwardly rectifying K+ (KIR3.x) currents were made from rat locus coeruleus neurons in brain slices to investigate the potency and relative efficacy of tapentadol and compare its intrinsic activity with other clinically used opioids.KEY RESULTS
Tapentadol showed agonist activity at μ receptors and was approximately six times less potent than morphine with respect to KIR3.x current modulation. The intrinsic activity of tapentadol was lower than [Met]enkephalin, morphine and oxycodone, but higher than buprenorphine and pentazocine. Tapentadol inhibited the noradrenaline transporter (NAT) with potency similar to that at μ receptors. The interaction between these two mechanisms of action was additive in individual LC neurons.CONCLUSIONS AND IMPLICATIONS
Tapentadol displays similar potency for both µ receptor activation and NAT inhibition in functioning neurons. The intrinsic activity of tapentadol at the μ receptor lies between that of buprenorphine and oxycodone, potentially explaining the favourable profile of side effects, related to μ receptors.LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 相似文献8.
J Y Moon D H Roh S Y Yoon S R Choi S G Kwon H S Choi S Y Kang H J Han A J Beitz S B Oh J H Lee 《British journal of pharmacology》2014,171(24):5881-5897
Background and Purpose
Spinal astrocytes have emerged as important mechanistic contributors to the genesis of mechanical allodynia (MA) in neuropathic pain. We recently demonstrated that the spinal sigma non-opioid intracellular receptor 1 (σ1 receptor) modulates p38 MAPK phosphorylation (p-p38), which plays a critical role in the induction of MA in neuropathic rats. However, the histological and physiological relationships among σ1, p-p38 and astrocyte activation is unclear.Experimental Approach
We investigated: (i) the precise location of σ1 receptors and p-p38 in spinal dorsal horn; (ii) whether the inhibition of σ1 receptors or p38 modulates chronic constriction injury (CCI)-induced astrocyte activation; and (iii) whether this modulation of astrocyte activity is associated with MA development in CCI mice.Key Results
The expression of σ1 receptors was significantly increased in astrocytes on day 3 following CCI surgery. Sustained intrathecal treatment with the σ1 antagonist, BD-1047, attenuated CCI-induced increase in GFAP-immunoreactive astrocytes, and the treatment combined with fluorocitrate, an astrocyte metabolic inhibitor, synergistically reduced the development of MA, but not thermal hyperalgesia. The number of p-p38-ir astrocytes and neurons, but not microglia was significantly increased. Interestingly, intrathecal BD-1047 attenuated the expression of p-p38 selectively in astrocytes but not in neurons. Moreover, intrathecal treatment with a p38 inhibitor attenuated the GFAP expression, and this treatment combined with fluorocitrate synergistically blocked the induction of MA.Conclusions and Implications
Spinal σ1 receptors are localized in astrocytes and blockade of σ1 receptors inhibits the pathological activation of astrocytes via modulation of p-p38, which ultimately prevents the development of MA in neuropathic mice.Tables of LinksTARGETS | |
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Other protein targetsa,2008 | Enzymesc,2008 |
Sigma non-opioid intracellular receptor 1 | p38 MAPK |
Ligand-gated ion channelsb,2008 | |
GluN1 |
LIGANDS |
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BD-1047 |
SB203580 |
9.
Nicoletta Galeotti Elisa Vivoli Franco Francesco Vincieri 《Biochemical pharmacology》2010,79(9):1327-9
Current pharmacological treatments for neuropathic pain have limited efficacy and severe side-effect limitations. St. John's Wort (SJW) is a medicinal plant, mainly used as antidepressant, with a favourable side-effect profile. We here demonstrate the ability of SJW to relieve neuropathic pain in rat models. The antihyperalgesic profile and mechanism of action of SJW and its main components were studied in two rat models of neuropathic pain: the chronic constriction injury and the repeated administration of oxaliplatin. SJW, acutely administered at low doses (30-60 mg kg−1 p.o.), reversed mechanical hyperalgesia with a prolonged effect, being effective up to 180 min after injection. Further examinations of the SJW main components revealed that hyperforin and hypericin were responsible for the antihyperalgesic properties whereas flavonoids were ineffective. The effect of SJW on the PKC expression and activation was investigated in the periaqueductal grey (PAG) area by immunoblotting experiments. Mechanistic studies showed a robust over-expression and hyperphosphorylation of the PKCγ (227.0 ± 15.0% of control) and PKC? (213.9 ± 17.0) isoforms in the rat PAG area. A single oral administration of SJW produced a significant decrease of the PKCγ (131.8 ± 10.0) and PKC? (105.2 ± 12.0) phosphorylation in the PAG area due to the presence of hypericin. Furthermore, SJW showed a dual mechanism of action since hyperforin antinociception involves an opioid-dependent pathway. Rats undergoing treatment with SJW and purified components did not show any behavioural side effects or signs of altered locomotor activity. Our results indicate SJW as a prolonged antihyperalgesic treatment through inhibition of PKC isoforms and their phosphorylation. 相似文献
10.
Morales-Medina JC Dumont Y Benoit CE Bastianetto S Flores G Fournier A Quirion R 《Neuropharmacology》2012,62(1):200-208
Accumulated evidence suggests that neuropeptide Y (NPY) is involved in emotional disorders by acting on Y1 and Y2 receptors. This hypothesis is based on animal studies carried out in naïve normal animals but not in animal models of depression, including the olfactory bulbectomized (OBX) rat. The OBX rat produces a wide array of symptoms that mimic several aspects of human depression and anxiety disorders. In the present study, we aimed to investigate the effects of sustained (2 weeks) intracerebroventricular administration of NPY Y1 and Y2 agonists and antagonists in a battery of behavioral tests including the open field, forced swim test (FST) and social interaction (SI) tests in OBX rats. The levels of Y1 and Y2 receptors in the hippocampus and basolateral amygdala (BLA) were also evaluated. Treatment with the Y1-like receptor agonist, [Leu31Pro34]PYY, decreased both depressive- and anxiogenic-like behaviors. The Y2 receptor antagonist, BIIE0246, decreased the immobility time in the FST in OBX animals and increased active contacts in the SI test in sham rats. The Y2 agonist, PYY3-36, increased the immobility time in the FST in OBX rats. Additionally, increased levels of Y2 receptor binding were quantified in the dorsal hippocampus and BLA in OBX rats. Taken together, the autoradiographic results add further evidence that the NPYergic system is altered in disturbed emotional states. Moreover, we demonstrate a differential role for NPY Y1 and Y2 receptors in emotional processes under control and challenged conditions.This article is part of a Special Issue entitled ‘Anxiety and Depression’. 相似文献
11.
We previously showed that electrical stimulation of the nucleus locus coeruleus was followed 4 weeks later by a greatly improved performance in the acquisition of a food-reinforced operant task. To ascertain whether adrenergic receptors were involved in this long-term behavioral modification, we studied the characteristics of the 1, 2, and -adrenoreceptors of the cerebral cortex 4 weeks after stimulation of the locus coeruleus. This stimulation induced a slight (14%) but significant increase in the number of 1-receptor [(3H) WB 4101 binding sites] as well a rise in the number of 2-receptor [(3H) clonidine binding sites]. The later rise mainly affected high-affinity 2 sites (36%) and the number of low-affinity sites remained unchanged. No significant alteration in the number of -receptors [(3H)-dihydroalprenolol binding sites] was observed. To confirm this biochemical result, the effect of very small doses of clonidine (1, 2.5, 5 and 10 g/kg) was tested on locomotor activity in the open-field. In rats stimulated 4 weeks before injection, clonidine induced a biphasic effect, comprising firstly sedation which occurred 30 min after injection, and secondly, long-term hyperactivity which began 24 h after injection. For the 5 g/kg dose, this rebound of activity was detectable 8 days after injection. In implanted, control rats, only the sedative effect was observed. These findings are interpreted in relation to the current theories about -adrenoreceptors. 相似文献
12.
Salim Megat Yohann Bohren Stephane Doridot Claire Gaveriaux-Ruff Brigitte L Kieffer Marie-José Freund-Mercier Ipek Yalcin Michel Barrot 《British journal of pharmacology》2015,172(4):1034-1044
Background and Purpose
Tricyclic antidepressants are used clinically as first-line treatments for neuropathic pain. Opioid receptors participate in this pain-relieving action, and preclinical studies in receptor-deficient mice have highlighted a critical role for δ-, but not μ-opioid receptors. In this study, we investigated whether κ-opioid (KOP) receptors have a role in the antiallodynic action of tricyclic antidepressants.Experimental Approach
We used a model of neuropathic pain induced by unilateral sciatic nerve cuffing. In this model, the mechanical allodynia was evaluated using von Frey filaments. Experiments were conducted in C57BL/6J mice, and in KOP receptor-deficient mice and their wild-type littermates. The tricyclic antidepressant nortriptyline (5 mg·kg−1) was delivered twice a day for over 2 weeks. Agonists and antagonists of opioid receptors were used to test the selectivity of the KOP receptor antagonist norbinaltorphimine (nor-BNI) in mice with neuropathic pain.Key Results
After 12 days of treatment, nortriptyline relieved neuropathic allodynia in both wild-type and KOP receptor-deficient mice. Surprisingly, acute nor-BNI reversed the effect of nortriptyline in both wild-type and KOP receptor-deficient mice. Further experiments showed that nor-BNI action was selective for KOP receptors at a late time-point after its administration (8 h), but not at an early time-point, when it may also interact with δ-opioid (DOP) receptors.Conclusions and Implications
KOP receptors are not necessary for the effect of a tricyclic antidepressant against neuropathic allodynia. These findings together with previous data indicate that the DOP receptor is the only opioid receptor that is necessary for the antiallodynic action of antidepressants. 相似文献13.
Ohno Y Okano M Masui A Imaki J Egawa M Yoshihara C Tatara A Mizuguchi Y Sasa M Shimizu S 《Neuropharmacology》2012,63(4):547-554
Spontaneously hypertensive rats (SHR) are widely used as a rat model of attention deficit/hyperactivity disorder (AD/HD). Here, we conducted neurochemical and behavioral studies in SHR to clarify the topographical alterations in neurotransmissions linked to their behavioral abnormalities. In the open-field test, juvenile SHR showed a significant hyperactivity in ambulation and rearing as compared with Wistar Kyoto rats (WKY). Brain mapping analysis of Fos-immunoreactivity (IR) revealed that SHR showed a marked increase in Fos expression in the core part (AcC) of the nucleus accumbens (NAc). Small to moderate increases were also observed in the shell part of the NAc and some regions of the cerebral cortex (e.g., parietal association cortex). These changes in Fos expression were region-specific and the Fos-IR levels in other brain regions (e.g., hippocampus, amygdala, striatum, thalamus and hypothalamus) were unaltered. In addition, treatment of SHR with the selective D(1) antagonist SCH-23390 significantly reversed both behavioral hyperactivity and elevated Fos expression in the AcC and cerebral cortex. The present study suggests that D(1) receptor-mediated neurotransmission in the AcC is region-specifically elevated in SHR, which could be responsible for behavioral hyperactivity. 相似文献
14.
15.
Previous work demonstrated that basal alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activity did not contribute to the elevated regional cerebral O2 consumption in the brains of Eker rat (an autism-tuberous sclerosis model). We tested the hypothesis that increased stimulation of AMPA receptors also would not augment cerebral O2 consumption in the Eker rat. Three cortical sites were prepared for administration of saline, 10?4 and 10?3 M AMPA in young (4 weeks) male control Long Evans and Eker rats (70–100 g). Cerebral blood flow (14C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane anesthetized rats. Receptor levels were studied through Western analysis of the GLuR1 subunit of the AMPA receptor. We found significantly increased cortical O2 consumption (+33%) after 10?4 M AMPA in control rats. The higher dose of AMPA did not further increase consumption. In the Eker rats, neither dose led to a significant increase in cortical O2 consumption. Regional blood flow followed a similar pattern to oxygen consumption but cortical O2 extraction did not differ. Cortical AMPA receptor protein levels were significantly reduced (?21%) in the Eker compared to control rats. Both O2 consumption and blood flow were significantly elevated in the pons of the Eker rats compared to control. These data demonstrate a reduced importance of AMPA receptors in the control of cortical metabolism, related to reduced AMPA receptor protein, in the Eker rat. This suggests that increasing AMPA receptor activity may not be an effective treatment for children with autism spectrum disorders as they also have reduced AMPA receptor number. 相似文献
16.
Radomir Radomirov Christina Ivancheva Dimitar Itzev Polina Petkova-Kirova 《Acta pharmacologica Sinica》2009,30(9):1276-1282
Aim:
Since the distal part of the intestine is targeted by a wide range of pathogens, the motility of the recto-anal region has been the object of many experimental and clinical observations. In this study, we investigated descending motor responses in the anal canal as a measure of the activation of autonomic reflex pathways underlying evacuatory recto-anal activity.Methods:
The partitioned organ bath method was used to register motor responses of the anal canal as induced by balloon distension of the rectum in isolated rat recto-anal preparations.Results:
Distension-induced descending responses of the anal canal comprised contractions (with distension at a distance of 15 mm), initial contractions and secondary relaxations (at 10 mm) and short contractions followed by deep relaxations (at 3−5 mm). Decreasing the distance between the distension stimulus and the anal canal resulted in a decreased contraction response and increased relaxation. Tetrodotoxin (0.1 μmol/L) inhibited these responses. Atropine (0.3 μmol/L) decreased contraction and did not change the relaxation response. NG-nitro-L-arginine (0.5 mmol/L) enhanced contraction in both the absence and presence of atropine. L-arginine (0.5 mmol/L) inhibited contraction and extended relaxation in atropine-pretreated preparations. The actions of NG-nitro-L-arginine and L-arginine were more pronounced in the aboral direction. ChAT-positive nerve fibers were observed in myenteric ganglia of the rectum and the anal canal. The density of NADPH-diaphorase-positive neurons was higher in the anal canal region.Conclusion:
Our results suggest that locality-dependent activation of the descending reflex neuromuscular communications underlie evacuatory activity in the recto-anal region. This activation response involves long excitatory cholinergic and non-cholinergic pathways along the rectum and short inhibitory nitrergic pathways located predominantly in the anal canal region. 相似文献17.
Shen H Fuchino Y Miyamoto D Nomura H Matsuki N 《The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP)》2012,15(4):523-530
Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression and has cognition-enhancing effects in patients with Alzheimer's disease. The hippocampus is widely recognized to be related to epilepsy, depression, and Alzheimer's disease. One possible mechanism of VNS involves its effect on the hippocampus; i.e. it increases the release of noradrenaline in the hippocampus. However, the effect of VNS on synaptic transmission in the hippocampus is unknown. To determine whether VNS modulates neurotransmission in the hippocampus, we examined the effects of VNS on perforant path (PP)-CA3 synaptic transmission electrophysiologically in anaesthetized rats. VNS induces a persistent enhancement of PP-CA3 field excitatory post-synaptic potentials (fEPSPs). Arc, an immediate early gene, was used to identify active brain regions after VNS. The locus coeruleus (LC), which contains the perikarya of noradrenergic projections, harboured more Arc-positive cells, as measured by in-situ hybridization, after 10-min VNS. In addition, electrical lesions of LC neurons or intraventricular administration of the β-adrenergic receptor antagonist timolol prevented the enhancement of PP-CA3 responses by VNS. In conclusion, the protracted increase in PP-CA3 synaptic transmission that is induced by VNS entails activation of the LC and β-adrenergic receptors. Our novel findings suggest that information from the periphery modulates synaptic transmission in the CA3 region of the hippocampus. 相似文献
18.
《Xenobiotica; the fate of foreign compounds in biological systems》2013,43(10):941-951
Abstract1.?The more relevant primary co-cultures of brain microvessel endothelial cells and astrocytes (BMEC) are less utilized for screening of potential CNS uptake when compared to intestinal and renal cell lines.2.?In this study, we characterized the temporal mRNA expression of major CNS transporters and receptors, including the transporter regulators Pxr, Ahr and Car in a rat BMEC co-cultured model. Permeability was compared with the Madin–Darby canine kidney (MDCKII)-MDR1 cell line and rat brain in situ perfusion model.3.?Our data demonstrated differential changes in expression of individual transporters and receptors over the culture period. Expression of ATP-binding cassette transporters was better retained than that of solute carrier transporters. The insulin receptor (IR) was best maintained among investigated receptors. AhR demonstrated high mRNA expression in rat brain capillaries and expression was better retained than Pxr or Car in culture. Mdr1b expression was up-regulated during primary culture, albeit Mdr1a mRNA levels were much higher. P-gp and Bcrp-1 were highly expressed and functional in this in vitro system.4.?Permeability measurements with 18 CNS marketed drugs demonstrated weak correlation between rBMEC model and rat in situ permeability and moderate correlation with MDCKII-MDR1 cells.5.?We have provided appropriate methodologies, as well as detailed and quantitative characterization data to facilitate improved understanding and rational use of this in vitro rat BBB model. 相似文献
19.
Filippo Caraci Flaminia Coluzzi Franco Marinangeli Sebastiano Mercadante Giuseppe Rinonapoli Patrizia Romualdi 《Current medical research and opinion》2020,36(6):1015-1024
AbstractObjective: This paper presents and discusses recent evidence on the pathophysiological mechanisms of pain. The role of tapentadol – an opioid characterized by an innovative mechanism of action (i.e. µ-opioid receptor [MOR] agonism and inhibition of noradrenaline [NA] reuptake [NRI]) – in the modulation of pain, and the most recent pharmacological evidence on this molecule (e.g. the µ-load concept) are also presented and commented upon.Methods: Narrative review.Results: Solid evidence has highlighted the importance of central sensitization in the transition from acute to chronic pain. In particular, the noradrenergic system holds a major role in limiting central sensitization and the progression to chronic pain. Therefore, pharmacological modulation of the noradrenergic system appears to be a well-grounded strategy for the control of chronic pain. Tapentadol is characterized by a to-date-unique mechanism of action, since it acts both as a MOR agonist and as an inhibitor of NA reuptake. The synergistic interaction of these two mechanisms allows a strong analgesic effect by acting on both ascending and descending pathways. Of note, the reduced µ-load of tapentadol limits the risk of opioid-related adverse events, such as gastrointestinal disturbances. Moreover, the NA component becomes predominant, at least, in some types of pain, with consequent specific clinical efficacy in the treatment of neuropathic and chronic pain.Conclusions: According to these characteristics, tapentadol appears suitable in the treatment of severe uncontrolled chronic pain characterized by both a nociceptive and a neuropathic component, such as osteoarthritis or back pain. 相似文献
20.
Malherbe P Knoflach F Hernandez MC Hoffmann T Schnider P Porter RH Wettstein JG Ballard TM Spooren W Steward L 《British journal of pharmacology》2011,162(4):929-946