Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of ...Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of the most common deleterious diabetic complications,being the leading cause of mortality among diabetic patients.The mechanisms of diabetic cardiomyopathy are multi-factorial,involving increased oxidative stress,accumulation of advanced glycation end products(AGEs),activation of various pro-inflammatory and cell death signaling pathways,and changes in the composition of extracellular matrix with enhanced cardiac fibrosis.The novel lipid signaling system,the endocannabinoid system,has been implicated in the pathogenesis of diabetes and its complications through its two main receptors:Cannabinoid receptor type 1 and cannabinoid receptor type 2,alongside other components.However,the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated.This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy.These mechanisms include oxidative/nitrative stress,inflammation,accumulation of AGEs,cardiac remodeling,and autophagy.A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.展开更多
One of the most important causes of brain injury in the neonatal period is a perinatal hypoxicischemic event.This devastating condition can lead to long-term neurological deficits or even death.After hypoxic-ischemic ...One of the most important causes of brain injury in the neonatal period is a perinatal hypoxicischemic event.This devastating condition can lead to long-term neurological deficits or even death.After hypoxic-ischemic brain injury,a variety of specific cellular mechanisms are set in motion,triggering cell damage and finally producing cell death.Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury.After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury,various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes.Among them,the endocannabinoid system emerges as a natural system of neuroprotection.The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury,acting as a natural neuroprotectant.The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury,and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.展开更多
Neurodegenerative diseases are characterized by progressive degeneration and/or death of neuronal cells and results in a wide array of cognitive impairments and other serious neurological defects. The signaling pathwa...Neurodegenerative diseases are characterized by progressive degeneration and/or death of neuronal cells and results in a wide array of cognitive impairments and other serious neurological defects. The signaling pathways and definite cause underlying the development of neurodegenerative nerve diseases have not been well defined. There is evidence of mechanisms within the endocannabinoid system that may suggest important pathways involved the progression of neurodegenerative diseases as well as some cancers. The endocannabinoid system is an endogenous ubiquitous neuromodulatory system that plays a critical in the development of the central nervous system (CNS), synaptic plasticity, as well as other primary neuronal functions. The recent identification of various cannabinoid receptors and their endogenous lipid ligands has generated an interest and significant increase in research of the endocannabinoid system and its role in human health and diseases. The Endocannabinoid system possesses essential endogenous receptors—cannabinoid receptors type 1 (CB1R) and type 2 (CB2R)—which are involved in mechanisms that contribute to the progression of neurodegenerative diseases and some cancers. In this review, we discuss the role of the endocannabinoid system in various neurodegenerative diseases as well as some cancers, and its promise as a targeted pharmacological therapy for patients of neurodegenerative diseases.展开更多
Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body.They have been studied in cellular and animal models as well as in human clinical trials for th...Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body.They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.Some of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric disorders.In addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS diseases.This review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies.In addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.展开更多
Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor(CB1R)could affect novel object recognition(NOR)memory in chronically rapid eye movement sleep-deprived(RSD)rats.Methods The animals ...Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor(CB1R)could affect novel object recognition(NOR)memory in chronically rapid eye movement sleep-deprived(RSD)rats.Methods The animals were examined for recognition memory following a 7-day chronic partial RSD paradigm using the multiple platform technique.The CB1R antagonist rimonabant(1 or 3 mg/kg,i.p.)was administered either at one hour prior to the sample phase for acquisition,or immediately after the sample phase for consolidation,or at one hour before the test phase for retrieval of NOR memory.For the reconsolidation task,rimonabant was administered immediately after the second sample phase.Results The RSD episode impaired acquisition,consolidation,and retrieval,but it did not affect the reconsolidation of NOR memory.Rimonabant administration did not affect acquisition,consolidation,and reconsolidation;however,it attenuated impairment of the retrieval of NOR memory induced by chronic RSD.Conclusions These findings,along with our previous report,would seem to suggest that RSD may affect different phases of recognition memory based on its duration.Importantly,it seems that the CB1R may,at least in part,be involved in the adverse effects of chronic RSD on the retrieval,but not in the acquisition,consolidation,and reconsolidation,of NOR memory.展开更多
Cannabis sativa L. is used as fiber, food, and medicine in several countries. Though it is illegal for recreational use in most of the world, there are some countries that have legalized production and sale. There is ...Cannabis sativa L. is used as fiber, food, and medicine in several countries. Though it is illegal for recreational use in most of the world, there are some countries that have legalized production and sale. There is a lot of research on production of cannabis, but less so on storage technologies. Cannabis contains several high value compounds, such as cannabinoids and terpenoids, that are susceptible to degradation via light, temperature, and oxygen. Several studies have explored temperature and light, and industry has adjusted accordingly. However, less is known about oxygen-induced degradation. Biochemical studies have demonstrated oxidative degradation of high value compounds, and many producers use some form of modified atmospheric packaging (MAP) for storage. However, the efficacy of MAP is unclear. The objective of this paper is to review our current understanding of MAP in postharvest cannabis storage and identify avenues where additional research is needed.展开更多
AIM To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid(CB) receptors, WIN55-212-2(WIN55), in mice with experimental colitis, so as to supply experimental evidence for ...AIM To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid(CB) receptors, WIN55-212-2(WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future. METHODS We established the colitis model in C57BL/6 mice by replacing the animals' water supply with 4% dextran sulfate sodium(DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha(TNF-α) and interleukin-6(IL-6), and the myeloperoxidase(MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase(p38MAPK) and its phosphorylated form(p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580(SB), an inhibitor of p38, was investigated in parallel experiments, andthe data were compared with those from intervention groups of WIN55 and SB alone or used together. RESULTS The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38 MAPK was inhibited. CONCLUSION These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38 MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38 MAPK signaling pathway and the endogenous CB system.展开更多
In the present work,dispersive liquid-liquid microextraction(DLLME)was used to extract six synthetic cannabinoids(JWH-018,JWH-019,JWH-073,JWH-200,or WIN 55,225,JWH-250,and AM-694)from oral fluids.A rapid baseline sepa...In the present work,dispersive liquid-liquid microextraction(DLLME)was used to extract six synthetic cannabinoids(JWH-018,JWH-019,JWH-073,JWH-200,or WIN 55,225,JWH-250,and AM-694)from oral fluids.A rapid baseline separation of the analytes was achieved on a bidentate octadecyl silica hydride phase(Cogent Bidentate C18;4.6 mm×250 mm,4μm)maintained at 37℃,by eluting in isocratic conditions(water:acetonitrile(25:75,V/V)).Detection was performed using positive electrospray ionization-tandem mass spectrometry.The parameters affecting DLLME(pH and ionic strength of the aqueous phase,type and volume of the extractant and dispersive solvent,vortex and centrifugation time)were optimized for maximizing yields.In particular,using 0.5 mL of oral fluid,acetonitrile(1 mL),was identified as the best option,both as a solvent to precipitate proteins and as a dispersing solvent in the DLLME procedure.To select an extraction solvent,a low transition temperature mixture(LTTM;composed of sesamol and chlorine chloride with a molar ratio of 1:3)and dichloromethane were compared;the latter(100μL)was proved to be a better extractant,with recoveries ranging from 73%to 101%by vortexing for 2 min.The method was validated according to the guidelines of Food and Drug Administration bioanalytical methods:intra-day and inter-day precisions ranged between 4%and 18%depending on the spike level and analyte;limits of detection spanned from 2 to 18 ng/mL;matrixmatched calibration curves were characterized by determination coefficients greater than 0.9914.Finally,the extraction procedure was compared with previous methods and with innovative techniques,presenting superior reliability,rapidity,simplicity,inexpensiveness,and efficiency.展开更多
Synthetic cannabinoids have become a common drug of abuse in recent years and their toxicities have come to light as well. They are known to be notorious for the kidneys, with acute tubular necrosis, acute interstitia...Synthetic cannabinoids have become a common drug of abuse in recent years and their toxicities have come to light as well. They are known to be notorious for the kidneys, with acute tubular necrosis, acute interstitial nephritis and rhabdomyolysis induced renal injury being the frequent nephrotoxic outcomes in users. We report a case of bilateral renal cortical necrosis, leading to irreversible renal damage and lifelong dialysis dependency.展开更多
AIM To determine whether Nucb2/nesfatin1 production is regulated by the cannabinoid system through the intracellular m TOR pathway in the stomach.METHODS Sprague Dawley rats were treated with vehicle, rimonabant, rapa...AIM To determine whether Nucb2/nesfatin1 production is regulated by the cannabinoid system through the intracellular m TOR pathway in the stomach.METHODS Sprague Dawley rats were treated with vehicle, rimonabant, rapamycin or rapamycin+rimonabant. Gastric tissue obtained from the animals was used for biochemical assays: Nucb2 m RNA measurement by real time PCR, gastric Nucb2/nesfatin protein content by western blot, and gastric explants to obtain gastric secretomes. Nucb2/nesfatin levels were measured in gastric secretomes and plasma using enzyme-linked immunosorbent assay. RESULTS The inhibition of cannabinoid receptor 1(CB1) by the peripheral injection of an inverse agonist, namely rimonabant, decreases food intake and increases the gastric secretion and circulating levels of Nucb2/nesfatin-1. In addition, rimonabant treatment activates m TOR pathway in the stomach as showed by the increase in pm TOR/m TOR expression in gastric tissue obtained from rimonabant treated animals. These effects were confirmed by the use of a CB1 antagonist, AM281. When the intracellular pathway m TOR/S6 k was inactivated by chronic treatment with rapamycin, rimonabant treatment was no longer able to stimulate the gastric secretion of Nucb2/nesfatin-1.CONCLUSION The peripheral cannabinoid system regulates food intake through a mechanism that implies gastric production and release of Nucb2/Nesfatin-1, which is mediated by the m TOR/S6 k pathway.展开更多
Synthetic cannabinoids are a group of substances in the world of designer drugs that have become increasingly popular over the past few years. Synthetic cannabinoids are a chemically diverse group of compounds functio...Synthetic cannabinoids are a group of substances in the world of designer drugs that have become increasingly popular over the past few years. Synthetic cannabinoids are a chemically diverse group of compounds functionally similar to THC. Since first appearing on the world market a few years ago these compounds have evolved rapidly. Newer more potent analogues have been developed. Identifying youth who abuse these substances can be difficult. Newer forms of consumption have also evolved. These products are now manufactured in products that look like natural cannabis resin and in liquid cartridges used in electronic cigarettes. Synthetic cannabinoids appear to be associated with potentially dangerous health effects that are more severe than that of marijuana. Some synthetic cannabinoid compounds have been associated with serious physical consequences, such as, seizures, myocardial infarction and renal damage. In addition, psychoactive effects, such as aggression, confusion, anxiety and psychosis have also been reported. The diagnosis remains primarily clinical with toxicological confirmation difficult due to manufacturers constantly developing new analogues to avoid detection. Pediatricians are urged to familiarize themselves with these drugs and the typical presentations of patients who use them.展开更多
Tetrahydrocannabinol (THC) derivatives are used clinically as analgesic, anti-inflammatory, appetite stimulant, anti-emetic and anti-tumor cannabinoids. THC and its related compounds are at present obtained by extract...Tetrahydrocannabinol (THC) derivatives are used clinically as analgesic, anti-inflammatory, appetite stimulant, anti-emetic and anti-tumor cannabinoids. THC and its related compounds are at present obtained by extraction from intact Cannabis plants or chemical synthesis, but plant cell cultures may be an alternative source of production. In the present study, hairy root cultures of C. sativa (Cannabaceae) were induced by incubation of aseptically grown callus culture with solid B5 medium supplemented with 4 mg/l naphthaleneacetic acid in darkness at 25°C. Hairy root growth profiles in shake flask, increased periodically during 35 days of growth cycle. The cannabinoid contents produced in minor levels and remained below 2.0 μg/g dry weight. The contents of can-nabinoid were analyzed by liquid chromatography and confirmed by mass spectrometry.展开更多
The in vitro study of tetracannabinolic acid(THCA)derivatives ALAM027 and ALAM108 was carried out on the following human tumor cells:T47D(breast,ductal carcinoma),PC-3(prostate,adenocarcinoma),HT 29(colorectal carcino...The in vitro study of tetracannabinolic acid(THCA)derivatives ALAM027 and ALAM108 was carried out on the following human tumor cells:T47D(breast,ductal carcinoma),PC-3(prostate,adenocarcinoma),HT 29(colorectal carcinoma),Caco-2(colon,adenocarcinoma),A549(lung,carcinoma),U87MG(human glioblastoma)and U266B1(multiple myeloma).The in vitro effects of THCA derivatives ALAM027 and ALAM108 on cell growth inhibition and IC50 values were measured using the CellTiter Glo assay.The ALAM027 compound showed good growth inhibition in all cell lines tested with the exception of U87MG cells.The ALAM108 compound also suppressed the growth of U87 MG cells but had little effect on T47D tumor cells.In vitro studies of THCA derivatives ALAM027 and ALAM108 showed antitumor activity in all cell lines tested.The difference in the activity of these compounds in relation to the T47D and U87MG tumor cells may be indicative of different functional mechanisms.展开更多
Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain,as well as and the involvement of the cannabinoid receptors type 2(CB2)and spinal microglia in this process.Methods:Male Swiss mice...Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain,as well as and the involvement of the cannabinoid receptors type 2(CB2)and spinal microglia in this process.Methods:Male Swiss mice were subjected to inflammatory pain induced by intraplantar injection of carrageenan.The nociceptive threshold was measured by von Frey filaments test.Tingenone was administered orally 60 min before carrageenan injection.To evaluate the involvement of CB2 receptor,endocannabinoids,and microglia,AM630(a CB2 receptor antagonist),MAFP(an inhibitor of an enzyme that hydrolyses endocannabinoids),and minocycline(a microglial inhibitor)were given intrathecally 20 min before tingenone administration.In addition,an immunofluorescence assay was used to evaluate CB2 receptor and CD11 B(a microglial marker)expression in the spinal cord dorsal horn.Results:Tingenone significantly reduced carrageenan-induced hyperalgesia,which was reversed by pretreatment with AM630.MAFP and minocycline potentiated and prolonged the tingenoneinduced antinociception.CD11 B expression was increased in the spinal cord dorsal horn of mice with inflammatory pain pretreated with tingenone,which was reduced by AM630,MAFP,and minocycline.Conclusions:CB2 receptors and endocannabinoids participate in the tingenone-induced antinociception which may involve the inhibition of microglia at spinal level.展开更多
Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports....Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e.,≥95°C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors.展开更多
OBJECTIVE Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this...OBJECTIVE Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature,and appears to be a novel compound developed specifically as a "graymarket" drug of abuse bystructurally combining the known synthetic cannabinoids JWH-122 and AM-2201.There is currently no published information regarding the pharmacology of MAM-2201.METHODS The present studies characterized cannabinoid-like effects of MAM-2201 in vitro(interactions with cannabinoid type 1 receptors[CB1 Rs]) and in vivo(in mice and rats).RESULTS In a radioligand binding assay using [3 H]CP55,940 in HEK cell membranes transfected with the CB1 R,MAM-2201(K i=5.4 nmol·L^(-1)),had higher binding affinity than WIN 55,212-2(K i=80 nmol·L^(-1)),and D9-THC(K i=8.3 nmol·L^(-1)).The E max values for MAM-2201 and WIN 55,212-2 in an assay of agonist inhibition of forskolin-stimulated c AMP were 85%(EC50=0.45 nmol·L^(-1)) and 95%,respectively,as compared with the D9-THC E max of 74%.In mice,MAM-2201(0.003-1.0 mg·kg^(-1),IP) produced dose-dependent cannabimimetic effects which were both more potent and more effective than those of D9-THC.MAM-2201 and D9-THC dose-dependently produced hypothermia:ED50=0.287 and 25.4 mg·kg^(-1),analgesia:ED50=0.125 and 29.4 mg·kg^(-1),and catalepsy:ED50=0.301 and18.9 mg·kg^(-1) in adult male CD1 mice.Importantly,MAM-2201 also elicited convulsant effects at a dose of 1.0 mg·kg^(-1) in 8/8 murine subjects.In rats,MAM-2201 produced dose-dependent D9-THC-like interoceptive effects in subjects trained to discriminate 3.0 mg·kg^(-1)(IP) D9-THC from saline.CONCLUSION MAM-2201 binds CB1 Rs with high affinity and agonist efficacy,and functions as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species.展开更多
Long-term cannabis use may be associated with attacks of severe nausea and vomiting, and a characteristic learned behavior of compulsive hot bathing, termed cannabinoid hyperemesis syndrome(CHS). Long-term follow-up a...Long-term cannabis use may be associated with attacks of severe nausea and vomiting, and a characteristic learned behavior of compulsive hot bathing, termed cannabinoid hyperemesis syndrome(CHS). Long-term follow-up and prognosis of CHS have not been reported previously. A 44-year-old Caucasian man with a long history of addiction to marijuana presented with chronic abdominal pain complicated by attacks of uncontrollable vomiting for 16 years. He had a compulsion to take scalding hot showers, as many as 15 times a day, to relieve his symptoms. All previous therapies had been ineffective. However, abstinence from marijuana led to rapid and complete resolution of all symptoms and his compulsive hot showering behavior. He has been followed for nine years, and is still doing well without recurrence of symptoms. Physicians should have a high index of suspicion for this under-recognized condition, as excellent long-term prognosis of CHS can be achieved when abstinence is maintained.展开更多
Cannabinoid and nicotinic acetylcholine receptors are strongly associated with algesia. Previous studies in our laboratory have reported inhibitory effects of synthetic cannabinoid WIN55, 212-2 on nicotine-activated c...Cannabinoid and nicotinic acetylcholine receptors are strongly associated with algesia. Previous studies in our laboratory have reported inhibitory effects of synthetic cannabinoid WIN55, 212-2 on nicotine-activated currents (Inic), but the underlying mechanisms remain poorly understood. The present study used whole-cell patch clamp techniques to investigate the modulatory effects of synthetic cannabinoid WIN55, 212-2 on Inic in cultured rat trigeminal ganglion neurons. The results revealed several major findings: WIN55, 212-2 inhibited Inic in rat trigeminal ganglion neurons. In addition, when WIN55, 212-2 (3 μmol/L) was applied simultaneously with nicotine (100 μmol/L), the inhibition of WIN55, 212-2 on Inic was reversible, concentration-dependent and voltage-independent This effect was not mediated by CB1, CB2 or VR1 receptors; neither the selective CB1 receptor antagonist AM281, CB2 receptor antagonist AM630 nor VR1 receptor antagonist capsazepine reduced the inhibitory effect of WIN55, 212-2. Further, the inhibition of nicotinic responses by WIN55, 212-2 was not sensitive to the membrane permeable cyclic adenosine monophosphate (cAMP) analog 8-Br-cAMP. The G-protein inhibitor GDP-I3-S (1 mmol/L) did not block the inhibitory effects of WIN55, 212-2 on/n^c, excluding the involvement of G-protein mediation. The results suggested that WIN55, 212-2 inhibits/n^o directly via the neuronal nicotinic acetylcholine receptor, and that this inhibition is non-competitive. WIN55, 212-2 did not act as an open channel blocker of the neuronal nicotinic acetylcholine receptor, and did not affect the desensitization of Into. The results suggest that nicotine receptors may be physically plugged from outside the membrane by drugs containing WIN55, 212-2.展开更多
This study examined endogenous carmabinoid (ECB)-anandamide (AEA) and its cannabinoid receptors (CBR) in mice liver with the development ofschistosomajaponicum. Mice were infected with schistosoma by means of pa...This study examined endogenous carmabinoid (ECB)-anandamide (AEA) and its cannabinoid receptors (CBR) in mice liver with the development ofschistosomajaponicum. Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens. Liver fibrosis was pathologically confirmed nine weeks after the infection. High performance liquid chromatography (HPLC) was employed to determine the concentration of AEA in the plasma of mice. Immunofluo-rescence was used to detect the expression of CBR1 and CBR2 in liver tissue. Morphological examination showed typical pathological changes, with worm tubercles of schistosoma deposited in the liver tissue, fibrosis around the worm tubercles and infiltration or soakage of inflammatory cells. Also, CBR1 and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups, but they were obviously enhanced in the schistosoma-infected mice. However, the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78, and CBR2 were 28.13±6.42 and 52.29±4.24 (P〈0.05). The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group. The concentrations of AEA were (0.37±0.07) and (5.67±1.34) ng/mL (P〈0.05). It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice. Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.展开更多
文摘Diabetic complications,chiefly seen in long-term situations,are persistently deleterious to a large extent,requiring multi-factorial risk reduction strategies beyond glycemic control.Diabetic cardiomyopathy is one of the most common deleterious diabetic complications,being the leading cause of mortality among diabetic patients.The mechanisms of diabetic cardiomyopathy are multi-factorial,involving increased oxidative stress,accumulation of advanced glycation end products(AGEs),activation of various pro-inflammatory and cell death signaling pathways,and changes in the composition of extracellular matrix with enhanced cardiac fibrosis.The novel lipid signaling system,the endocannabinoid system,has been implicated in the pathogenesis of diabetes and its complications through its two main receptors:Cannabinoid receptor type 1 and cannabinoid receptor type 2,alongside other components.However,the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated.This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy.These mechanisms include oxidative/nitrative stress,inflammation,accumulation of AGEs,cardiac remodeling,and autophagy.A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
基金supported by grants from Funding Health Care of Spanish Ministry of Health,No. PS09/ 02326from the Basque Government,No. GCI-07/79,IT-287-07
文摘One of the most important causes of brain injury in the neonatal period is a perinatal hypoxicischemic event.This devastating condition can lead to long-term neurological deficits or even death.After hypoxic-ischemic brain injury,a variety of specific cellular mechanisms are set in motion,triggering cell damage and finally producing cell death.Effective therapeutic treatments against this phenomenon are still unavailable because of complex molecular mechanisms underlying hypoxic-ischemic brain injury.After a thorough understanding of the mechanism underlying neural plasticity following hypoxic-ischemic brain injury,various neuroprotective therapies have been developed for alleviating brain injury and improving long-term outcomes.Among them,the endocannabinoid system emerges as a natural system of neuroprotection.The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury,acting as a natural neuroprotectant.The aim of this review is to study the use of different therapies to induce long-term therapeutic effects after hypoxic-ischemic brain injury,and analyze the important role of the endocannabinoid system as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.
文摘Neurodegenerative diseases are characterized by progressive degeneration and/or death of neuronal cells and results in a wide array of cognitive impairments and other serious neurological defects. The signaling pathways and definite cause underlying the development of neurodegenerative nerve diseases have not been well defined. There is evidence of mechanisms within the endocannabinoid system that may suggest important pathways involved the progression of neurodegenerative diseases as well as some cancers. The endocannabinoid system is an endogenous ubiquitous neuromodulatory system that plays a critical in the development of the central nervous system (CNS), synaptic plasticity, as well as other primary neuronal functions. The recent identification of various cannabinoid receptors and their endogenous lipid ligands has generated an interest and significant increase in research of the endocannabinoid system and its role in human health and diseases. The Endocannabinoid system possesses essential endogenous receptors—cannabinoid receptors type 1 (CB1R) and type 2 (CB2R)—which are involved in mechanisms that contribute to the progression of neurodegenerative diseases and some cancers. In this review, we discuss the role of the endocannabinoid system in various neurodegenerative diseases as well as some cancers, and its promise as a targeted pharmacological therapy for patients of neurodegenerative diseases.
基金supported in part by grants from the National Institute on Aging and National Eye Institute[EY030747(3R01EY030747-02S2)and EY031248(3R01EY03124802S1)]of the National Institutes of Health(to PK)Additional support by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Researchthe Vision Research Foundation of Kansas City。
文摘Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body.They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.Some of these include central nervous system(CNS)diseases and dysfunctions such as forms of epilepsy,multiple sclerosis,Parkinson’s disease,pain and neuropsychiatric disorders.In addition,the endogenously produced cannabinoid lipids,endocannabinoids,are critical for normal CNS function,and if controlled or modified,may represent an additional therapeutic avenue for CNS diseases.This review discusses in vitro cellular,ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies.In addition,the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.
基金Supported by the Research Council of Kermanshah University of Medical Sciences,Kermanshah,Iran for financial support(grant no.:990812).
文摘Objective We aimed to investigate whether antagonism of the cannabinoid CB1 receptor(CB1R)could affect novel object recognition(NOR)memory in chronically rapid eye movement sleep-deprived(RSD)rats.Methods The animals were examined for recognition memory following a 7-day chronic partial RSD paradigm using the multiple platform technique.The CB1R antagonist rimonabant(1 or 3 mg/kg,i.p.)was administered either at one hour prior to the sample phase for acquisition,or immediately after the sample phase for consolidation,or at one hour before the test phase for retrieval of NOR memory.For the reconsolidation task,rimonabant was administered immediately after the second sample phase.Results The RSD episode impaired acquisition,consolidation,and retrieval,but it did not affect the reconsolidation of NOR memory.Rimonabant administration did not affect acquisition,consolidation,and reconsolidation;however,it attenuated impairment of the retrieval of NOR memory induced by chronic RSD.Conclusions These findings,along with our previous report,would seem to suggest that RSD may affect different phases of recognition memory based on its duration.Importantly,it seems that the CB1R may,at least in part,be involved in the adverse effects of chronic RSD on the retrieval,but not in the acquisition,consolidation,and reconsolidation,of NOR memory.
文摘Cannabis sativa L. is used as fiber, food, and medicine in several countries. Though it is illegal for recreational use in most of the world, there are some countries that have legalized production and sale. There is a lot of research on production of cannabis, but less so on storage technologies. Cannabis contains several high value compounds, such as cannabinoids and terpenoids, that are susceptible to degradation via light, temperature, and oxygen. Several studies have explored temperature and light, and industry has adjusted accordingly. However, less is known about oxygen-induced degradation. Biochemical studies have demonstrated oxidative degradation of high value compounds, and many producers use some form of modified atmospheric packaging (MAP) for storage. However, the efficacy of MAP is unclear. The objective of this paper is to review our current understanding of MAP in postharvest cannabis storage and identify avenues where additional research is needed.
基金Supported by the National Natural Science Foundation of China,No.81400581(to Feng YJ) and No.81270477(to Li YY)
文摘AIM To investigate the anti-inflammatory effect and the possible mechanisms of an agonist of cannabinoid(CB) receptors, WIN55-212-2(WIN55), in mice with experimental colitis, so as to supply experimental evidence for its clinical use in future. METHODS We established the colitis model in C57BL/6 mice by replacing the animals' water supply with 4% dextran sulfate sodium(DSS) for 7 consecutive days. A colitis scoring system was used to evaluate the severity of colon local lesion. The plasma levels of proinflammatory cytokines, such as tumor necrosis factor-alpha(TNF-α) and interleukin-6(IL-6), and the myeloperoxidase(MPO) activity in colon tissue were measured. The expressions of cannabinoid receptors, claudin-1 protein, p38 mitogen-activated protein kinase(p38MAPK) and its phosphorylated form(p-p38) in colon tissue were determined by immunohistochemistry and Western blot. In addition, the effect of SB203580(SB), an inhibitor of p38, was investigated in parallel experiments, andthe data were compared with those from intervention groups of WIN55 and SB alone or used together. RESULTS The results demonstrated that WIN55 or SB treatment alone or together improved the pathological changes in mice with DSS colitis, decreased the plasma levels of TNF-α, and IL-6, and MPO activity in colon. The enhanced expression of claudin-1 and the inhibited expression of p-p38 in colon tissues were found in the WIN55-treated group. Besides, the expression of CB1 and CB2 receptors was enhanced in the colon after the induction of DSS colitis, but reduced when p38 MAPK was inhibited. CONCLUSION These results confirmed the anti-inflammatory effect and protective role of WIN55 on the mice with experimental colitis, and revealed that this agent exercises its action at least partially by inhibiting p38 MAPK. Furthermore, the results showed that SB203580, affected the expression of CB1 and CB2 receptors in the mouse colon, suggesting a close linkage and cross-talk between the p38 MAPK signaling pathway and the endogenous CB system.
基金supported by the Sapienza University of Rome through the project RICERCA 2019(protocol number:RG11916B6451D44A)。
文摘In the present work,dispersive liquid-liquid microextraction(DLLME)was used to extract six synthetic cannabinoids(JWH-018,JWH-019,JWH-073,JWH-200,or WIN 55,225,JWH-250,and AM-694)from oral fluids.A rapid baseline separation of the analytes was achieved on a bidentate octadecyl silica hydride phase(Cogent Bidentate C18;4.6 mm×250 mm,4μm)maintained at 37℃,by eluting in isocratic conditions(water:acetonitrile(25:75,V/V)).Detection was performed using positive electrospray ionization-tandem mass spectrometry.The parameters affecting DLLME(pH and ionic strength of the aqueous phase,type and volume of the extractant and dispersive solvent,vortex and centrifugation time)were optimized for maximizing yields.In particular,using 0.5 mL of oral fluid,acetonitrile(1 mL),was identified as the best option,both as a solvent to precipitate proteins and as a dispersing solvent in the DLLME procedure.To select an extraction solvent,a low transition temperature mixture(LTTM;composed of sesamol and chlorine chloride with a molar ratio of 1:3)and dichloromethane were compared;the latter(100μL)was proved to be a better extractant,with recoveries ranging from 73%to 101%by vortexing for 2 min.The method was validated according to the guidelines of Food and Drug Administration bioanalytical methods:intra-day and inter-day precisions ranged between 4%and 18%depending on the spike level and analyte;limits of detection spanned from 2 to 18 ng/mL;matrixmatched calibration curves were characterized by determination coefficients greater than 0.9914.Finally,the extraction procedure was compared with previous methods and with innovative techniques,presenting superior reliability,rapidity,simplicity,inexpensiveness,and efficiency.
基金Supported by Internal Medicine Department,Joan C Edwards School of Medicine,Marshall University
文摘Synthetic cannabinoids have become a common drug of abuse in recent years and their toxicities have come to light as well. They are known to be notorious for the kidneys, with acute tubular necrosis, acute interstitial nephritis and rhabdomyolysis induced renal injury being the frequent nephrotoxic outcomes in users. We report a case of bilateral renal cortical necrosis, leading to irreversible renal damage and lifelong dialysis dependency.
基金Supported by Instituto de Salud Carlos III,No.PI15/01272 cofounded by FEDERFondo de Investigaciones Sanitarias(LS:I3SNS-SERGAS/ISCIII)Centro de Investigacion Biomedica en Red Fisiopatología de la Obesidad y Nutrición(CIBERobn)is a iniciative of the Instituto de Salud Carlos III(ISCIII)of Spain which is supported by FEDER funds
文摘AIM To determine whether Nucb2/nesfatin1 production is regulated by the cannabinoid system through the intracellular m TOR pathway in the stomach.METHODS Sprague Dawley rats were treated with vehicle, rimonabant, rapamycin or rapamycin+rimonabant. Gastric tissue obtained from the animals was used for biochemical assays: Nucb2 m RNA measurement by real time PCR, gastric Nucb2/nesfatin protein content by western blot, and gastric explants to obtain gastric secretomes. Nucb2/nesfatin levels were measured in gastric secretomes and plasma using enzyme-linked immunosorbent assay. RESULTS The inhibition of cannabinoid receptor 1(CB1) by the peripheral injection of an inverse agonist, namely rimonabant, decreases food intake and increases the gastric secretion and circulating levels of Nucb2/nesfatin-1. In addition, rimonabant treatment activates m TOR pathway in the stomach as showed by the increase in pm TOR/m TOR expression in gastric tissue obtained from rimonabant treated animals. These effects were confirmed by the use of a CB1 antagonist, AM281. When the intracellular pathway m TOR/S6 k was inactivated by chronic treatment with rapamycin, rimonabant treatment was no longer able to stimulate the gastric secretion of Nucb2/nesfatin-1.CONCLUSION The peripheral cannabinoid system regulates food intake through a mechanism that implies gastric production and release of Nucb2/Nesfatin-1, which is mediated by the m TOR/S6 k pathway.
文摘Synthetic cannabinoids are a group of substances in the world of designer drugs that have become increasingly popular over the past few years. Synthetic cannabinoids are a chemically diverse group of compounds functionally similar to THC. Since first appearing on the world market a few years ago these compounds have evolved rapidly. Newer more potent analogues have been developed. Identifying youth who abuse these substances can be difficult. Newer forms of consumption have also evolved. These products are now manufactured in products that look like natural cannabis resin and in liquid cartridges used in electronic cigarettes. Synthetic cannabinoids appear to be associated with potentially dangerous health effects that are more severe than that of marijuana. Some synthetic cannabinoid compounds have been associated with serious physical consequences, such as, seizures, myocardial infarction and renal damage. In addition, psychoactive effects, such as aggression, confusion, anxiety and psychosis have also been reported. The diagnosis remains primarily clinical with toxicological confirmation difficult due to manufacturers constantly developing new analogues to avoid detection. Pediatricians are urged to familiarize themselves with these drugs and the typical presentations of patients who use them.
文摘Tetrahydrocannabinol (THC) derivatives are used clinically as analgesic, anti-inflammatory, appetite stimulant, anti-emetic and anti-tumor cannabinoids. THC and its related compounds are at present obtained by extraction from intact Cannabis plants or chemical synthesis, but plant cell cultures may be an alternative source of production. In the present study, hairy root cultures of C. sativa (Cannabaceae) were induced by incubation of aseptically grown callus culture with solid B5 medium supplemented with 4 mg/l naphthaleneacetic acid in darkness at 25°C. Hairy root growth profiles in shake flask, increased periodically during 35 days of growth cycle. The cannabinoid contents produced in minor levels and remained below 2.0 μg/g dry weight. The contents of can-nabinoid were analyzed by liquid chromatography and confirmed by mass spectrometry.
基金This work was funded from the AL&AM Pharmachem Ltd.company's own funds.(Grant ALAM2019-001).
文摘The in vitro study of tetracannabinolic acid(THCA)derivatives ALAM027 and ALAM108 was carried out on the following human tumor cells:T47D(breast,ductal carcinoma),PC-3(prostate,adenocarcinoma),HT 29(colorectal carcinoma),Caco-2(colon,adenocarcinoma),A549(lung,carcinoma),U87MG(human glioblastoma)and U266B1(multiple myeloma).The in vitro effects of THCA derivatives ALAM027 and ALAM108 on cell growth inhibition and IC50 values were measured using the CellTiter Glo assay.The ALAM027 compound showed good growth inhibition in all cell lines tested with the exception of U87MG cells.The ALAM108 compound also suppressed the growth of U87 MG cells but had little effect on T47D tumor cells.In vitro studies of THCA derivatives ALAM027 and ALAM108 showed antitumor activity in all cell lines tested.The difference in the activity of these compounds in relation to the T47D and U87MG tumor cells may be indicative of different functional mechanisms.
基金supported by the Coordenacao de Aperfeicoamento de Pessoal de Nível Superior-Brasil(CAPES)(Finance Code 001)
文摘Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain,as well as and the involvement of the cannabinoid receptors type 2(CB2)and spinal microglia in this process.Methods:Male Swiss mice were subjected to inflammatory pain induced by intraplantar injection of carrageenan.The nociceptive threshold was measured by von Frey filaments test.Tingenone was administered orally 60 min before carrageenan injection.To evaluate the involvement of CB2 receptor,endocannabinoids,and microglia,AM630(a CB2 receptor antagonist),MAFP(an inhibitor of an enzyme that hydrolyses endocannabinoids),and minocycline(a microglial inhibitor)were given intrathecally 20 min before tingenone administration.In addition,an immunofluorescence assay was used to evaluate CB2 receptor and CD11 B(a microglial marker)expression in the spinal cord dorsal horn.Results:Tingenone significantly reduced carrageenan-induced hyperalgesia,which was reversed by pretreatment with AM630.MAFP and minocycline potentiated and prolonged the tingenoneinduced antinociception.CD11 B expression was increased in the spinal cord dorsal horn of mice with inflammatory pain pretreated with tingenone,which was reduced by AM630,MAFP,and minocycline.Conclusions:CB2 receptors and endocannabinoids participate in the tingenone-induced antinociception which may involve the inhibition of microglia at spinal level.
基金supported by a grant from Army Medical Research Program of China(No.08G168)
文摘Many researchers employed mammalian expression system to artificially express cannabinoid receptors, but immunoblot data that directly prove efficient protein expression can hardly be seen in related research reports. In present study, we demonstrated cannabinoid receptor protein was not able to be properly expressed with routine mammalian expression system. This inefficient expression was rescued by endowing an exogenous signal peptide ahead of cannabinoid receptor peptide. In addition, the artificially synthesized cannabinoid receptor was found to aggregate under routine sample denaturing temperatures (i.e.,≥95°C), forming a large molecular weight band when analyzed by immuno-blotting. Only denaturing temperatures ≤75°C yielded a clear band at the predicted molecular weight. Collectively, we showed that efficient mammalian expression of cannabinoid receptors need a signal peptide sequence, and described the requirement for a low sample denaturing temperature in immuno-blot analysis. These findings provide very useful information for efficient mammalian expression and immuno-blotting of membrane receptors.
基金supported by Drug Enforcement Administration,National Center for Toxicological Research(protocol#E0763601)University of Arkansas for Medical Sciences
文摘OBJECTIVE Over 30% of all new psychoactive substances identified by the UN Office on Drugs and Crime in 2016 were synthetic cannabinoids.The recent emergence of MAM-2201 on the illicit market is troubling because this drug has no precedent in either the scientific or patent literature,and appears to be a novel compound developed specifically as a "graymarket" drug of abuse bystructurally combining the known synthetic cannabinoids JWH-122 and AM-2201.There is currently no published information regarding the pharmacology of MAM-2201.METHODS The present studies characterized cannabinoid-like effects of MAM-2201 in vitro(interactions with cannabinoid type 1 receptors[CB1 Rs]) and in vivo(in mice and rats).RESULTS In a radioligand binding assay using [3 H]CP55,940 in HEK cell membranes transfected with the CB1 R,MAM-2201(K i=5.4 nmol·L^(-1)),had higher binding affinity than WIN 55,212-2(K i=80 nmol·L^(-1)),and D9-THC(K i=8.3 nmol·L^(-1)).The E max values for MAM-2201 and WIN 55,212-2 in an assay of agonist inhibition of forskolin-stimulated c AMP were 85%(EC50=0.45 nmol·L^(-1)) and 95%,respectively,as compared with the D9-THC E max of 74%.In mice,MAM-2201(0.003-1.0 mg·kg^(-1),IP) produced dose-dependent cannabimimetic effects which were both more potent and more effective than those of D9-THC.MAM-2201 and D9-THC dose-dependently produced hypothermia:ED50=0.287 and 25.4 mg·kg^(-1),analgesia:ED50=0.125 and 29.4 mg·kg^(-1),and catalepsy:ED50=0.301 and18.9 mg·kg^(-1) in adult male CD1 mice.Importantly,MAM-2201 also elicited convulsant effects at a dose of 1.0 mg·kg^(-1) in 8/8 murine subjects.In rats,MAM-2201 produced dose-dependent D9-THC-like interoceptive effects in subjects trained to discriminate 3.0 mg·kg^(-1)(IP) D9-THC from saline.CONCLUSION MAM-2201 binds CB1 Rs with high affinity and agonist efficacy,and functions as a potent cannabinoid agonist in vivo across several complementary measures of cannabinoid activity in two rodent species.
文摘Long-term cannabis use may be associated with attacks of severe nausea and vomiting, and a characteristic learned behavior of compulsive hot bathing, termed cannabinoid hyperemesis syndrome(CHS). Long-term follow-up and prognosis of CHS have not been reported previously. A 44-year-old Caucasian man with a long history of addiction to marijuana presented with chronic abdominal pain complicated by attacks of uncontrollable vomiting for 16 years. He had a compulsion to take scalding hot showers, as many as 15 times a day, to relieve his symptoms. All previous therapies had been ineffective. However, abstinence from marijuana led to rapid and complete resolution of all symptoms and his compulsive hot showering behavior. He has been followed for nine years, and is still doing well without recurrence of symptoms. Physicians should have a high index of suspicion for this under-recognized condition, as excellent long-term prognosis of CHS can be achieved when abstinence is maintained.
基金the National Natural Science Foundation of China, No. 30970930
文摘Cannabinoid and nicotinic acetylcholine receptors are strongly associated with algesia. Previous studies in our laboratory have reported inhibitory effects of synthetic cannabinoid WIN55, 212-2 on nicotine-activated currents (Inic), but the underlying mechanisms remain poorly understood. The present study used whole-cell patch clamp techniques to investigate the modulatory effects of synthetic cannabinoid WIN55, 212-2 on Inic in cultured rat trigeminal ganglion neurons. The results revealed several major findings: WIN55, 212-2 inhibited Inic in rat trigeminal ganglion neurons. In addition, when WIN55, 212-2 (3 μmol/L) was applied simultaneously with nicotine (100 μmol/L), the inhibition of WIN55, 212-2 on Inic was reversible, concentration-dependent and voltage-independent This effect was not mediated by CB1, CB2 or VR1 receptors; neither the selective CB1 receptor antagonist AM281, CB2 receptor antagonist AM630 nor VR1 receptor antagonist capsazepine reduced the inhibitory effect of WIN55, 212-2. Further, the inhibition of nicotinic responses by WIN55, 212-2 was not sensitive to the membrane permeable cyclic adenosine monophosphate (cAMP) analog 8-Br-cAMP. The G-protein inhibitor GDP-I3-S (1 mmol/L) did not block the inhibitory effects of WIN55, 212-2 on/n^c, excluding the involvement of G-protein mediation. The results suggested that WIN55, 212-2 inhibits/n^o directly via the neuronal nicotinic acetylcholine receptor, and that this inhibition is non-competitive. WIN55, 212-2 did not act as an open channel blocker of the neuronal nicotinic acetylcholine receptor, and did not affect the desensitization of Into. The results suggest that nicotine receptors may be physically plugged from outside the membrane by drugs containing WIN55, 212-2.
基金supported by a grant from the National Natural Sciences Foundation of China (No.30571627)
文摘This study examined endogenous carmabinoid (ECB)-anandamide (AEA) and its cannabinoid receptors (CBR) in mice liver with the development ofschistosomajaponicum. Mice were infected with schistosoma by means of pasting the cercaria onto their abdomens. Liver fibrosis was pathologically confirmed nine weeks after the infection. High performance liquid chromatography (HPLC) was employed to determine the concentration of AEA in the plasma of mice. Immunofluo-rescence was used to detect the expression of CBR1 and CBR2 in liver tissue. Morphological examination showed typical pathological changes, with worm tubercles of schistosoma deposited in the liver tissue, fibrosis around the worm tubercles and infiltration or soakage of inflammatory cells. Also, CBR1 and CBR2 were present in hepatocytes and hepatic sinusoids of the two groups, but they were obviously enhanced in the schistosoma-infected mice. However, the average optical density of CBR1 in the negative control and fibrosis group was 13.28±7.32 and 30.55±7.78, and CBR2 were 28.13±6.42 and 52.29±4.24 (P〈0.05). The levels of AEA in the fibrosis group were significantly increased as compared with those of the control group. The concentrations of AEA were (0.37±0.07) and (5.67±1.34) ng/mL (P〈0.05). It is concluded that the expression of endocannabinoids AEA and its cannabinoid receptor CBR were significantly increased in schistosoma-infected mice. Endogenous endocannabinoids may be involved in the development of schistosoma-induced liver fibrosis.