Biomedical subjects

Nissar A Darmani

Publications and source records attributed to Nissar A Darmani.

9 recordsLinked to original sources

PubMed2006

Methods evaluating cannabinoid and endocannabinoid effects on gastrointestinal functions.

This chapter briefly describes the physiological neural mechanisms by which diverse neurotransmitter receptor systems control several aspects of gastrointestinal functions such as motility, secretion, feeding, and emesis. The current techniques used to study the effects of cannabinoids on these gastrointestinal functions are then sequentially described, starting with isolated gastrointestinal muscle preparations and ultimately evolving to whole animal models. Both delta9-tetrahydrocannibinol (delta9-THC) and well-studied representatives of other classes of exogenous cannabinoid CB1/CB2 receptor agonists inhibit gastrointestinal motility, peristalsis, defecation, and secretions via cannabinoid CB1 receptors since the CB1 (SR141716A)- and not the CB2 (SR144528)-receptor antagonist reverses these effects in a dose-dependent manner. In addition, exogenous cannabinoids inhibit vomiting produced by diverse emetic stimuli in a SR141716A-sensitive manner in different animal models of emesis. Often these cannabinoids produce hyperphagic effects under laboratory conditions in most human and animal models of feeding. Administration of SR141716A by itself can produce effects opposite to cannabinoid agonists (e.g., increases in gastrointestinal motility and secretions, hyperphagia and vomiting), which suggests an important role for endocannabinoids in these gastrointestinal functions. Indeed, the presence of cannabinoid CB1 receptor markers, endocannabinoids such as anandamide and 2-arachidonoylglycerol (2-AG), their metabolic enzymes, and an endocannabinoid reuptake system have been confirmed in the gastrointestinal tract (GIT). The well-studied endocannabinoid anandamide also seems to reduce both gastrointestinal motility and secretion while producing hyperphagia. On the other hand, while the less well-investigated endocannabinoid 2-AG is a potent emetogen, anandamide may possess weak antiemetic activity.

Animals↗

PubMed2005

Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: review of the available pre-clinical data, and first human studies.

The endogenous cannabimimetic compound, and anandamide analogue, N-palmitoyl-ethanolamine (PEA), was shown to exert potent anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic and inflammatory pain by acting via several possible mechanisms. However, only scant data have been reported on the regulation of PEA levels during pathological conditions in animals or, particularly, humans. We review the current literature on PEA and report the results of three separate studies indicating that its concentrations are significantly increased during three different inflammatory and neuropathic conditions, two of which have been assessed in humans, and one in a mouse model. In patients affected with chronic low back pain, blood PEA levels were not significantly different from those of healthy volunteers, but were significantly and differentially increased (1.6-fold, P<0.01, N=10 per group) 30 min following an osteopathic manipulative treatment. In the second study, the paw skin levels of PEA in mice with streptozotocin-induced diabetic neuropathic pain were found to be significantly higher (1.5-fold, P<0.005, N=5) than those of control mice. In the third study, colonic PEA levels in biopsies from patients with ulcerative colitis were found to be 1.8-fold higher (P<0.05, N=8-10) than those in healthy subjects. These heterogeneous data, together with previous findings reviewed here, substantiate the hypothesis that PEA is an endogenous mediator whose levels are increased following neuroinflammatory or neuropathic conditions in both animals and humans, possibly to exert a local anti-inflammatory and analgesic action.

Amides↗

PubMed2005

Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew.

The chemotherapeutic agent cisplatin may produce emesis via release of several neurotransmitters such as serotonin (5-HT), substance P and/or dopamine as well as production of prostaglandins (PGs). Administration of synthetic 2-arachidonoylglycerol (2-AG) but not of anandamide, which are two putative endocannabinoids, causes vomiting via its downstream metabolites such as arachidonic acid (AA) and PGs in the least shrew (Cryptotis parva). We report here that cisplatin (0, 5, 10 and 20 mg/kg, i.p.) causes dose- and time-dependent increases in brain tissue levels of 2-AG but not anandamide in this vomiting species. Concomitantly, intestinal tissue levels of both endocannabinoids are relatively reduced. Selective inhibitors [arachidonoyl-serotonin (AA-5-HT) and URB597, 0-5 and 0-10 mg/kg, i.p.] of one of the major endocannabinoid metabolic enzymes, the intracellular fatty acid amide hydrolase (FAAH), do not significantly prevent vomiting produced by emetic doses of i.p.-administered 2-AG, cisplatin or the dopamine receptor agonist apomorphine. At large doses (10 and 20 mg/kg, respectively), both FAAH inhibitors caused emesis per se. Administration of one selective uptake inhibitor of endocannabinoids, OMDM1 (0-5 mg/kg, i.p.), also did not significantly prevent emesis by the direct and indirect emetic stimuli, and likewise caused emesis by itself at a high (10 mg/kg) dose. However, another selective uptake inhibitor, VDM11, did not produce significant emesis per se and prevented emesis caused by apomorphine. Both the corticosteroid dexamethasone, and the cyclooxygenase inhibitor indomethacin, reduced vomiting produced by cisplatin. These data: (a) provide the first evidence that cisplatin causes a selective increase in 2-AG levels in the brain, and (b) support the established notion that 2-AG may produce some of its effects, including emesis, via downstream metabolites produced independently of FAAH.

Analysis of Variance↗

PubMed2005

1,3-dinitrobenzene toxicity in the least shrew, Cryptotis parva.

Shrews are abundant in most areas of toxic chemical contamination and bioaccumulate pollutants at much higher rates than sympatric rodent species. As a part of studies to provide information concerning the toxicity of 1,3-dinitrobenzene (DNB) in least shrews (Cryptotis parva), groups of 10 females and 10 males received DNB at 0 (control), 0.7, 2.9, 11.6, and 46.3 microl/L (equivalent mean daily dosage of 0, 0.26, 1.06, 4.26, and 17.0 mg/kg body wt in each sex) in their diet for 14 d. Leukocytosis present at the 0.26 mg/kg body weight/d dosage established the lowest-observed-adverse effect level (LOAEL). Adrenal enlargement was noted at the 1.06 mg/kg body weight/d level. Splenic enlargement and reductions in hematocrit and hemoglobin values occurred at the 4.26 mg/kg body weight/d treatment. Enlargements in the liver and heart and reductions in brown fat weight, granulocyte numbers, and alanine aminotransferase levels were present at high dose levels. Histopathologic examinations showed Kupffer's cell hemosiderosis and suggested testicular damage at the two highest tested doses but failed to confirm brain lesions. Least shrews do not follow standard scaling estimates for lifespan or metabolic rates. The LOAEL calculated from the standard terrestrial screening benchmark equation was higher than our findings, suggesting that these estimates must be viewed with caution.

Animals↗

PubMed2004

Delta-9-tetrahydrocannabinol differentially suppresses emesis versus enhanced locomotor activity produced by chemically diverse dopamine D2/D3 receptor agonists in the least shrew (Cryptotis parva).

The principal psychoactive component of marijuana, delta-9-tetrahydrocannabinol (Delta9-THC), suppresses nausea and vomiting in cancer patients caused by chemotherapeutics such as cisplatin. Cisplatin induces vomiting via a number of emetic stimuli, including dopamine. Currently, there is controversy as to whether Delta9-THC can prevent emesis produced by dopaminergic agonists such as apomorphine. The present investigation utilizes the least shrew to evaluate the antiemetic potential and the cannabinoid receptor by which Delta9-THC may prevent emesis produced by four dopamine receptor agonists with differing selectivity for D2 and D3 receptors, i.e., a nonselective dopamine receptor agonist (apomorphine), a D2-preferring receptor agonist (quinpirole), and two D3-preferring receptor agonists (quinelorane and 7-OH DPAT). In addition, relative to its antiemetic doses, the motor suppressive doses of Delta9-THC in dopamine D2/D3-receptor-agonist-treated shrews were also evaluated. Thus, different groups of shrews were injected with either vehicle (V) or varying doses of Delta9-THC [0.5, 1, 2.5, 5, or 10 mg/kg, intraperitoneal (i.p.)] 10 min prior to administration of a 2 mg/kg dose of one of the four cited D2/D3 agonists. Immediately after the last injection, the frequency of vomiting for each shrew was recorded for the next 30 min. To investigate which cannabinoid receptor is involved in the antiemetic action of Delta9-THC, various doses of the CB1 receptor antagonist SR 141716A [0, 5, 10, and 20 mg/kg, subcutaneous (s.c.)] were administered to shrews 10 min prior to an injection of a fully effective antiemetic dose of Delta9-THC (5 mg/kg, i.p.). Ten minutes later, each treated shrew was administered with a 2 mg/kg dose of apomorphine. The emesis frequency was recorded for the next 30 min. For locomotor studies, different groups of shrews received either vehicle or various doses of Delta9-THC (0, 5, 10, 20, or 30 mg/kg) 10 min prior to an injection of vehicle or a 2 mg/kg dose of one of the four D2/D3 receptor agonists. The triad of motor behaviors (spontaneous locomotor activity, total duration of movement, and rearing frequency) were recorded for the next 30 min by a computerized video tracking system. Delta9-THC dose-dependently attenuated the frequency of emesis as well as fully protecting shrews from vomiting produced by each one of the four cited dopamine D2/D3 receptor agonists with ID50s ranging from 1 to 4 mg/kg. SR 141716A reversed the antiemetic activity of Delta9-THC against apomorphine-induced emesis. Delta9-THC also differentially suppressed the triad of motor activities in dopamine D2/D3-receptor-agonist-treated shrews with ID50s ranging from 7 to 21 mg/kg. The results suggest that Delta9-THC prevents emesis via cannabinoid CB1 receptors in a potent and dose-dependent manner in D2/D3-receptor-agonist-treated shrews at doses well below those which cause significant motor depression.

Animals↗

PubMed2004

Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis.

Delta-9-tetrahydrocannabinol (delta-9-THC) prevents cisplatin-induced emesis via cannabinoid CB(1) receptors. Whether central and/or peripheral cannabinoid CB(1) receptors account for the antiemetic action(s) of delta-9-THC remains to be investigated. The 5-hydroxytryptamine (5-HT=serotonin) precursor, 5-hydroxytryptophan (5-HTP), is an indirect 5-HT agonist and simultaneously produces the head-twitch response (a centrally mediated serotonin 5-HT(2A) receptor-induced behavior) and emesis (a serotonin 5-HT(3) receptor-induced response, mediated by both peripheral and central mechanisms) in the least shrew (Cryptotis parva). The peripheral amino acid decarboxylase inhibitor, carbidopa, prevents the conversion of 5-HTP to 5-HT in the periphery and elevates 5-HTP levels in the central nervous system (CNS). When administered i.p. alone, a 50 mg/kg dose of 5-HTP failed to induce either behaviour while its 100 mg/kg dose produced robust frequencies of both head-twitch response and emesis. Pretreatment with carbidopa (0, 10, 20 and 40 mg/kg) potentiated the ability of both doses of 5-HTP to produce the head-twitch response in a dose-dependent but bell-shaped manner, with maximal potentiation occurring at 20 mg/kg carbidopa. Carbidopa dose-dependently reduced the frequency of 5-HTP (100 mg/kg)-induced emesis, whereas the 10 mg/kg dose potentiated, and the 20 and 40 mg/kg doses suppressed the frequency of vomits produced by the 50 mg/kg dose of 5-HTP. The peripheral and/or central antiemetic action(s) of delta-9-THC (0, 1, 2.5, 5, 10 and 20 mg/kg) against 5-HTP (100 mg/kg)-induced head-twitch response and emesis were investigated in different groups of carbidopa (0, 10 and 20 mg/kg) pretreated shrews. Irrespective of carbidopa treatment, delta-9-THC attenuated the frequency of 5-HTP-induced head-twitch response in a dose-dependent manner with similar ID(50) values. Although delta-9-THC also reduced the frequency of 5-HTP-induced emesis with similar ID(50s), at the 5 mg/kg delta-9-THC dose however, 5-HTP induced significantly less vomits in the 10 and 20 mg/kg carbidopa-treated groups relative to its 0 mg/kg control group. Moreover, increasing doses of carbidopa significantly shifted the inhibitory dose-response effect of delta-9-THC in protecting shrews from 5-HTP-induced emesis to the left. Relatively, a large dose of delta-9-THC (20 mg/kg) was required to significantly reduce the number of vomits produced by direct acting serotonergic 5-HT(3) receptor agonists, serotonin and 2-methylserotonin. Low doses of delta-9-THC (0.1-1 mg/kg) nearly completely prevented 2-methylserotonin-induced, centrally mediated, head-twitch and ear-scratch responses. The results indicate that delta-9-THC probably acts pre- and postsynaptically to attenuate emesis produced by indirect and direct acting 5-HT(3) receptor agonists via both central and peripheral mechanisms. In addition, delta-9-THC prevents 5-HTP-induced head-twitch and emesis via cannabinoid CB(1) receptors since the CB(1) receptor antagonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], countered the inhibitory actions of an effective dose of delta-9-THC against both behaviours.

5-Hydroxytryptophan↗

PubMed2003

Antiemetic and motor-depressive actions of CP55,940: cannabinoid CB1 receptor characterization, distribution, and G-protein activation.

Dibenzopyran (Delta(9)-tetrahydrocannabinol) and aminoalkylindole [R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl) methanone mesylate; (WIN55,212-2)] cannabinoids suppress vomiting produced by cisplatin via cannabinoid CB(1) receptors. This study investigates the antiemetic potential of the "nonclassical" cannabinoid CP55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol] against cisplatin-induced vomiting and assesses the presence and functionality of cannabinoid CB(1) receptors in the least shrew (Cryptotis parva) brain. CP55,940 (0.025-0.3 mg/kg) reduced both the frequency of cisplatin-induced emesis (ID(50)=0.025 mg/kg) and the percentage of shrews vomiting (ID(50)=0.09 mg/kg). CP55,940 also suppressed shrew motor behaviors (ID(50)=0.06- 0.21 mg/kg) at such doses. The antiemetic and motor-suppressant actions of CP55,940 were countered by SR141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], indicating both effects are cannabinoid CB(1) receptor-mediated. Autoradiographic studies with [3H]-SR141716A and [35S]-GTPgammaS binding revealed that the distribution of the cannabinoid CB(1) receptor and its activation pattern are similar to rodent brain and significant levels are present in brain loci (e.g., nucleus tractus solitarius (NTS)) that control emesis. The affinity rank order of structurally diverse cannabinoid ligands for cannabinoid CB(1) receptor in shrew brain is similar to rodent brain: HU-210=CP55,940=SR141716A>/=WIN55,212-2>/=delta-9-tetrahydrocannabinol>methanandamide=HU-211=cannabidiol=2-arachidonoylglycerol. This affinity order is also similar and is highly correlated to the cannabinoid EC(50) potency rank order for GTPgammaS stimulation except WIN55,212-2 and delta-9-tetrahydrocannabinol potency order were reversed. The affinity and the potency rank order of tested cannabinoids were significantly correlated with their antiemetic ID(50) potency order against cisplatin-induced vomiting (CP55,940>WIN55,212-2=delta-9-tetrahydrocannabinol) as well as emesis produced by 2-arachidonoylglycerol or SR141716A (CP55,940>WIN55,212-2>delta-9-tetrahydrocannabinol).

Animals↗

PubMed2002

The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol and other cannnabinoids.

Cannabinoids, including the endogenous cannabinoid or endocannabinoid, anandamide, modulate several gastrointestinal functions. To date, the gastrointestinal effects of the second putative endocannabinoid 2-arachidonoylglycerol (2-AG) have not been studied. In the present study using a shrew (Cryptotis parva) emetic model, 2-AG (0.25-10 mg/kg, i.p.) potently and dose-dependently increased vomiting frequency (ED(50) = 1.13 mg/kg) and the number of animals vomiting (ED(50) = 0.48 mg/kg). In contrast, neither anandamide (2.5-20 mg/kg) nor methanandamide (5-10 mg/kg) induced a dose-dependent emetogenic response, but both could partially block the induced emetic effects. Delta(9)-Tetrahydrocannabinol and its synthetic analogs reduced 2-AG-induced vomiting with the rank order potency: CP 55,940 > WIN 55,212-2 > Delta(9)-tetrahydrocannabinol. The nonpsychoactive cannabinoid, cannabidiol, was inactive. Nonemetic doses of SR 141716A (1-5 mg/kg) also blocked 2-AG-induced vomiting. The 2-AG metabolite arachidonic acid also caused vomiting. Indomethacin, a cyclooxygenase inhibitor, blocked the emetogenic effects of both arachidonic acid and 2-AG. CP 55,940 also blocked the emetic effects of arachidonic acid. 2-AG (0.25-10 mg/kg) reduced spontaneous locomotor activity (ED(50) = 11 mg/kg) and rearing frequency (ED(50) = 4.3 mg/kg) in the shrew, whereas such doses of both anandamide and methanandamide had no effect on locomotor parameters. The present study indicates that: 1) 2-AG is an efficacious endogenous emetogenic cannabinoid involved in vomiting circuits, 2) the emetic action of 2-AG and the antiemetic effects of tested cannabinoids are mediated via CB(1) receptors, and 3) the emetic effects of 2-AG occur in lower doses relative to its locomotor suppressant actions.

Animals↗

PubMedDate not supplied

Reversal of SR 141716A-induced head-twitch and ear-scratch responses in mice by delta 9-THC and other cannabinoids.

Recently, we have shown that cannabinoids of diverse structure block the ability of the selective 5-HT(2A/C) agonist DOI to produce the head-twitch response (HTR) and the ear-scratch response (ESR) in mice. The cannabinoid CB(1) antagonist/inverse agonist SR 141716A also induces these behaviors in mice. The purposes of the present study were: (1) to investigate whether Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and other cannabinoids HU-210 and WIN 55, 212-2 can prevent SR 141716A-induced HTR and ESR and (2) to evaluate any correlation between the ID(50) potency order of the cited cannabinoids in blocking SR 141716A-induced HTR and ESR and their ED(50) order of potency in reducing spontaneous locomotor activity and rearing behavior. For the SR 141716A reversal study, different groups of mice were injected intraperitoneally with either vehicle or varying doses of the following cannabinoids: Delta(9)-THC (2.5-20 mg/kg), Delta(8)-THC (5-20 mg/kg), HU-210 (0.05-0.5 mg/kg), CP 55, 940 (0.5-2.5 mg/kg) and WIN 55, 212-2 (2.5-10 mg/kg). Thirty minutes later, each mouse received SR 141716A (2.5 mg/kg ip) and the frequencies of the induced behaviors (mean +/- S.E.M.) were recorded for the next 30 min. The effects of the cited doses of cannabinoids were also examined on spontaneous locomotor activity and rearing frequency for a 20-min duration 10 min after cannabinoid injection. The tested cannabinoids reduced the frequencies of HTR and ESR in SR 141716A-injected mice. These agents also attenuated the cited naturally occurring repertoire of motor parameters in mice. Although large potency differences were observed among the cited cannabinoids, each tested cannabinoid was relatively equipotent in preventing locomotor parameters and SR 141716A-induced behaviors. The ID(50) potency order of cannabinoids in blocking SR 141716A-induced HTR and ESR were similar (HU-210>CP 55, 940>WIN 55, 212-2 > or = Delta 9)-THC=Delta(8)-THC), and are comparable with: (1) their ED(50) potency order in attenuating both spontaneous locomotor activity and rearing behavior (HU-210>CP 55, 940>WIN 55, 212-2>Delta(9)-THC=Delta(8)-THC) and (2) their published ED(50) potency order for producing the tetrad of behaviors in mice as well as their rank order of binding affinities for cannabinoid CB(1) receptors. The present data show that cannabinoids of diverse structure prevent SR 141716A-induced HTR and ESR, and inhibition of these behaviors by cannabinoids could be used as a new index of cannabimimetic activity.

Analgesics, Non-Narcotic↗