A. T. Evans

Analgesic and antiinflammatory activity of constituents of Cannabis sativa L.

Two extacts ofCannabis sativa herb, one being cannabinoid-free (ethanol) and the other containing the cannabinoids (petroleum), were shown to inhibit PBQ-induced writhing in mouse when given orally and also to antagonize tetradecanoyl-phorbol acetate (TPA) -induced erythema of mouse skin when applied topically. With the exception of cannabinol (CBN) and δ1-tetrahydrocannabinol (δ1-THC), the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100Μg/kg. δ1-THC only became maximally effective in doses of 10 mg/kg. This higher dose corresponded to that which induced catalepsy and is indicative of a central action. CBN demonstrated little activity and even at doses in excess of 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. Cannabidiol (CBD) was the most effective of the cannabinoids at doses of 100Μg/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. The fact that δ1-THC and CBN were the least effective in this test suggests a structural relationship between analgesic activity and antiin-flammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of δ1-THC.

The Inhibitory Effects of Cannabinoids, The Active Constituents of Cannabis sativa L. on Human and Rabbit Platelet Aggregation

Olivetol, cannabigerol (CBG), cannabidiol (CBD), cannabinol (CBN) and tetrahydrocannabinol (δ1‐THC) were assessed for their ability to inhibit agonist‐induced platelet aggregation and [14C]5‐HT release. With the exception of olivetol, (40% maximal effectiveness), none of the compounds inhibited tetradecanoylphorbolacetate (TPA)‐induced aggregation of human or rabbit platelets. All of these cannabinoids partially inhibited primary aggregation and totally inhibited secondary aggregation of human platelets when adrenaline was used as the agonist. Inhibition was dose‐dependent over the range 10−3–10−5 M. Both rabbit and human platelet aggregation induced by adenosine diphosphate was inhibited in a dose‐dependent manner and the order of potency was CBG > CBD > olivetol > THC > CBN, the IC50 of CBG being 2·7 × 10−4M. PAF‐induced aggregation of rabbit platelets was also inhibited by these compounds in a dose‐dependent manner over the concentration range 10−3 to 10−4 M, however [14C]5‐HT release was only partially prevented by the cannabinoids in a manner which did not correlate with inhibition of aggregation.

Activation of phospholipase A2 by cannabinoids: Lack of correlation with CNS effects

Cannabinoids Δ1-tetrahydrocannabinol, cannabinol, cannabidiol and cannabigerol have been shown to affect directly the activity of phospholipase A2 in a cell-free assay. The compounds produced a biphasic activation of the enzyme, with EC50 values in the range 6.0–20.0 × 10−6 M and IC50 values in the range 50.0–150.0 × 10−6M. These results correlated well with the relative potencies reported for the stimulation of prostaglandin release from human synovial cells in vitro, confirming that activation of phospholipase A2 is the predominant action of cannabinoids on arachidonate metabolism in tissue culture. However, since Δ1-tetrahydrocannabinol is unique among these compounds in possessing cataleptic activity, it is unlikely that phospholipase A2 is the major receptor mediating the psychotropic effects of cannabis.Cannabinoids Δ1‐tetrahydrocannabinol, cannabinol, cannabidiol and cannabigerol have been shown to affect directly the activity of phospholipase A2 in a cell‐free assay. The compounds produced a biphasic activation of the enzyme, with EC50 values in the range 6.0–20.0 × 10−6 M and IC50 values in the range 50.0–150.0 × 10−6M. These results correlated well with the relative potencies reported for the stimulation of prostaglandin release from human synovial cells in vitro, confirming that activation of phospholipase A2 is the predominant action of cannabinoids on arachidonate metabolism in tissue culture. However, since Δ1‐tetrahydrocannabinol is unique among these compounds in possessing cataleptic activity, it is unlikely that phospholipase A2 is the major receptor mediating the psychotropic effects of cannabis.

Toxic phorbol esters from Chinese tallow stimulate protein kinase C

Phorbol esters were isolated from the seeds of Chinese tallow (Sapium sebiferum L. Roxb.). These compounds were based on the tigliane nuclei, 4-deoxyphorbol, 12-deoxyphorbol and 4,20-dideoxy-5-hydroxyphorbol. The pro-inflammatory activity (ID50) of the pure compounds was between 0.042 and 2.6 nmoles per ear. Protein kinase C activation assays were carried out on samples of enzyme purified from mammalian brain and the activities (Ka) were in the range 76-176 nM. The 4,20-dideoxy-5-hydroxy analogue was inactive in both tests. Chinese tallow, which is used as a substitute for linseed oil, may represent an industrial toxic hazard in terms of both pro-inflammatory and tumour-promoting effects.

Inhibition of the cataleptic effect of tetrahydrocannabinol by other constituents of Cannabis sativa L.

Abstract— Tetrahydrocannabinol (THC) induced catalepsy in mice, whereas a cannabis oil (6.68% w/w THC), four cannabinoids and a synthetic mixture did not. Cannabinol (CBN) and olivetol inhibited THC‐induced catalepsy in the mornings and the evenings, but cannabidiol (CBD) exhibited this effect only in the evenings. A combination of CBN and CBD inhibited THC‐induced catalepsy equal to that of CBN alone in the mornings, but this inhibition was greater than that produced by CBN alone in the evenings.