Circadian phase-dependent antinociceptive reaction in mice determined by the hot-plate test and the tail-flick test after intravenous injection of dalargin-loaded nanoparticles

Peptides normally do not cross the blood-brain barrier (BBB). Previously, it has been shown that the hexapeptide enkephalin analogue dalargin with polysorbate-80-coated nanoparticles (DAL/NP) can be transported across the BBB and is able to exhibit an antinociceptive effect in mice. In the present study, the circadian time and dose dependencies of the antinociceptive effect of different dalargin preparations were investigated. The active preparation (DAL/NP, 5 mg/kg, 10 mg/kg), as well as a dalargin solution in phosphate buffered saline (DAL/SOL, 10 mg/kg) were injected intravenously to groups of 10-12 inbred DBA/2 mice at 12 different circadian times; mice were synchronized to a light-dark (LD) 12:12 regimen. The antinociceptive effect was determined 15 minutes postinjection by the hot-plate test. Experiments with DAL/NP were repeated using the tail-flick test system at two selected times (08:00 and 20:00) to test for dose dependency (2.5, 5, 7.5, 10 mg/kg). Hot-plate latencies were rhythmic under baseline and after DAL/SOL, with acrophases in the dark phase; DAL/SOL did not influence latency time. In contrast, DAL/NP significantly increased reaction time dose dependency; the maximal possible effect was rhythmic with the 10 mg/kg preparation, with a peak effect in the early light phase. Results were confirmed by the tail-flick test. The experiments demonstrate that an enkephalin analogue coated with nanoparticles can easily cross the BBB and is able to display a dose- and time-dependent antinociceptive effect.     

Synthesis and antinociceptive effects of endomorphin-1 analogs with C-terminal linked by oligoarginine

Endomorphins (EMs) cannot be delivered into the central nervous system (CNS) in sufficient quantity to elicit antinociception when given systemically because they are severely restricted by the blood-brain barrier (BBB). In the present study, we investigated herein a series of EM-1 analogs with C-terminal linked by oligoarginine in order to improve the brain delivery and antinociception after systemic administration. Indeed, all these analogs decreased the opioid receptor affinity and in vitro pharmacological activity. Moreover, analogs 4, 7-9 produced a less potent antinociceptive activity after intracerebroventricular (i.c.v.) administration, with the ED₅₀ values about 11- to 13-fold lower potencies than that of EM-1. Nevertheless, our results revealed that EM-1 failed to induce any significant antinociception at a dose of 50 μmol/kg after subcutaneous (s.c.) administration, whereas equimolar dose of these four analogs produced a little low but significant antinociceptive effects. Naloxone (10 nmol/kg, i.c.v.) significantly blocked the antinociceptive effects, indicating an opioid and central mechanism. These results demonstrated that C-terminal of EM-1 linked to oligoarginine improved the brain delivery, eliciting potent antinociception following peripheral administration.     

Intranasal Drug Delivery of Olanzapine-Loaded Chitosan Nanoparticles

The aim of this study was to investigate olanzapine (OZ) systemic absolute bioavailability after intranasal (i.n.) administration in vivo to conscious rabbits. Furthermore, the study investigated the potential use of chitosan nanoparticles as a delivery system to enhance the systemic bioavailability of olanzapine following intranasal administration. Olanzapine-loaded chitosan nanoparticles were prepared through ionotropic gelation of chitosan with tripolyphosphate anions and studied in terms of their size, drug loading, and in vitro release. The OZ nanoparticles were administered i.n. to rabbits, and OZ plasma concentration at predetermined time points was compared to i.n. administration of OZ in solution. The concentrations of OZ in plasma were analyzed by ultra performance liquid chromatography mass spectroscopy (UPLC/MS). OZ-loaded chitosan nanoparticles significantly (p < 0.05) enhanced systemic absorption with 51 ± 11.2% absolute bioavailability as compared to 28 ± 6.7% after i.n. administration of OZ solution. The results of the present study suggest that intranasal administration of OZ-loaded chitosan nanoparticles formulation could be an attractive modality for delivery of OZ systemically.KEY WORDS: bioavailability, intranasal, nanoparticles, olanzapine, pharmacokinetic     

聚乳酸纳米粒穿透血脑屏障的分析电镜研究

观察以聚乳酸 (D ,L-polylacticacid,PLA)为材料制备、经吐温-80(T-80)表面改性的纳米粒对血脑屏障的穿透效果并探讨其机制 ,分别将FITC-Dextran、叶绿素铜作为PLA纳米粒的示踪标记 ,应用荧光显微镜、透射电镜及分析电镜观察经静脉注射入小鼠体内的PLA纳米粒在脑组织中的分布、穿透血脑屏障的特性。荧光显微镜观察到小鼠脑组织中散在及沿毛细血管壁分布的荧光颗粒 ,透射电镜可观察到小鼠脑毛细血管内皮细胞及周围脑组织中圆形或类圆形的外源性纳米粒 ;进一步采用分析电镜对颗粒处组织进行能谱分析证实其为叶绿素铜标记的PLA纳米粒。证实了T-80修饰的PLA纳米粒具有穿透血脑屏障的特性 ,机制可能是毛细血管内皮细胞的胞吞转运作用 ,同时 ,为研究纳米粒在组织内的定位提供了新的标记方法.     

The involvement of nitric oxide in the analgesic effects of ketamine

We investigated the contribution of NO-cyclic GMP (cGMP) pathway to the antinociceptive effects of ketamine in mice by using the nitric oxide synthase inhibitor, nitro(g)- L-arginine methyl ester (L-NAME). Intraperitoneal (i.p.) (1, 5 or 10 mg/kg) or intrathecal (i.th.) (10, 30 or 60 microg/mouse) administration of ketamine produced dose-dependent antinociceptive effects in the acetic acid-induced writhing and formalin tests but not in the tail-flick nor in hot-plate tests. Pretreatment of mice with L-NAME (10 mg/kg, i.p.) which produced no antinociception on its own, significantly inhibited the antinociceptive effect of ketamine (1, 5 or 10 mg/kg, i.p.). However, L-NAME (30 microg/mouse) was given intrathecally, it neither modified the antinociceptive effect of i.th. ketamine (10, 30 or 60 microg/mouse) nor did it produce an antinociceptive effect alone. These data suggest that the activation of the NO-cGMP pathway probably at the supraspinal level, but not spinal level, contributes to the antinociceptive effects of ketamine.     

Body distribution of 3H-labelled dalargin bound to poly(butyl cyanoacrylate) nanoparticles after i.v. injections to mice

The blood-brain barrier (BBB) limits the penetration of substances into the brain. Because many drugs, particularly peptides, therefore can not be delivered to the brain, carrier systems were developed to overcome this problem. In earlier studies we demonstrated central analgesic effects of a peptide, dalargin (dal), after systemic administration when this substance was bound onto the surface of polybutylcyanoacrylate nanoparticles and coated with polysorbate 80 but not when it was given alone. The aim of the present study was to investigate the body distribution of 3H-labelled dal bound to nanoparticles compared to unbound dal after i.v. injection in mice. The radioactivity in several tissues, including the brain, was separated in subcellular preparations and was measured after a single i.v. injection over time. Dal radioactivity level in brain preparations was 3 times higher when the drug was bound to nanoparticles whereas the first pass pathway in liver was reduced. The results support previous data that nanoparticles can be used to transport peptides across the BBB.     

Antidepressant-like effects exerted by the intranasal administration of a glucagon-like peptide-2 derivative containing cell-penetrating peptides and a penetration-accelerating sequence in mice

The intracerebroventicular (i.c.v.) administration of glucagon-like peptide-2 (GLP-2) to rodents was shown to have antidepressant-like effects in imipramine-resistant depression-model mice. In order to utilize GLP-2 as a clinical treatment tool for depression, we herein focused on the intranasal delivery that is non-invasive approach, because the i.c.v. administration is invasive and impractical. In the present study, we prepared a GLP-2 derivative containing cell penetrating peptides (CPPs) and a penetration accelerating sequence (PAS) (PAS-CPPs-GLP-2) for the intranasal (i.n.) administration. PAS-CPPs-GLP-2 (i.n.) exhibited antidepressant-like effects in the forced-swim test (FST) and tail suspension test (TST) in naïve mice as well as adrenocorticotropic hormone (ACTH) treated-mice. However, PAS-CPPs-GLP-2 (i.v.) and the GLP-2 derivative containing CPPs without a PAS (CPPs-GLP-2) (i.n.) did not affect the immobility time in the mouse FST. Moreover, fluorescein isothiocyanate (FITC)-labeled PAS-CPPs-GLP-2 (i.n.), but not FITC-labeled CPPs-GLP-2 (i.n.) was distributed through the mouse brain after the FST session. These results suggest that PAS-CPPs-GLP-2 is effective for i.n. delivery to the brain, and may be useful in the clinical treatment of major depression.     

Antinociception induced by beta-lactotensin,a neurotensin agonist peptide derived from beta-lactoglobulin,is mediated by NT2 and D1 receptors

In this study, we examined the antinociceptive effect of beta-lactotensin, a neurotensin agonist that has been isolated from the chymotrypsin digest of beta-lactoglobulin as an ileum-contracting peptide. Beta-lactotensin showed naloxone-insensitive antinociceptive activity by the tail-pinch test after i.c.v. (200 nmol/mouse) or s.c. (300 mg/kg) administration in ddY mice. Tolerance was not developed to antinociception induced by beta-lactotensin after repeated s.c. administration for 5 days. The antinociceptive activity of beta-lactotensin was blocked by treatment with the neurotensin NT2 receptor antisense ODN, while treatment with the NT1 receptor antisense ODN had no effect. The antinociceptive activity was also blocked by a dopamine D1 receptor antagonist, SCH23390 (1 microg/mouse, i.c.v.), while a D2 receptor antagonist, raclopride (0.5 microg/mouse, i.c.v.), did not block the activity. These results indicate that the antinociceptive activity of beta-lactotensin is mediated by NT2 and D1 receptors.     

Effect of hypophysectomy, adrenalectomy, pituitary hormone secretion and gastric acid secretion on neurotensin induced gastric protection against stress gastric lesions

In previous studies we have established that intracisternal (i.c.) but not peripheral (intravenous) administration of neurotensin (NT), a brain and gastrointestinal tridecapeptide, totally prevents the development of gastric lesions produced by cold-restraint stress (CRS) with food-deprived rats. In this investigation, removal of the pituitary and adrenal gland, anterior pituitary hormone secretion and gastric acid secretion were evaluated independently as potential intermediates for NT's protective effect. NT (30 micrograms) produced a significant reduction of gastric lesions incidence and severity in intact and sham-operated controls. Adrenalectomy, but not hypophysectomy totally blocked the protective effect of i.c. NT. In addition, replacement therapy with s.c. prednisone (1 mg/kg) for 5 days following adrenalectomy did not restore the protective activity of central (i.c.) NT in adrenalectomized rats. A significant reduction of serum levels of TSH, PRL and GH following i.c. NT (30 micrograms) was observed after 2h of CRS. The gastrosecretory studies revealed that i.c. NT (30 micrograms) did not affect gastric acid secretion in pylorus ligated rats. However, blockade of peripheral (gut) cholinergic (muscarinic) receptors with i.p. atropine methylbromide (1 mg/kg) significantly raised gastric pH and reduced gastric acid concentration and output. In conclusion, the results of this study indicate that the acute protective effect of brain NT appears to be mediated, at least in part, by the sympathoadrenomedullary axis, and not by the pituitary gland or substances derived from the pituitary or by inhibition of gastric acid secretion.     

Centrally-mediated antinociceptive action of RWJ-22757 (formerly McN-5195): involvement of spinal descending inhibitory pathways (an hypothesis)

The present studies were an attempt to examine the mechanism of action of the novel antinociceptive compound RWJ-22757, (+/-)-trans-3-(2-bromophenyl)-octahydroindolizine (McN-5195). Intracerebroventricular (i.c.v.) administration of RWJ-22757 produced dose-related antinociception in the mouse tail-flick (48 degrees C) and rat hot-plate (51 degrees C) tests (ED50 = 243.3 and 261.3 micrograms, respectively). In contrast, intrathecal (i.t.) administration was without effect. The antinociception produced by peripherally (i.p.) or centrally (i.c.v.) administered RWJ-22757 was attenuated by i.t. administration of 2 micrograms phentolamine, 5 micrograms yohimbine, or 10 micrograms methysergide. I.t. administration of naloxone, at a dose (0.5 micrograms) that significantly attenuated the antinociceptive effects of peripherally or centrally administered morphine, had no effect on RWJ-22757-induced antinociception. We conclude from these results, coupled with the overall pharmacological and neurochemical profile of RWJ-22757, that the data are consistent with the hypothesis that RWJ-22757 produces antinociception predominantly at a site or sites located supraspinally with little or no activity at the spinal level and that RWJ-22757 activates adrenergic and serotonergic descending inhibitory pathways, increasing the tonic activity of endogenous antinociceptive systems.     

Antinociceptive effect induced by intraperitoneal administration of vitamin K2 (menatetrenone) in ICR mice

The antinociceptive effect of vitamin K2 (menatetrenone) in mice was examined using tail-flick and formalin test. Menatetrenone at doses of 10, 50 and 100 mg/kg, i.p. produced a dose-dependent and significant inhibition of the tail-flick response in mice. Menatetrenone (50 and 100 mg/kg, i.p.) had no significant effect on the duration of the first phase of the formalin-induced flinching. However, menatetrenone (100 mg/kg, i.p.) significantly inhibited the second phase of the formalin-induced flinching. I.p. administration of menatetrenone (100 mg/kg) significantly reduced the duration of nociceptive responses induced by i.t. injection of bradykinin, but not of substance P, prostaglandin E2 or N-methyl-D-aspartate (NMDA). These present data suggest that i.p. pretreatment with menatetrenone produced dose-dependent antinociceptive effect in mice. This effect may be, at least in part, mediated by the inhibition of bradykinin dependent nociceptive transmission in the spinal cord.     

The spinal antinociceptive effect of FR140423 is mediated through kyotorphin receptors

We investigated the antinociceptive effect of a novel anti-inflammatory and analgesic drug, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (FR140423), in the tail-pinch test in mice, and evaluated the mechanism of action of FR140423 using L-leucyl-L-arginine (Leu-Arg), a kyotorphin (endogenous Met-enkephalin releaser) receptor antagonist, L-NG-nitroarginine methylester (L-NAME), an inhibitor of nitric oxide (NO) synthase, and methylene blue (MB), an inhibitor of activation of guanylate cyclase. Oral administration of FR140423, at doses of 5-80 mg/kg, produced a dose-dependent antinociceptive effect with an ED50 value of 18 mg/kg. This antinociception was reversed by intrathecal (i.t.) (10 microg/mouse), but not by intracerebroventricular (i.c.v.) (100 microg/mouse), injection of Leu-Arg. Moreover, the antinociceptive effect of i.t. injection of FR140423 with an ED50 value of 3.7 microg/mouse was completely antagonized by co-administered Leu-Arg 10 microg/mouse. However, L-NAME (2000 mg/kg s.c.) and MB (200 mg/kg s.c.) did not antagonize the antinociception of FR140423. These findings suggest that FR140423 plays a role in nociceptive modulation in the spinal cord, being antinociceptive via the kyotorphin-Met-enkephalin pathway but not via the peripheral NO-cyclic GMP pathway.     

Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma

In vitro and in vivo studies, in both animal models and human asthmatics, have implicated IL-4 as an important inflammatory mediator in asthma. In a murine asthma model, we examined the anti-inflammatory activities of soluble IL-4R (sIL-4R). In this model, mice sensitized to OVA by i.p. and intranasal (i.n.) routes are challenged with the allergen by i.n. administration. The OVA challenge elicits an eosinophil infiltration into the lungs, with widespread mucus occlusion of the airways, and results in bronchial hyperreactivity. sIL-4R (0.1-100 microgram) was administered by either i.n. or i.p. routes before OVA challenge in OVA-sensitized mice. Both blood and bronchoalveolar lavage fluid levels of sIL-4R were significantly elevated compared with controls by i.n. delivery of 100 microgram sIL-4R; i.p. delivery of 100 microgram sIL-4R only raised blood levels of sIL-4R. The i.n. administration of 100 microgram sIL-4R before allergen challenge significantly reduced late phase pulmonary inflammation, blocking airway eosinophil infiltration, VCAM-1 expression, and mucus hypersecretion. In contrast, i.p. delivery of 100 microgram sIL-4R inhibited only the influx of eosinophils into the lungs, but not airway mucus release. Furthermore, sIL-4R treatment by either i.n. or i.p. routes did not reduce airway hyperreactivity in response to methacholine challenge. Thus, elevating airway levels of sIL-4R through the administration of exogenous sIL-4R is effective in blocking the late phase pulmonary inflammation that occurs in this murine allergen-challenge asthma model. These results suggest that sIL-4R may have beneficial anti-inflammatory effects in asthmatic patients.     

Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26

The inhibition of the caspase-3 enzyme is reported to increase neuronal cell survival following cerebral ischemia. The peptide Z-DEVD-FMK is a specific caspase inhibitor, which significantly reduces vulnerability to the neuronal cell death. However, this molecule is unable to cross the blood-brain barrier (BBB) and to diffuse into the brain tissue. Thus, the development of an effective delivery system is needed to provide sufficient drug concentration into the brain to prevent cell death. Using the avidin (SA)-biotin (BIO) technology, we describe here the design of chitosan (CS) nanospheres conjugated with poly(ethylene glycol) (PEG) bearing the OX26 monoclonal antibody whose affinity for the transferrin receptor (TfR) may trigger receptor-mediated transport across the BBB. These functionalized CS-PEG-BIO-SA/OX26 nanoparticles (NPs) were characterized for their particle size, zeta potential, drug loading capacity, and release properties. Fluorescently labeled CS-PEG-BIO-SA/OX26 nanoparticles were administered systemically to mice in order to evaluate their efficacy for brain translocation. The results showed that an important amount of nanoparticles were located in the brain, outside of the intravascular compartment. These findings, which were also confirmed by electron microscopic examination of the brain tissue indicate that this novel targeted nanoparticulate drug delivery system was able to translocate into the brain tissue after iv administration. Consequently, these novel nanoparticles are promising carriers for the transport of the anticaspase peptide Z-DEVD-FMK into the brain.     

Analgesic and anti-inflammatory activities of a fraction rich in oncocalyxone A isolated from Auxemma oncocalyx.

In the present work we studied the antinociceptive and antiedematogenic effects of a quinone fraction (QF) isolated from the heartwood of Auxemma oncocalyx Taub. The major constituent of QF, which represented around 80% of this fraction, was a terpenoid quinone named oncocalyxone A (1). Results show that QF (10 and 30 mg/kg body wt., i.p.) significantly inhibited paw edema induced by carrageenan at the second, third, and fourth hours. The effect was dose-dependent and long lasting, and QF was less effective orally. An antiedematogenic effect was also demonstrated in the dextran-induced paw edema. In this model, however, QF was somewhat less potent. QF (1 and 5 mg/kg body wt., i.p.) inhibited acetic acid-induced abdominal contractions in mice in a dose-dependent manner. In addition, QF (5 and 10 mg/kg body wt., i.p.) inhibited only the second phase (inflammatory) in the formalin test, and showed no effect in the hot-plate test in mice. The antinociceptive activity of QF was predominantly peripheral and independent of the opioid system. The observed effects of QF are, at least in part, probably due to the presence of oncocalyxone A (1).     

Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin A and B (hypocretin-1 and -2) in mice

Orexins are neuropeptides located exclusively in neurons of the lateral hypothalamic area, which send projections to most monoaminergic nuclei, such as noradrenergic locus coeruleus, dopaminergic ventral tegmental areas, and histaminergic tuberomammillary nuclei. The present work was carried out to examine the role of orexins in nociception in mice. C57BL/6 mice were administered with orexin A and B intracerebroventricularly (i.c.v.), intrathecally (i.t.) and subcutaneously (s.c.) to reveal the sites of action of these peptides and to examine the pain thresholds using four kinds of nociceptive tasks. Orexins showed antinociceptive effects in all four types of assays for thermal (hot-plate, tail-flick, paw-withdrawal), mechanical (tail-pressure), chemical (formalin, capsaicin and abdominal stretch) nociceptions and nociceptin-induced behavioral responses, when administered i.c.v. or i.t., whereas the s.c. administration was ineffective. The antinociceptive effects of orexin A were more remarkable than those of orexin B. The i.c.v. administration of orexin A was as effective as, or more potent than the i.t. administration. The effects of orexin A were completely blocked by adenosine type 1 receptor antagonists, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and theophylline, but not by naloxone, suggesting a possible involvement of the adenosine-containing neurons and/or the adenosine pathway in these orexin actions. The i.c.v. administration of nociceptin had no significant effects on orexin expression in the brain and spinal cord. The present findings suggest that orexins have an antinociceptive role in at least four different types of pains, probably acting on both the brain and spinal cord.     

Antinociceptive, antiedematogenic and antiangiogenic effects of benzaldehyde semicarbazone

Semicarbazones induce an anticonvulsant effect in different experimental models. As some anticonvulsant drugs also have anti-inflammatory activity, the effects of benzaldehyde semicarbazone (BS) on models of nociception, edema and angiogenesis were investigated. BS (10, 25 or 50 mg/kg, i.p.) markedly inhibited the second phase of nociceptive response induced by formaldehyde (0.34%, 20 microl) in mice, but only the highest dose inhibited the first phase of this response. The thermal hyperalgesia and mechanical allodynia induced by carrageenan (1%, 50 microl, i.pl.) in rats were also inhibited by BS (50 mg/kg, i.p.). However, treatment of mice with BS did not induce an antinociceptive effect in the hot-plate model. The paw edema induced by carrageenan (1%, 50 microl, i.pl.) in rats was inhibited by BS (25 or 50 mg/kg, i.p.). Treatment of mice with BS (0.25, 0.5 or 2.5 mg/kg/day, i.p., 7 days) also inhibited angiogenesis induced by subcutaneous implantation of a sponge disc. It is unlikely that the antinociceptive effect induced by BS results from motor incoordination or a muscle relaxing effect, as the mice treated with this drug displayed no behavioral impairment in the rotarod apparatus. In conclusion, we demonstrated that BS presents antinociceptive, antiedematogenic and antiangiogenic activities. An extensive investigation of the pharmacological actions of BS and its derivatives is justified and may lead to the development of new clinically useful drugs.     

载两性霉素B的聚乳酸纳米粒对大鼠血液系统（溶血）及肝肾功能的影响

目的研究携载两性霉素B的聚乳酸纳米粒（AmB-PLA-NP）对大鼠肝、肾及血液系统的影响。方法将大鼠随机分4组,分别经尾静脉注射AmB、AmB-PLA-NP、PLA-NP（聚乳酸纳米粒）及表面活性剂聚山梨酯-80,定时取血检测丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、尿素氮（BUN）、肌酐（Cr）及红细胞（RBC）、血红蛋白（Hb）、白细胞（WBC）、血小板（PLT）等指标。结果AmB组大鼠给药前及给药后1d、1周的RBC分别为（5.84±0.37）×10^12/L、（4.302±0.3）×10^12/L和（3.3±0.37）×10^12/L,AmB-PLA-NP组分别为（6.142±0.55）×10^12/L、（6.38±0.35）×10^12/L和（6.14±0.18）×10^12/L,溶血反应明显降低;AmB组给药后ALT及AST水平显著升高,分别为（1059.2±119.22）μmol/L、（466.6±357.30）μmol/L（给药1d后）和（1755±175.39）μmol/L、（2684.2±494.74）μmol/L（给药1周后）,而AmB-PLA-NP组、PLA组及聚山梨酯-80组的大鼠肝、肾功能未发生明显变化。结论AmB-PLA-NP能够显著降低AmB对肝、肾及血液系统的毒副作用。     

Mechanisms of enhanced antiglioma efficacy of polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles by focused ultrasound

The presence of blood‐brain barrier (BBB) greatly limits the availability of drugs and their efficacy against glioma. Focused ultrasound (FUS) can induce transient and local BBB opening for enhanced drug delivery. Here, we developed polysorbate 80‐modified paclitaxel‐loaded PLGA nanoparticles (PS‐80‐PTX‐NPs, PPNP) and examined the enhanced local delivery into the brain for glioma treatment by combining with FUS. Our result showed PPNP had good stability, fast drug release rate and significant toxicity to glioma cells. Combined with FUS, PPNP showed a stronger BBB permeation efficiency both in the in vitro and in vivo BBB models. Mechanism studies revealed the disrupted tight junction, reduced P‐glycoprotein expression and ApoE‐dependent PS‐80 permeation collectively contribute to the enhanced drug delivery, resulting in significantly stronger antitumour efficacy and longer survival time in the tumour‐bearing mice. Our study provided a new strategy to efficiently and locally deliver drugs into the brain to treat glioma.     

Opiate-like substances mediate norepinephrine-induced but not serotonin-induced antinociception at spinal level: reevaluation by an electrophysiological model of formalin test in rats

After subcutaneous injection of formalin (5%, 50 microl) into a hindpaw of rats, biphasic excitatory nociceptive discharges were recorded extracellularly in thalamic parafascicular neurons. Intrathecal (i.t.) administration of either norepinephrine (NE. 6 nmol, 10 microl) or serotonin (5-HT, 120 nmol, 10 microl) prior to the second phase significantly inhibited the second phase of the formalin-induced parafascicular nociceptive discharges. Intrathecal naloxone (Nal, 50 nmol, 10 microl) did not show any effect on the parafascicular nociceptive discharges. However, when i.t. Nal was given 5 min before NE, Nal prevented the NE antinociceptive effect. Pre-administration of Nal before 5-HT did not affect the antinociceptive effects of 5-HT on the second phase of nociceptive discharges. These results indicate that opiate-like substances are involved in the mediation of NE-induced antinociception. It is suggested that endogenous NE and 5-HT released from brainstem descending terminals at the spinal level carry out their antinociceptive actions differently.