Pharmacological evaluation of the natural constituent of Cannabis sativa, cannabichromene and its modulation by Δ9-tetrahydrocannabinol☆

Abstract

In contrast to the numerous reports on the pharmacological effects of Δ 9 -tetrahydrocannabinol (THC), the pharmacological activity of another substituent of Cannabis sativa, cannabichromene (CBC) remains comparatively unknown. In the present study, we investigated whether CBC elicits cannabinoid activity in the tetrad assay, which consists of the following four endpoints: hypomotility, antinociception, catalepsy, and hypothermia. Because cannabinoids are well documented to possess anti-inflammatory properties, we examined CBC, THC, and combination of both phytocannabinoids in the lipopolysaccharide (LPS) paw edema assay. CBC elicited activity in the tetrad that was not blocked by the CB 1 receptor antagonist, rimonabant. Moreover, a behaviorally inactive dose of THC augmented the effects of CBC in the tetrad that was associated with an increase in THC brain concentrations. Both CBC and THC elicited dose-dependent anti-inflammatory effects in the LPSinduced paw edema model. The CB 2 receptor, SR144528 blocked the anti-edematous actions of THC, but not those produced by CBC. Isobolographic analysis revealed that the anti-edematous effects of these cannabinoids in combination were additive. Although CBC produced pharmacological effects, unlike THC, its underlying mechanism of action did not involve CB 1 or CB 2 receptors. In addition, there was evidence of a possible pharmacokinetic component in which CBC dose-dependently increased THC brain levels following an i.v. injection of 0.3 mg/kg THC. In conclusion, CBC produced a subset of behavioral activity in the tetrad assay and reduced LPS- To whom correspondence should be addressed: Aron H. Lichtman. Tel: (804) 828-8480; Fax (804) 828-2117; alichtma@vcu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Contributors G.T. DeLong conducted the bulk of the studies, analysis of data, and writing of the manuscript. C.E. Wolf contributed to the laboratory procedures for analytical studies. A. Poklis contributed to the design of the analytical studies. A.H. Lichtman oversaw the study, along with contributing to the writing of the manuscript. Conflict of InterestNone of the authors report a conflict of interest that could have influenced, or be perceived to influence, this work. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript induced paw edema through a noncannabinoid receptor mechanism of action. These effects were augmented when CBC and THC were co-administered.

Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation

“…in vivo to mice at the dose of 15 mg kg −1 , could at least modify the mRNA expression of these channels and evaluated the effect of this major cannabinoid on the levels of the mRNA encoding for TRPV1–4 channels in the jejunum and ileum. Given the pro‐inflammatory effects of TRP channels and the anti‐inflammatory effect of CBC (DeLong et al. 2010), we have also carried out these experiments in croton oil‐treated mice, in which there is inflammation of the upper gastrointestinal tract.…”

Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

“…More recently, THCV was shown to antagonise some of the effects of THC in mice, such as analgesia and hypothermia, due to THCV behaving as a cannabinoid receptor antagonist (Pertwee et al, 2007). The co-administration of CBC with THC promoted additive effects on catalepsy, analgesia and inflammation in mice, which might be attributable to CBC enhancing the brain concentrations of THC (DeLong et al, 2010). Clearly more studies are needed in this area, to carefully evaluate the pros and cons of cannabinoid combination psychopharmacology, and assist in the development of medicinal cannabis and cannabinoid therapies.…”

Different receptor mechanisms underlying phytocannabinoid‐ versus synthetic cannabinoid‐induced tetrad effects: Opposite roles of CB1/CB2 versus GPR55 receptors

“…However, little is known about other non-CB 1 receptor mechanisms in cannabinoid action. We and others have recently reported that functional CB 2 receptors are also expressed in the brain (see a comprehensive review by Jordan & Xi, 2019) and are involved in multiple behavioural effects of Δ 9 -THC or other cannabinoids in experimental animals (DeLong, Wolf, Poklis, & Lichtman, 2010;Lesniak et al, 2019;Liu et al, 2017). Although, little is known if brain CB 2 receptors are also involved in cannabinoidinduced tetrad effects.…”