1,721,036 research outputs found
Effect of intracerebroventricular administration of morphine upon intestinal motility in rat and its antagonism with naloxone.
No full textMorphine, intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) administered to rats, inhibited intestinal propulsion as tested by a charcoal meal. Such an inhibition was shown to be linearly related to the log of administered doses for both routes of administration and the two linear regressions are parallel, so that morphine was calculated to be 206 times more potent when administered i.c.v. than i.p. A dose of morphine fully active by the i.c.v. route was completely inactive when injected by the i.v., i.p., i.m. and s.c. routes. Naloxone, administered i.c.v., blocked the antipropulsive effect of morphine i.c.v. or i.p. The pA2 of naloxone versus morphine, both administered i.c.v. was determined and calculated to be 7.14 (6.76-7.62)
Cannabinoids, immune system and cytokine network
No full textHow cannabinoids influence immune function has been examined extensively in the last 30 years. Studies on drug-abusing humans and animals, as well as in vitro models employing immune cell cultures, have shown that marijuana, natural and endogenous cannabinoid compounds are immunomodulators. These substances modulate host resistance to bacterial, protozoan and viral infections as well as they can profoundly affect the Th1/Th2 response. Recently, two types of cannabinoid receptor, CB1 and CB2, have been discovered. While CBI is expressed primarily in the brain, CB2 is peculiar of the immune cells. Cannabinoid receptors have been shown to be involved in some but not all of immune effects. Nevertheless, their identification provides a specific mechanism of action in the attempting to find out how exogenous cannabinoids and endogenous cannabinoid system affect the immune apparatus, strengthen the hypothesis of cannabinoids as immunomodulators. As support to this theory, enough evidence exists to suggest that the cannabinoid system significantly affects almost every component of the immune response machinery and impacts the functioning also of the cytokine network. The evaluation of the biological consequences of these drug-induced cytokine changes has also dramatically become important considering not only the impact of cytokines on immune system per se but also envisaging their influence in cancer, inflammation, autoimmune disease, brain injury, hematopoictic colony formation in which cannabinoids have demonstrated a clear role as important modulators
Regulation of immune functions in rat splenocytes after acute and chronic in vivo treatment with CP-55,940, a synthetic cannabinoid compound
No full textChanges in mitogen-induced splenocyte proliferation and NK activity were evaluated after acute (1 h) and chronic (6 d) in vivo treatment of rats with the synthetic cannabinoid compound CP-55,940. At a dose of 0.4 mg/kg i.p. it significantly inhibited the splenocyte proliferative response to PHA and NK activity but half this dose (0.2 mg/kg) had no effect on immune responses. Pretreatment of rats with the cannabinoid receptor CB1 antagonist SR141716A did not antagonize the CP-55,940-induced immunosuppression, excluding the activation of this receptor subtype in the mediation of this effect. When immune function studies were done on rats tolerant to CP-55,940-induced analgesia, full tolerance also developed for the inhibition of splenocyte proliferation and NK activity. The data provided indicate that CB1 cannabinoid receptors are not involved in mediating the acute and chronic effects of cannabinoids on the immune system and suggest a possible implication of CB2 receptor although other modalities of CP-55,940 action can not be ruled ou
Cerebral sites of central action of dermorphin on intestinal motility in the rat.
No full textDermorphin (DM), microinjected at 0.4 nmoles/rat into various sites of the periaqueductal gray matter (PAG), provokes complete inhibition of intestinal propulsion always coupled with full analgesia and catalepsy. When electrolytic lesions were made in the raphe magnus nucleus (NRM), a slight but significant reduction of intestinal inhibition evoked by DM into the PAG was observed. In contrast, pretreatment into the NRM 10 days before DM with a selective antiserotoninergic agent (5,6 DHT 15 μg/rat), did not influence intestinal inhibition. As expected, both lesions reduced DM-induced analgesia but catalepsy was not affected. DM-induced inhibition of intestinal transit was therefore unaffected by subdiaphragmatic vagotomy. Finally, some other central brain regions were found sensitive to DM for the above effects such as the lateral and medial hypothalamus and mid-line thalamus. Negative results were obtained for the supraoptic nuclei and postero-medial cortical amygdaloid nucleus. Some considerations are put forward about the existence in the central nervous system of selective areas involved in intestinal modulation and their relationship with those mediating other opiate behavioural effects
In vivo characterization of the specific cannabinoid receptor antagonist, SR141716a: behavioral and cellular responses after acute and chronic treatments
No full textTo characterize the behavioral and biochemical effects of the cannabinoid CB1 antagonist SR141716A, we injected the compound intraperitoneally (ip) at doses from 0.625 mg/kg to 5 mg/kg in rats. SR141716A per se induced a dose-dependent increase of some behavioral signs such as wet dog and head shakes, forepaw fluttering, grooming, and facial rubbing. When the highest dose of SR141716A (5 mg/kg ip) was injected once a day for four days, tolerance developed to most of the behavioral signs, although with different time courses, except for grooming behavior, which was still significantly different from controls after the fourth injection although reduced by 38% from the first. To characterize the biochemical mechanism underlying these effects, we designed a series of biochemical studies on specific cerebral areas from rats treated with the highest dose of SR141716A (5 mg/kg ip). Thirty minutes after SR141716A injection, cAMP accumulation in the cortex, striatum, hippocampus, mesencephalon, and cerebellum was the same as in controls, whereas protein kinase A (PKA) activity was significantly increased in the hippocampus (65%) and striatum (87%). To explain this difference, we performed a cAMP assay at an early time (10 min) and found a significant increase in the striatum and hippocampus, suggesting that the change in cAMP level is the earliest event in the G protein-coupled receptor transduction pathway ending in a pharmacological effect after 30 min. When the same assays were done in tolerant animals, no change was seen in either cAMP levels or PKA activity in the brain areas considered. To conclude, we found in vivo that SR141716A acts through activation of the cAMP cascade and our results represent an important point for developing potential therapeutic application for SR141716A
Cannabidiol, a non-psychoactive cannabinoid compound, inhibits human glioma cell migration and invasiveness
No full textMalignant glioma is the most common primary brain tumor, and its high ability to invade the surrounding brain parenchyma is a leading cause of tumor recurrence and treatment failure. We recently demonstrated that the non-psychoactive cannabinoid compound cannabidiol (CBD) can be effective, both in vitro and in vivo, in limiting tumor cell growth and triggering apoptosis in human glioma cells (1) through an oxidative stress-based mechanism and modulation of LOX pathway and endocannabinoid system (2,3). We were also able to provide the first demonstration of CBD-induced inhibition of cell migration in Boyden chamber assay (4). Since tumor cell motility represents a fundamental aspect in tumor invasion, in the present work we were interested in analyzing further the ability of CBD in inhibiting glioma cell migration and invasiveness. Among the various factors involved in the acquisition of increasing levels of malignancy, matrix metalloproteinases (MMPs) are a group of enzymes that play a pivotal role in promoting tissue breakdown and remodelling during angiogenesis and invasiveness through degradation of extracellular matrix components.
Therefore, since MMP-2 is one of the most important MMPs in the spreading of glioma, we investigated the influence of CBD on MMP-2 production and activity. We found that U87 glioma cells exposed in vitro for 24 h to different concentrations of CBD showed a significant inhibition of MMP-2 release in the supernatants of cell cultures, as evaluated by ELISA assay. CBD was also able to alter the MMP-2 gelatinolitic activity, as detected by gelatine zymography analysis. Moreover, using a scratch wound healing assay, we found that the in vitro exposure to CBD for 16 and 24 h, induced a significant inhibition in the rate of glioma cells invasion into the artificial wounded areas. The exposure of U87 cells to CBD also down-regulated signalling pathways critical for cell survival, proliferation and angiogenesis as Akt , ERK and the hypoxia-inducible factor HIF1-.
In conclusion, the present investigation adds further insights into the antitumoral action of the non psychoactive CBD, showing multiple mechanisms through which the cannabinoid inhibits glioma cells growth/invasiveness. Considering that CBD is a natural compound without psychotropic and side effects, these data lead us to consider CBD to have high potential as a new anticancer drug alone or in combinatory therapy
Effect on intestinal transit of neurotensin administered intracerebroventricularly to rats
No full textNeurotensin (NT) administered intracerebroventricularly (i.c.v.) to rats, blocks intestinal transit (tested by charcoal meal) in linear relation to the log of the doses within the range of 0.6-2.5 nmoles/rat. NT in this test is about 40 times more active than morphine (M) and 6 times less active than dermorphin (DM) on a molar basis. Within this dose range NT does not induce analgesia (tail-flick test) or hypothermia (tested at 22 degrees C). The intestinal effect can also be elicited by injecting the peptide into the periaqueductal gray matter (PAG). NT injected intraperitoneally (i.p.) is inactive up to doses 4 times the maximal active i.c.v. dose. Naloxone (Nx) and dynorphin 1-13 could not antagonize the intestinal effect of i.c.v. NT. The relationship between this central intestinal effect and many other central effects of NT is discussed
Cannabinoids as potential new therapy for the treatment of gliomas.
No full textGliomas constitute the most frequent and malignant primary brain tumors. Current standard therapeutic strategies (surgery, radiotherapy and chemotherapeutics, e.g., temozolomide, carmustin or carboplatin) for their treatment are only palliative and survival diagnosis is normally 6-12 months. The development of new therapeutic strategies for the management of gliomas is therefore essential. Interestingly, cannabinoids have been shown to exert antiproliferative effects on a wide spectrum of cells in culture. Of interest, cannabinoids have displayed a great potency in reducing glioma tumor growth either in vitro or in animal experimental models, curbing the growth of xenografts generated by subcutaneous or intratecal injection of glioma cells in immune-deficient mice. Moreover, cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of nontransformed counterparts. A pilot clinical trial on patients with glioblastoma multiforme demonstrated their good safety profile together and remarkable antitumor effects, and may set the basis for further studies aimed at better evaluating the potential anticancer activity of cannabinoids
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