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Nissar A Darmani - One of the best experts on this subject based on the ideXlab platform.
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reversal of sr 141716a induced head twitch and ear scratch responses in mice by δ9 thc and other cannabinoids
Pharmacology Biochemistry and Behavior, 2002Co-Authors: Jano J Janoyan, Jennifer L Crim, Nissar A DarmaniAbstract:Abstract 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 Δ 9 -tetrahydrocannabinol (Δ 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: Δ 9 -THC (2.5–20 mg/kg), Δ 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≥Δ 9 -THC=Δ 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>Δ 9 -THC=Δ 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.
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Reversal of SR 141716A-induced head-twitch and ear-scratch responses in mice by delta 9-THC and other cannabinoids.
Pharmacology biochemistry and behavior, 2002Co-Authors: Jano J Janoyan, Jennifer L Crim, Nissar A DarmaniAbstract: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.
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δ9 tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid cb1 receptor antagonist inverse agonist sr 141716a
Neuropsychopharmacology, 2001Co-Authors: Nissar A DarmaniAbstract:There is substantial clinical evidence that Δ9-tetrahydrocannabinol (Δ9-THC) and its synthetic analogs (nabilone and levonantradol) can prevent emesis in cancer patients receiving chemotherapy. Limited available animal studies also support the antiemetic potential of these cannabinoids. The present study investigates the mechanism of antiemetic action of cannabinoids in an established animal model of emesis, the least shew (Cryptotis parva). Since cannabinoid agonists prevent emesis, it was hypothesized that blockade of either the cannabinoid CB1 receptor or the cannabinoid CB2 receptor would induce vomiting. Thus, the emetic potential of SR 141716A (CB1 receptor antagonist) or SR 144528 (CB2 receptor antagonist) was investigated. Both intraperitoneal (0, 1, 2.5, 5, 10 and 20 mg/kg, n = 7–15 per group) and subcutaneous (0, 10, 20 and 40 mg/kg, n = 6–9 per group) administration of SR 141716A caused emesis (ED50 = 5.52 ± 1.23 and 20.2 ± 1.02 mg/kg, respectively) in the least shrew in a dose-dependent manner. Indeed, both the frequency of emesis and the percentage of animals vomiting increased with increasing doses of SR 141716A. Significant effects were seen at the 10- and 20-mg/kg doses for the IP route, while only the 40-mg/kg dose produced significant emesis via the SC route. The CB2 antagonist failed to produce emesis via either route of administration. SR 141716A at an IP dose of 20 mg/kg was used to induce emesis for drug interaction studies. Thus, varying doses of three different classes of cannabinoid agonists [CP 55, 940 (0, 0.1, 0.5 and 1 mg/kg), WIN 55, 212-2 (0, 1, 5 and 10 mg/kg), and Δ9-THC (0, 5, 10 and 20 mg/kg)], were administered IP to different groups of shrews 10 min prior to SR 141716A injection. The frequency of emesis was recorded for 30 min following the administration of SR 141716A. The order of potency for redcing both the frequency of emesis and the percentage of shrews vomiting was CP 55, 940 > WIN 55, 212-2 > Δ9-THC which is consistent with an action on the CB1 receptor. These results suggest that the antiemetic activity of Δ9-THC and its synthetic analogs reside in their ability to stimulate the cannabinoid CB1 receptor. Furthermore, the antiemetic potency of CP 55, 940 is 45 times greater than Δ9-THC. On the other hand, blockade of CB1 receptors can induce vomiting, which implicates an important role for endogenous cannabinoids in emetic circuits.
Iain S Mcgregor - One of the best experts on this subject based on the ideXlab platform.
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pre exposure to the cannabinoid receptor agonist CP 55 940 enhances morphine behavioral sensitization and alters morphine self administration in lewis rats
European Journal of Pharmacology, 2003Co-Authors: Christy S Norwood, Jennifer L Cornish, Paul E Mallet, Iain S McgregorAbstract:Three experiments examined the influence of pre-exposure to the cannabinoid receptor agonist CP 55,940 ((−)-cis-3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-trans-4-(3-hydroxypropyl)cyclohexanol) on the sensitization of morphine-induced locomotor hyperactivity and self-administration in Lewis rats. In Experiment 1, rats received daily injections of vehicle or CP 55,940 (0.1 mg/kg for 7 days then 0.2 mg/kg for a further 7 days). Four weeks later, the locomotor response to morphine (10 mg/kg s.c.) was tested once per day over a 3-h period for 14 consecutive days. Rats given morphine showed hypoactivity during the first hour following morphine but hyperactivity during the second and third hours. A progressive increase in hyperactivity to morphine was seen over the 14 days of administration, which was significantly greater in rats pre-treated with CP 55,940. In Experiment 2, rats were given morphine (10 mg/kg) once a day for 14 days in combination with either vehicle, CP 55,940 (0.1 mg/kg) or the cannabinoid CB1 receptor antagonist SR 141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride) (3 mg/kg). Both CP 55,940 and SR 141716 initially inhibited the hyperactive response to morphine, but these effects gradually wore off and by the end of 14 days, hyperactivity was similar in all morphine-treated groups. When tested 3 weeks later for their response to morphine (10 mg/kg) given alone, rats previously given the morphine/CP 55,940 combination, but not the SR 141716/morphine combination, showed a greater locomotor stimulation than those previously exposed to morphine only. In Experiment 3, rats were pre-exposed to CP 55,940 or vehicle for 14 days and were subsequently trained to self-administer morphine intravenously (1 mg/kg per lever press) for 14 days. Rats pre-exposed to CP 55,940 self-administered a significantly greater number of morphine infusions than vehicle pre-exposed rats. However, both active and inactive (‘dummy’) lever presses were increased by cannabinoid pre-treatment. Overall, these results suggest that cannabinoid pre-exposure can lead to an exaggeration of morphine-induced hyperactivity and may alter the reinforcing effects of morphine in Lewis rats. The implications for ‘gateway’ theories of cannabinoid effects in humans are discussed.
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effects of the cannabinoid receptor agonist CP 55 940 and the cannabinoid receptor antagonist sr 141716 on intracranial self stimulation in lewis rats
Life Sciences, 2001Co-Authors: Jonathon C Arnold, Glenn E Hunt, Iain S McgregorAbstract:Abstract Lewis rats were trained to self-stimulate the medial forebrain bundle (MFB) using a rate-frequency paradigm. They were then tested for the effects of the cannabinoid receptor agonist CP 55,940, the selective cannabinoid receptor antagonist SR 141716 and the dopamine D 1 receptor antagonist SCH 23390. CP 55,940 (0, 10, 25 and 50 μg/kg i.p.) had no effect on MFB self-stimulation behaviour as assessed by the M 50 , the stimulation frequency at which half-maximal response rates were obtained. With SR 141716, only a very high dose (20 mg/kg i.p.) caused a significant inhibition of the rewarding efficacy of the stimulation. This was seen as an increase in the M 50 . All other doses of SR 141716 (0, 1, 3, 10 mg/kg i.p.) were ineffective in modulating the M 50 . By comparison, a relatively low dose (0.06 mg/kg i.p.) of SCH 23390 caused a large increase in M 50 . These results indicate a relatively modest influence, if any at all, of exogenous or endogenous cannabinoids on reward-relevant neurotransmission.
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effects of pre exposure and co administration of the cannabinoid receptor agonist CP 55 940 on behavioral sensitization to cocaine
European Journal of Pharmacology, 1998Co-Authors: Jonathon C Arnold, Ann N Topple, Glenn E Hunt, Iain S McgregorAbstract:Rats given cocaine (15 mg/kg, i.p.) every second day over a 2-week period displayed a progressively greater locomotor response to the drug over days indicating behavioral sensitization. When the cannabinoid receptor agonist CP 55,940 ((-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hyd roxypropyl)cyclohexanol) (10, 25 or 50 microg/kg) was administered under a similar regime, no such sensitization was observed. Rather, the two highest doses of CP 55,940 (25 and 50 microg/kg) caused locomotor suppression that lasted throughout administration. When rats pre-exposed 10 times to CP 55,940 were challenged with cocaine (15 mg/kg), no exaggerated locomotor response to cocaine was evident relative to non pre-exposed rats. When these rats were subsequently re-tested with CP 55,940, the cannabinoid continued to produce a dose-dependent suppression of locomotor activity. Finally, when CP 55,940 (50 microg/kg) was co-administered with cocaine, it significantly reduced the locomotor hyperactivity produced by the drug but did not block the development of behavioral sensitization. These results show that CP 55,940 does not sensitize locomotor activity with repeated administration in the same way as cocaine, and that pre-exposure or concurrent exposure to CP 55,940 does not enhance sensitivity to the subsequent behavioral effects of cocaine.
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aversive effects of the synthetic cannabinoid CP 55 940 in rats
Pharmacology Biochemistry and Behavior, 1996Co-Authors: Iain S Mcgregor, Cathy Issakidis, Gabrielle PriorAbstract:Abstract A series of experiments investigated the behavioral and hedonic effects of the synthetic cannabinoid CP 55,940 in male Wistar rats. CP 55,940 had a biphasic effect on locomotor activity, with a 10 μg/kg dose causing locomotor stimulation and a 100 μg/kg dose causing profound hypoactivity. CP 55,940 (100 μg/kg) also caused a marked hypothermia for at least 3 h following administration, while lower doses (2.5 and 10 μg/kg) had no effect. CP 55,940 (100 gmg/kg) had anorexic and hyperdipsic effects for up to 24 h following administration and caused significant reductions in body weight. CP 55,940 (100 μg/kg) also caused significant avoidance to a flavoured fluid (saccharin) with which it was paired. In the conditioned place preference paradigm both the 10 μg/kg and 100 μg/kg doses of CP 55,940 produced significant place avoidance. It is concluded that CP 55,940 is aversive to rats. The possible mechanisms underlying this aversion are discussed.
Billy R Martin - One of the best experts on this subject based on the ideXlab platform.
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synthesis and pharmacology of 1 deoxy analogs of CP 47 497 and CP 55 940
Bioorganic & Medicinal Chemistry, 2008Co-Authors: John W Huffman, Alicia L S Thompson, Jenny L Wiley, Billy R MartinAbstract:A series of 1-deoxy analogs of CP-47,497 (8 and 13, n = 0 to 7) and 1-deoxy analogs of CP-55,940 (9, n = 0 to 7) have been synthesized and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. Although the majority of these compounds exhibit selectivity for the CB2 receptor none have greater than modest affinity for either receptor. The interactions of these 1-deoxy nontraditional cannabinoids with the CB2 receptor are discussed.
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cannabinoid receptor down regulation without alteration of the inhibitory effect of CP 55 940 on adenylyl cyclase in the cerebellum of CP 55 940 tolerant mice
Brain Research, 1996Co-Authors: Fang Fan, Qing Tao, Mary E Abood, Billy R MartinAbstract:The objective of this study was to determine whether the development of tolerance to CP 55,940, a potent cannabinoid agonist, was due to changes in the receptor or second messenger system. ICR mice treated with CP 55,940 (2 mg/kg) twice a day for 6 and one-half days developed a high degree of tolerance to the pharmacological effects of CP 55,940. The ability of CP 55,940 to produce motor hypoactivity, hypothermia and immobility was reduced 163-, 97- and 19-fold, respectively. Evaluation of 3H-CP 55,940 binding to rat brain membranes indicated no difference in receptor affinity between the vehicle- and CP 55,940-treated animals. However, these binding studies revealed a 50% decrease in receptor number in the cerebellum of the CP 55,940-tolerant mice. Although cAMP is generally considered to be the second messenger for cannabinoid receptors, little difference was observed in the inhibitory effects of CP 55,940 on adenylyl cyclase activity in cerebellum between vehicle and drug-treated mice. However, there was an increase in receptor mRNA which suggests a compensation for receptor loss. There are several possible explanations for these results. There may be sufficient spare receptors such that CP 55,940-tolerant mice are capable of producing a maximal effect on the second messenger system. On the other hand, one could conclude that cannabinoid receptor down-regulation does not account for the development of tolerance to all of the effects of CP 55,940 in mice.
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Evaluation of cAMP involvement in cannabinoid-induced antinociception
Life sciences, 1995Co-Authors: Stacie A. Cook, Sandra P. Welch, Aron H. Lichtman, Billy R MartinAbstract:Abstract It has been proposed that cannabinoids act at a Gi protein-coupled receptor to produce antinociception. One action of Gi-proteins is to decrease intracellular cAMP via inhibition of adenylyl cyclase activity. Although cannabinoid inhibition of forskolin-stimulated adenylyl cyclase is used as a confirmation of functional cannabinoid receptors, it is unknown whether this second messenger system specifically mediates cannabinoid-induced antinociception. This in vivo study was conducted using enantiomeric cAMP analogs, Rp-cAMPS (an antagonist) and Sp-cAMPS (an agonist), and the cAMP agonist Cl-cAMP to test the hypothesis that cannabinoid-induced antinociception is due to decreased adenylyl cyclase activity. None of the cAMP analogs, forskolin, or 1,9-dideoxy-forskolin affected Δ 9 -THC or CP-55,940-induced antinociception produced by intrathecal (i.t.) or intracerebroventricular (i.c.v.) injections in mice. Experiments were also conducted to investigate whether i.c.v. administration of Sp-cAMPS would block i.c.v. cannabinoid-induced antinociception in rats. Sp-cAMPS failed to block CP-55, 940-induced antinociception. However, Sp-cAMPS produced hyper-excitability and reactive behavior indicating that it did elicit a pharmacological effect. Although, adenylyl cyclase may mediate other cannabinoid-induced actions, these results do not support the hypothesis that it is involved in cannabinoid-induced antinociception. Alternatively, other effector systems such as calcium or potassium channels coupled to cannabinoid receptors may mediate cannabinoid-induced antinociception.
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a comparison of the discriminative stimulus properties of delta 9 tetrahydrocannabinol and CP 55 940 in rats and rhesus monkeys
Journal of Pharmacology and Experimental Therapeutics, 1992Co-Authors: Lisa H Gold, Robert L Balster, R L Barrett, D T Britt, Billy R MartinAbstract:CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3- hydroxypropyl)cyclohexanol] is a potent bicyclic analog of delta 9-tetrahydrocannabinol (THC) which has been used as a probe for a cannabinoid recognition site in neural tissue. In the present study, CP 55,490 was evaluated for delta 9-THC-like effects in rats and rhesus monkeys trained to discriminate delta 9-THC from vehicle. Rats trained to discriminate delta 9-THC (3.0 mg/kg i.p.) from vehicle were tested with various doses of delta 9-THC and CP 55,940 at both 30 and 90 min postinjection. Catalepsy was measured immediately after these operant tests using an adaptation of the mouse ring-test. In rats, CP 55,940 substituted for delta 9-THC at both 30 and 90 min postinjection at a dose of 0.1 mg/kg that had minimal effects on rates of responding. Doses of delta 9-THC (greater than 3.0 mg/kg) and CP 55,940 (greater than 0.1 mg/kg) that reduced response rates by greater than 50% also produced substantial increases in catalepsy. CP 55,940 and delta 9-THC had a similar time course for discriminative stimulus effects, but CP 55,940 was about 30 times more potent. In monkeys, the training dose of delta 9-THC ranged from 0.04 to 0.16 mg/kg i.m., adjusted individually to minimize response-rate disruption. After training, monkeys were tested with various doses of delta 9-THC and CP 55,940 at 30 min postinjection.(ABSTRACT TRUNCATED AT 250 WORDS)
Jano J Janoyan - One of the best experts on this subject based on the ideXlab platform.
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reversal of sr 141716a induced head twitch and ear scratch responses in mice by δ9 thc and other cannabinoids
Pharmacology Biochemistry and Behavior, 2002Co-Authors: Jano J Janoyan, Jennifer L Crim, Nissar A DarmaniAbstract:Abstract 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 Δ 9 -tetrahydrocannabinol (Δ 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: Δ 9 -THC (2.5–20 mg/kg), Δ 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≥Δ 9 -THC=Δ 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>Δ 9 -THC=Δ 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.
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Reversal of SR 141716A-induced head-twitch and ear-scratch responses in mice by delta 9-THC and other cannabinoids.
Pharmacology biochemistry and behavior, 2002Co-Authors: Jano J Janoyan, Jennifer L Crim, Nissar A DarmaniAbstract: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.
Daniela Parolaro - One of the best experts on this subject based on the ideXlab platform.
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Chronic Morphine Modulates the Contents of the Endocannabinoid, 2-Arachidonoyl Glycerol, in Rat Brain
Neuropsychopharmacology, 2003Co-Authors: Daniela Viganò, Tiziana Rubino, Maria Grazia Cascio, Filomena Fezza, Angelo Vaccani, Vincenzo Di Marzo, Daniela ParolaroAbstract:Opioids and cannabinoids are among the most widely consumed drugs of abuse in humans and the phenomena of cross-tolerance or mutual potentiation have been demonstrated between the two drugs. Several authors have suggested that both drugs share common links in their molecular mechanisms of action, although this has been a matter of controversy. Furthermore, no data exist on the possible adaptive changes in the contents of arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), the two major endogenous ligands for cannabinoid receptors, in morphine-tolerant rats. In the present work, we investigated the alterations in cannabinoid receptor functionality and endocannabinoid levels in rats chronically treated with morphine (5 mg/kg, s.c., twice a day for 5 days). Autoradiographic-binding studies using [^3H]CP-55 940 revealed a slight but significant reduction in cannabinoid receptor level in the cerebellum and hippocampus of morphine-tolerant rats, while CP-55 940-stimulated [^35S]GTPγS binding showed a strong decrease (40%) in receptor/G protein coupling in the limbic area of these animals. Moreover, in the same brain regions we measured, by isotope-dilution gas chromatography/mass spectrometry, the contents of AEA and 2-AG. Chronic morphine exposure produced a strong reduction in 2-AG contents without changes in AEA levels in several brain regions (ie striatum, cortex, hippocampus, limbic area, and hypothalamus). These findings clearly demonstrate that prolonged activation of opioid receptors could alter the cannabinoid system, in terms of both receptor functionality and endocannabinoid levels, and suggest the involvement of this system, alone or in combination with other mediators, in the phenomenon of morphine tolerance.
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regulation of immune functions in rat splenocytes after acute and chronic in vivo treatment with CP 55 940 a synthetic cannabinoid compound
Journal of Neuroimmunology, 1997Co-Authors: Gabriela Patrini, Domenica Fuzio, Paola Sacerdote, Barbara Manfredi, Daniela ParolaroAbstract:Changes 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 out.
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changes in rat spleen cannabinoid receptors after chronic CP 55 940 an autoradiographic study
Pharmacology Biochemistry and Behavior, 1997Co-Authors: Paola Massi, Gabriela Patrini, Tiziana Rubino, Domenica Fuzio, Daniela ParolaroAbstract:Abstract We examined whether cannabinoid receptor density changes in the rat spleen after in vivo chronic exposure to cannabinoids. Rats received daily injections of 0.4 mg/kg IP of the synthetic cannabinoid receptor ligand CP-55,940 for 11 days. One h after the last injection on day 11, the rats were killed and spleen coronal sections were processed for receptor binding autoradiography with 10 nM of [ 3 H]CP-55,940 in the absence or presence of unlabeled CP-55,940 (10 μM). Densitometric analysis of the autoradiograms showed significant loss of [ 3 H]CP-55,940 binding of about 42% in chronic cannabinoid-treated, tolerant rats. Our findings indicate that cannabinoid receptors basically present in immune spleen cells are down-regulated by chronic exposure to cannabinoids, suggesting a role in immune modulation and in the impairment of immune function.
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chronic treatment with a synthetic cannabinoid CP 55 940 alters g protein expression in the rat central nervous system
Molecular Brain Research, 1997Co-Authors: Tiziana Rubino, Gabriela Patrini, Paola Massi, Marco Parenti, Daniela ParolaroAbstract:Prolonged exposure of rats to the synthetic cannabinoid receptor ligand, CP-55,940 (0.4 mg/kg, i.p. for 11 days), induced tolerance to analgesia, to the reduction in spontaneous locomotor activity and the incidence of splayed hind limbs. One hour after the last injection on day 11, the rats were killed and in situ hybridization was used to investigate the effect of treatment on G-protein α-subunit expression throughout the brain. Chronic cannabinoid exposure markedly reduced Gαs, Gαi and Gαo mRNA levels. The message for the αs-subunit was decreased in all the brain areas containing the basal autoradiographic signal; the decrease ranging from 25% in the thalamus to 45% in the mesencephalon. Also the basal Gαi expression was reduced in tolerant rats showing the greatest decrease in the forebrain (63%) in the cerebellum (58%) and in the mesencephalon (38%). The reduction in Gαo expression (25%) was more localized, being present only in the rostral portion of the brain (cortex, striatum and olfactory area). The alterations in α-subunits gene expression were not followed by any change in the amount of proteins. Our results indicate that, besides the receptor modification, alteration to the G-protein expression could be a molecular event associated with the development of cannabinoid tolerance.
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chronic cannabinoid CP 55 940 administration alters biotransformation in the rat
European Journal of Pharmacology, 1996Co-Authors: Barbara Costa, Daniela Parolaro, Mariapia ColleoniAbstract:The objective of this study was to investigate the effects of single and repeated administration of CP-55,940 [(-)-cis-3-[2-hydroxy-4-(1, 1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol)] on behaviour, energy metabolism and biotransformation. Single intraperitoneal administration to male Sprague-Dawley rats of CP-55,940 (0.4 mg/kg), induced a behavioural response characterized by 'splayed hind limbs', antinociception, hypothermia and a decrease in locomotor activity. Brain and liver mitochondria of the CP-55,940-treated rats exhibited an increase in respiration and no changes in ADP/O and citrate synthase specific activity. Repeated intraperitoneal administration of CP-55,940 (0.4 mg/kg, 11 days) induced behavioural tolerance, disappearance of the increase in the mitochondrial oxygen consumption as well as an increase in the monooxygenase activities and the content of liver microsomal cytochrome P450. Some hepatic metabolizing enzymes of the cytosolic glutathione-centre system were also affected. Previous studies had indicated that the tolerance after chronic administration of CP-55,940 could be due to down-regulation of brain cannabinoid receptors. The present findings demonstrate that the behavioural tolerance occurs together with modified biotransformation activities.
