Interactions among the cannabinoids in the antagonism of the abdominal constriction response in the mouse

The ability of ⁹-tetrahydrocannabinol (THC), cannabinol (CBN), cannabidiol (CBD), 11-OH THC and 8,11-diOH THC to antagonise the abdominal constriction response in the mouse induced by formic acid, phenylquinone, 5-hydroxytryptamine, prostaglandin E₁ (PGE₁) and bradykinin was tested. THC was an effective antagonist against all nociceptive agents with an ED₅₀ in all cases between 1.0 and 2.6 mg/kg. CBN, while also effective against all nociceptive agents, was less potent than THC, with an ED₅₀ range between 46.2 and 112.5 mg/kg. CBD in doses as high as 200 mg/kg was without effect. Using PGE₁ as the nociceptive agent, 11-OH THC was equipotent to THC while 8,11-diOH THC was inactive. Naloxone, while able to antagonise the antinociceptive effect of morphine against formic acid-induced writhing, did not reverse the antinociceptive effects of THC. There were no pharmacological interactions between THC, CBD and CBN.     

Pharmacological studies of lappaconitine. Analgesic activities

The analgesic activity of lappaconitine, which is contained in the root of Aconitum sinomantanum Nakai, was examined after oral and subcutaneous administration to mice or rats by using methods for screening of analgesics, i.e., hot plate, tail immersion, tail pinch, tail pressure, acetic acid-induced writhing, bradykinin-induced flexor reflex of hind limb and Randall-Selitto methods. The results were compared with those for morphine, indometacin and acetylsalicylic acid (ASA). Analgesic activities of lappaconitine were greater than those of indometacin and ASA, but generally about 2 to 5 times less than those of morphine. However, in the rat tail immersion test, orally administered lappaconitine exhibited more potent analgesic activity than morphine; in this test, lappaconitine was almost equipotent when given orally and subcutaneously, whereas the potency of orally administered morphine was only one-twentieth of that of subcutaneously administered morphine. Like morphine, lappaconitine increased the pain threshold of the normal paw as well as that of the inflamed paw when tested by the Randall-Selitto method. The results show that lappaconitine has strong analgesic activity, and further suggest that the central nervous system may be involved in the action on the pain threshold.     

Modification of Δ9-THC-actions by cannabinol and cannabidiol in the rat

Cannabinol (CBN) and Cannabidiol (CBD) were tested in several test procedures known to be altered by ⁹-tetrahydrocannabinol (THC) or crude cannabis preparations. They were inactive in doses up to 80 mg/kg in tests on animal motility, food and water intake, body temperature and catalepsy. In contrast, CBD enhanced the hexobarbitone sleeping time more pronounced than ⁹-THC whereas CBN increased the sleeping time only slightly. When administered in combination CBD prolonged all actions of THC, whereas CBN selectively blocked the effect of THC on hexobarbitone sleeping time. The enhancement by CBD is best explained by an inhibition of THC-metabolism.This paper was in part presented at the C.I.N.P., Copenhagen, 1972.Supported in part by a research grant of the Bundesminister für Jugend, Familie und Gesundheit.     

A comparison of some pharmacological actions of morphine and Δ9-tetrahydrocannabinol in the mouse

The effects of morphine and ⁹-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.     

Morphine and Δ9-tetrahydrocannabinol: Two-way cross tolerance for antinociceptive and heart-rate responses in the rat

Tail-flick analgesic responses and heart-rate changes were measured in male Sprague-Dawley rats challenged with an acute IP morphine sulfate (MS) or ⁹-THC injection after receiving daily injections of ⁹-THC or morphine, respectively. Degree of tolerance development to each agent was determined before the cross-tolerance challenge was administered. Cross tolerance occurred to analgesic and bradycardic effects of a 10 mg/kg THC challenge in rats receiving 50 mg/kg MS injections over a 23-day period. Cross tolerance to the bradycardic effects of a 20 mg/kg MS challenge occurred in rats receiving seven daily 10 mg/kg ⁹-THC injections and to MS tail-flick analgesia after 14 days. Although rapid tolerance occurred during administration of both agents, cross tolerance to THC bradycardia occurred only in groups exhibiting complete tolerance to MS injections; cross tolerance to MS bradycardia was observed in animals that were only partially tolerant to THC injections. The data extend earlier cross tolerance data in the mouse to the rat, and provide new information using heart rate, a response that may mirror aversive internal states induced by drugs.     

Effect of The effects of Δ 9-tetrahydrocannabinol on the metabolism of norepinephrine in rat brain on the morphine-induced hyperactivity of mice

The effect of ⁹-tetrahydrocannabinol (THC) on the locomotor activity-stimulating action of morphine has been investigated in mice. THC (10 mg/kg) has been found to potentiate morphineinduced hyperactivity. On the other hand, the stimulating action of morphine on motor activity strongly diminished in mice rendered tolerant by the implantation of a morphine pellet. The pretreatment of morphine-tolerant mice with the same dose of THC did not change the effect of morphine on the motor activity. These results suggest that tolerance also developed to the potentiating action of THC on morphine-induced hyperactivity during the development of tolerance to this action of morphine.     

The effects of morphine and Δ-9-tetrahydrocannabinol on motor activity in rats

Acute treatment of rats either by high doses of morphine or ⁹-tetrahydrocannabinol (THC) decreased locomotor activity. Naloxone reversed morphine-induced depression completely and reversed THC-induced depression only partially. On day 3 of treatment, tolerance developed to the locomotor inhibitory action of THC or morphine and partial cross-tolerance was observed to the depressant action of THC. Naloxone slightly depressed locomotor activity in THC-tolerant rats, but increased motor activity in morphine-tolerant rats.     

Interaction between Δ 9-tetrahydrocannabinol and morphine on the motor activity of mice

The present experiments dealt the effects of ⁹-tetrahydrocannabinol (THC) on the locomotor activity stimulating action of morphine in mice. In the first series of experiments, the pretreatments of mice by THC in doses up to 20 mg/kg have been found to potentiate the morphine-induced hyperactivity in dose-dependent manner, but higher doses of THC did not produce such an action. In the second series of experiments the dose-response curve of morphine for the motor activity has been found to shift to the left by the pretreatment of mice with 10 mg/kg of THC. These results show a synergism between morphine and THC and suggest that both drugs may share some common site of action.     

Effect of cannabinoids on the abdominal constriction response in mice: within cannabinoid interactions

After oral administration to mice, ⁹-tetrahydrocannabinol (THC) and cannabinol (CBN) caused a dosedependent suppression of the abdominal constriction response to formic acid. Cannabinol was 50 times less active than THC and cannabidiol (CBD) was without effect. The effects of THC and CBN were additive. CBD antagonised the antinociceptive effects of both THC and CBN in a dose-dependent manner.     

Analgesic activity of the ethanolic extract of Shorea robusta resin in experimental animals

Aim:

Shorea robusta (Sal), an important traditional Indian medicinal plant used in various ailments and rituals and the indigenous use of the resin of this plant as a medicament for treatment of various inflammatory conditions is well documented in literature. In the present study, ethanolic extract of S. robusta resin (SRE) was evaluated for its analgesic activity by making use of different central and peripheral pain models.

Materials and Methods:

The analgesic activity of SRE was assessed by employing different pain models such as, i) hot plate and tail flick tests for central analgesia, ii) acetic acid- induced writhing (peripheral analgesic model), iii) formalin-induced hind paw licking (both central and peripheral model), iv) carrageenan-induced hyperalgesia (peripheral analgesic model) and v) post-surgical pain (peripheral analgesic model).

Results:

The extract produced significant central and peripheral analgesic effects, as is evident from increase in reaction time in hot plate and tail flick tests, inhibition in writhing counts in acetic acid-induced writhing test, inhibition of licking time in formalin-induced hind paw licking, increased pain threshold in paw withdrawal latency in carrageenan-induced hyperalgesia and increased paw withdrawal threshold in post-surgical pain.

Conclusion:

The results of the present study demonstrate marked antinociceptive effects of SRE.KEY WORDS: Carrageenan, hot plate, post-surgical pain, resin, Shorea robusta, tail flick     

Analgesic and anti-inflammatory activity of amifostine, DRDE-07, and their analogs, in mice

Objectives:

To find out the analgesic and anti-inflammatory activity, if any, of Amifostine [S-2(3 amino propyl amino) ethyl phosphorothioate], DRDE-07 [S-2(3 amino ethyl amino) ethyl phenyl sulphide] and their analogs DRDE-30 and DRDE-35, the probable prophylactic agent for sulphur mustard (SM).

Materials and Methods:

In order to find out the analgesic activities of the compounds two methods were employed, namely, acetic acid-induced writhing test and formalin-induced paw licking. The persistent pain model of formalin-induced hind paw licking was carried out to test the effect of the compounds on neurogenic pain or early phase (0 to 5 minutes) and on the peripheral pain or the late phase (15 to 30 minutes). To test the effect of the compound in acute inflammation, carrageenan-induced hind paw edema was carried out. This model of inflammation involves a variety of mediators of inflammation.

Results:

DRDE-07 (81.7%) and DRDE-30 (79.4%) showed significant reduction in the acetic acid-induced writhing test. DRDE-07 (93.1%), DRDE-30 (82%), and DRDE-35 (61.3%) showed significant reduction in the second or late phase of formalin-induced paw licking. All the analogs (more than 60%) including amifostine (43.9%) showed significant reduction of paw edema in the carrageenan-induced paw edema in mice.

Conclusion:

The analgesic and anti-inflammatory activity of the antidotes were comparable with aspirin.     

Species differences in the relative analgesic potencies of some classical opiates and opioid peptides

The analgesic ED₅₀ values of some classical morphine congeners (morphine, methadone, fentanyl, azidomorphine) in the rat and mouse tail-flick tests were found to be similar. However, several synthetic derivatives of the natural enkephalins were more potent in mice than in rats. (These analogs contain d-amino acid in position 2 and d- or l-sulfonic (or phosphonic) acid residue in position 5). -Endorpin, d-Met², Pro⁵-enkephalinamide and two partial agonists showed intermediate interspecies relative potencies. According to the data obtained, similar opiate receptors might mediate the analgesic action of classical opiates in rats and in mice. However, the opiate receptors responsible for the antinociceptive effects of the above mentioned enkephalin analogues must be dissimilar in the two species examined. The results are discussed in terms of the role of - and -receptors in mediation of the analgesic effect induced by different types of opioids.     

Dissociation between behavioral effects and changes in metabolism of cerebral serotonin following δ9-tetrahydrocannabinol

Behavioral changes, reaction times in analgesic tests and effects on metabolism of cerebral serotonin (5 HT) were monitored in male Sprague-Dawley rats following the administration of ⁹-tetrahydrocannabinol (THC) as a propylene glycol-serum complex. THC (5.5 mg/kg i.p. and 1.0 mg/kg i.v.) produced characteristic and reproducible behavioral effects, including catalepsy and squealing, as well as significant increases in the reaction time as determined in both the hot plate and tail flick tests for analgesia. Intraventricular injection of THC caused many of the changes seen after systemic administration of the drug. The levels of 5 HT and its principle metabolite, 5-hydroxyindoleacetic acid (5 HIAA) were measured in forebrain and brainstem following THC. No significant change in the level of either indole was observed. Moreover, THC did not alter the turnover of cerebral 5 HT as determined by the probenecid method and did not change the increase in 5 HT following the administration of pargyline. It may thus be concluded that doses of THC which produce significant and reproducible behavioral modifications do not alter the dynamics of the cerebral serotonergic system.Supported by USPHS Grants MH-11468 and 5-T01-GM00058.Presented in part before the American Society for Pharmacology and Experimental Therapeutics, Burlington, Vermont, August 1971 [Pharmacologist13, 296 (1971)].     

Effect of cannabinoids on the turnover rate of acetylcholine in rat hippocampus,striatum and cortex

Summary The effects of ⁹-tetrahydrocannabinol, (⁹THC) the major psychoactive compound of marijuana, and cannabidiol (CBD), a non-psychoactive component, on the acetylcholine (ACh) concentration and the turnover rate of ACh (TR_ACh) have been studied in various regions of the rat brain. Neither ⁹THC doses from 0.2 to 10 mg/kg nor CBD (10 or 20 mg/kg) alter the ACh concentration in the brain areas examined 30 min, after the intravenous injection. However, ⁹-THC (doses from 0.2 to 10 mg/kg) causes a marked dose-related decrease in the TR_ACh in hippocampus whereas CBD is without effect in this brain region even when 20 mg/kg is given. Furthermore, high doses of ⁹-THC (5 mg/kg) and CBD (20 mg/kg) that produce a significant decrease in the TR_ACh of striatum fail to change the TR_ACh in parietal cortex. The low doses of ⁹-THC required to reduce hippocampal TR_ACh suggest that an action on these cholinergic mechanisms may play a role in the psychotomimetic activity of ⁹-THC.     

Sensory,perceptual, motor and cognitive functioning and subjective reports following oral administration ofΔ 9-Tetrahydrocannabinol

Three dose levels, 0.2, 0.4 and 0.6 mg/kg, of ⁹-tetrahydrocannabinol (THC) and a placebo were orally administered to 10 frequent and 10 occasional marijuana users. Following ingestion of each dose and the placebo, objective tests selected from a battery of sensory and perceptual motor tests routinely used to evaluate cerebral dysfunction in hospitalized patients were administered. The influence of ⁹-THC on proficiency and variability of performance was minimal. However, when individual test scores and variabilities were combined and converted to standard scores, allowing for analysis of overall performance, THC had a small but consistent detrimental effect on both proficiency and variability of performance. In contrast, THC exerted profound effects on the subjective experiences of the volunteers as assessed by the Subjective Drug Effects Questionnaire. Subjective changes in mood, feeling, perception and somatic sensations were reported by all subjects but were more pronounced in the occasional user group. It was proposed that the small impairment noted in objective test performance after ingestion of ⁹-THC as contrasted to the large effects on subjective responses suggests that the principal effects of marijuana are on the autonomic nervous system rather than on higher cortical functions.Veterans Administration approved Research Project 0864-03. Also supported by U.S. Public Health Service Research Grant No. DA000.56 from the National Institute of Mental Health.     

Synthesis, Analgesic, and Anti-Inflammatory Activities of [6-(3,5-Dimethyl-4-Chloropyrazole-1-yl)-3(2H)-Pyridazinon-2-yl]Acetamides

A series of structurally diverse amide derivatives of [6-(3,5-dimethyl-4-chloro-pyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were prepared and tested for their in vivo analgesic and anti-inflammatory activity by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds, 7c, 7d and 7k were found to be equipotent to aspirin (as an analgesic) and indometacin (as an anti-inflammatory drug), respectively. The other amide derivatives generally resulted in lower activity on comparision with reference compounds.     

1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido [1,2-a] pyrimidine-3-carboxamide (Chinoin-127), a potent non-narcotic analgesic and antiinflammatory agent.

1,6-Dimethyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido[1,2-a]pyrimidine-3-carbamide (Chinoin 127), a non-narcotic analgesic with potent antiinflammatory activity is described. Chinoin-127 is more potent as an analgesic in the hot plate, Randall-Selitto and writhing tests than is acetylsalicylic acid (ASA) and an effective antiphlogistic agent in a battery of tests (carrageenin, kaolin and dextran induced rat paw edema, Northover test, carrageenin induced abscess, implanted cotton pellet method, adjuvant arthritis) used for measuring antiinflammatory activity. The PG-synthesis inhibitors (indometacin, suprofen) were found to be devoid of analgesic activity, and great test-dependent variations in their antiinflammatory effect were observed. They proved to be inactive in the Northover test. Unusual grade of inhibition in the carrageenin-induced rat paw edema test was obtainable by the simultaneous administration of Chinoin 127 and indometacin.     

Comparison of tolerance development and dependence capacities of morphine, β-endorphin,and [D-MET2, PRO5]-enkephalinamide

The tolerance-development capacities of -endorphin, [D-Met², Pro⁵]-enkephalinamide, and morphine were compared in rats, and the dependence capacity of morphine was compared with that of the enkephalin analogue in mice. Tolerance to the analgesic effect, as measured by the tail-flick test, developed somewhat more rapidly in the [D-Met², Pro⁵]-enkephalinamide-treated group than in the others. A similar relationship was found for the dependence capacity. Considering that the enkephalin analogue displayed the strongest analgesic activity, the wellknown correlation between antinociceptive and tolerance development/dependence capacities of opiates seems to be valid for opioid peptides as well.     

Pharmacological interaction between cannabinol and δ9-tetrahydrocannabinol

The pharmacological activities of ⁹-THC [(–)-⁹-trans-tetrahydrocannabinol], CBN (Cannabinol) and mixtures of ⁹-THC + CBN were studied in rabbits, rats and mice.CBN, although in general less active, mimicked the effects of ⁹-THC in several pharmacological tests: corneal arreflexia in rabbits; climbing rope, open-field, irritability and aggressiveness after REM sleep deprivation in rats; catatonia, analgesia and sleeping time in mice.When the mixture ⁹-THC + CBN was used, a synergistic effect occurred on most of the depressant effects. On the other hand CBN did not interfere with or slightly inhibited the excitatory effects of ⁹-THC. In the one peripheral test used, CBN did not alter the ⁹-THC effect.With a fellowship from FundaÇÃo de Amparo a Pesquisa do Estado de S. Paulo.     

The effect of (-) Δ 9-tetrahydrocannabinol,alone and in combination with ethanol,on human performance

Twenty five volunteers received (-) ⁹-tetrahydrocannabinol (THC) (320 g/kg) or placebo (both orally, T₀), and, 60 min later, they consumed an ethanolic beverage (0.54 g/kg) or placebo. The effects of this medication were measured at T₁ (100 min after THC ingestion), T₂ (160 min), T₃ (220 min) and T₄ (280 min) using a battery of cognitive, perceptual and motor function tests. Factorial analysis indicated that the test procedures could be adequately expressed by four rotated factors: a reaction speed factor (I), a cognitive factor (II), a standing steadiness factor (III) and a psychomotor coordination factor (IV), The first principal component (I) was used as a measure of general performance across the whole test battery.Both THC and ethanol produced significant decrements in the general performance factor. Ethanol produced significant decrements in standing steadiness and psychomotor coordination, while THC caused a significant deterioration in performance on all the four rotated factors. In all cases the peak effect of ethanol occurred at T₁ and by T₄ the effect had worn off. The performance decrements induced by THC were slower in onset and lasted longer than those induced by ethanol. In general, the peak effect of THC occurred at T₁ and T₂. There was no evidence of any interaction between THC and ethanol, and the effects of a combination of THC and ethanol were no more than additive. THC (but not ethanol) produced a significant rise in pulse rate. Prior administration of THC did not significantly affect the blood ethanol levels obtained. The subjects were able to identify correctly which of the treatments they had received.