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Effect of cannabidiolic acid and ∆9-tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain

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Rationale Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ⁹-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties. Objectives The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD’s potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA. Results CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA’s effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation. Conclusion CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.
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ORIGINAL INVESTIGATION
Effect of cannabidiolic acid and Δ
9
-tetrahydrocannabinol
on carrageenan-induced hyperalgesia and edema in a rodent model
of inflammatory pain
Erin M. Rock
1
&Cheryl L. Limebeer
1
&Linda A. Parker
1
Received: 16 January 2018 /Accepted: 7 September 2018 /Published online: 17 September 2018
#Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Rationale
Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ
9
-tetrahydrocannabiol (THC), shows anti-
hyperalgesia and anti-inflammatory properties.
Objectives
The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBDs potent acidic precursor, cannabidiolic
acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically
(intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or
CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we
compare the efficacy of CBD and CBDA.
Results
CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and
anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-
hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a
cannabinoid 1 receptor antagonist), while CBDAs effects were blocked by AMG9810 (a transient receptor potential cation
channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce
hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of
CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation.
Conclusion
CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia
effects in this animal model of acute inflammation.
Keywords Inflammation .Hyperalgesia .Δ
9
-Tetrahydrocannabiol .Cannabidiolic acid .Cannabidiol .Rat .Carrageenan .
SR141716 .AMG9810
Introduction
Cannabis sativa has been used medicinally for centuries. The
cannabis plant consists of over 100 cannabinoid compounds,
the primary ones being the psychoactive component Δ
9
-tetra-
hydrocannabinol (THC), and the non-intoxicating component
cannabidiol (CBD). The most frequently reported use of med-
ical cannabis is for pain relief (e.g., Ogborne et al. 2000;
*Linda A. Parker
parkerl@uoguelph.ca
1
Department of Psychology and Collaborative Neuroscience
Program, University of Guelph, Guelph, ON N1G2W1, Canada
Psychopharmacology (2018) 235:32593271
https://doi.org/10.1007/s00213-018-5034-1
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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Aims: To investigate the effects and interactions of sex and stress (provoked by chronic restraint [RS]) on pain-like behavior in a rat model of trigeminal neuropathic pain. Methods: The effects of sex and RS (carried out for 14 days as a model for stress) on somatosensory measures (reaction to pinprick, von Frey threshold) in a rat model of trigeminal neuropathic pain were examined. The study design was 2 × 4, with surgery (pain) and sham surgery (no pain) interacting with male restrained (RS) and unrestrained (nRS) rats and female RS and nRS rats. A total of 64 Sprague Dawley rats (32 males and 32 females) were used. Half of the animals in each sex group underwent RS, and the remaining half were left unstressed. Following the RS period, trigeminal neuropathic pain was induced by unilateral infraorbital nerve chronic constriction injury (IOCCI). Half of the animals in the RS group and half in the nRS group (both males and females) were exposed to IOCCI, and the remaining halves to sham surgery. Elevated plus maze (EPM) assessment and plasma interferon gamma (IFN-γ) levels were used to measure the effects of RS. Analysis of variance (ANOVA) was used to assess the effects of stress, sex, and their interactions on plasma IFN-γ levels, changes in body weight, EPM parameters, tactile allodynia, and mechanohyperalgesia. Pairwise comparisons were performed by using Tukey post hoc test corrected for multiple comparisons. Results: Both male and female RS rats showed significantly altered exploratory behavior (as measured by EPM) and had significantly lower plasma IFN-γ levels than nRS rats. Rats exposed to RS gained weight significantly slower than the nRS rats, irrespective of sex. Following RS but before surgery, RS rats showed significant bilateral reductions in von Frey thresholds and significantly increased pinprick response difference scores compared to nRS rats, irrespective of sex. From 17 days postsurgery, RSIOCCI rats showed significantly reduced von Frey thresholds and significantly increased pinprick response difference scores compared to nRS-IOCCI rats, and the von Frey thresholds were significantly lower in females than in males. RS-sham females-but not RS-sham males-developed persistently reduced thresholds and increased pinprick response difference scores. Conclusion: RS produced an increased bilateral sensitivity to stimuli applied to the vibrissal pad following infraorbital nerve injury, irrespective of sex. This observed sensitivity subsequently persisted in RS-sham female rats but not in RS-sham male rats. Stress induced a significant but moderate increase in pain-like behavior in female rats compared to male rats. RS had no significant sex effects on IFN-γ levels, EPM parameters, or body weight gain. This suggests that stress may have a selective effect on pain-like behavior in both sexes, but the possible mechanisms are unclear.
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Objectives: Knowledge of the exact concentration of active compounds in galenic preparations is crucial to be able to ensure their quality and to properly administer the prescribed dose. Currently, the need for titration of extracts is still debated. Considering this, together with the absence of a standard preparation method, the aim of this study was to evaluate cannabinoids concentrations variability in galenic olive oil extracts, to evaluate the interlot and interlaboratory variability in the extraction yield and in the preparation composition. Methods: Two hundred and one extracts (123 (61.2%) from Bedrocan(®) , 54 (26.9%) from Bediol(®) , 11 (5.5%) from Bedrolite(®) , and 13 (6.5%) from mixed preparations) were analysed by liquid chromatography coupled with tandem mass spectrometry, quantifying cannabinoids (THC, CBD, THCA, CBDA and CBN) concentrations. Key findings: The RSD% of THC and CBD concentrations resulted higher than 50%. Specifically for Bedrocan(®) , Bediol(®) , Bedrolite(®) (5 g/50 ml), these were THC 82%, THC 53% and CBD 91%, THC 58% and CBD 59%, respectively. The median extraction yields were greater than 75% for all preparations. Conclusions: Our results highlighted a wide variability in THC and CBD concentrations that justify the need for titration and opens further questions about other pharmaceutical preparations without regulatory indication for this procedure.
Article
Significance: Cannabinoids consistently produced antinociceptive effects in preclinical models, whereas they heterogeneously influenced the perception of experimentally induced pain in humans and did not provide robust clinical analgesia, which jeopardizes the translation of preclinical research on cannabinoid-mediated antinociception into the human setting.
Article
The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are over 550 chemical compounds and over 100 phytocannabinoids isolated from cannabis, including Δ(9)-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC induced anxiety, psychosis and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from pre-clinical and human studies particularly with reference to anxiety and psychosis like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings including the individual and interactive effects of CBD and THC.Neuropsychopharmacology accepted article preview online, 06 September 2017. doi:10.1038/npp.2017.209.