Receptor mechanism and antiemetic activity of structurally-diverse cannabinoids against radiation-induced emesis in the least shrew

Abstract

Xenobiotic cannabinoid CB1/CB2-receptor agonists appear to possess broad-spectrum antiemetic activity since they prevent vomiting produced by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, serotonin 5-HT3-receptor agonists, dopamine D2/D3-receptor agonists and morphine, via the stimulation of CB1-receptors. The purpose of this study was to evaluate whether structurally-diverse cannabinoids [Delta9-THC, (delta-9-tetrahydrocannabinol); (Delta8-THC, delta-8-tetrahydrocannabinol); WIN55,212-2, (R (+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)), methyl] pyrolol [1,2,3-de]-1,4 benzoxazinyl]-(1-naphthalenyl) methenone mesylate); and CP55,940, ((-)-3-[2-hydroxy-4-(1,1-dimethylheptyl]-4-[3-hydroxypropyl] cyclohexane-1-ol)), can prevent radiation-induced emesis. Exposure to total body radiation (0, 5, 7.5 and 10 Gy) caused robust emesis in the least shrew (Cryptotis parva) in a dose-dependent manner (ED50=5.99 (5.77-6.23) Gy) and all animals vomited at the highest tested dose of radiation. In addition, the radiation exposure reduced locomotor behaviors to a significant but mild degree in a non-dose-dependent fashion up to one hour post-treatment. Radiation-induced emesis (10 Gy) was blocked in a dose-dependent manner by the CB1/CB2-receptor agonists with the following ID50 potency order: CP55,940 (0.11 (0.09-0.12) mg/kg)>WIN55,212,2 (3.65 (3.15-4.23) mg/kg)=Delta8-THC (4.36 (3.05-6.22) mg/kg)>Delta9-THC (6.76 (5.22-8.75) mg/kg). Although the greater antiemetic potency and efficacy of Delta8-THC relative to its isomer Delta9-THC is unusual as the latter cannabinoid possesses higher affinity and potency for cannabinoid receptors in functional assays, the current data support the results of a clinical study in children suggestive of complete protection from emesis by Delta8-THC. This effect has not been clinically observed for Delta9-THC in cancer patients receiving chemo- or radiation-therapy. Cannabinoids prevented the induced emesis via the stimulation of cannabinoid CB1-receptors because the CB1 (SR141716A)--and not the CB2 (SR144528)--receptor antagonist reversed both the observed reduction in emesis frequency and shrew emesis protection afforded by either Delta9-THC or CP55,940 against radiation-induced emesis. These findings further suggest that the least shrew can be utilized as a versatile and inexpensive small animal model to rapidly screen the efficacy of investigational antiemetics for the prevention of radiation-induced emesis.

Fig. 1

This figure shows the top (upper photograph) and the side (bottom photograph) views of the plastic shrew holder. The top view shows two parallel rectangular bed grooves (each 3×1×1 cm) in the middle of the plain of the plastic slab. Each shrew bed has 3 small holes drilled along its length and one hole along its width. The side view shows locations of drilled holes and coverslip as well as the position of bed groves relative to its upper and lower surfaces.

Fig. 2

This figure represents the emetic dose-response effects of total body radiation during the 30 min post exposure observation period in the least shrew. Graph A depicts enhancements in the frequency of emesis (mean ± S.E.M.) whereas graph B shows percentage of shrews vomiting. ^*Significantly different from sham-treated control at P < 0.05.

Fig. 3

The antiemetic effects of Δ⁹ – THC against radiation-induced emesis in the least shrew. Different groups of shrews received i.p. either vehicle (0 mg/kg) or the cited doses of Δ⁹ – THC 30 min prior to a 10 Gy radiation exposure. Emetic parameters were recorded for 30 min postradiation. Graph A depicts attenuation in the frequency (mean ± S.E.M.) of emesis whereas graph B shows reduction in the percentage of shrews vomiting. ^*Significantly different from vehicle control at P < 0.05.

Fig. 4

The antiemetic effects of Δ⁸– THC against radiation-induced emesis in the least shrew. Different groups of shrews received i.p. either vehicle (0 mg/kg) or the cited doses of Δ⁸ – THC 30 min prior to a 10 Gy radiation exposure. Emetic parameters were recorded for 30 min postradiation. Graph A depicts attenuation in the frequency (mean ± S.E.M.) of emesis whereas graph B shows reduction in the percentage of shrews vomiting. ^*Significantly different from vehicle control at P < 0.05.

Fig. 5

The antiemetic effects of WIN55,212-2 against radiation-induced emesis in the least shrew. Different groups of shrews received i.p. either vehicle (0 mg/kg) or the cited doses of WIN55,212-2 30 min prior to a 10 Gy radiation exposure. Emetic parameters were recorded for 30 min postradiation. Graph A depicts attenuation in the frequency (mean ± S.E.M.) of emesis whereas graph B shows reduction in the percentage of shrews vomiting. ^*Significantly different from vehicle control at P < 0.05.

Fig. 6

The antiemetic effects of CP55,940 against radiation-induced emesis in the least shrew. Different groups of shrews received i.p. either vehicle (0 mg/kg) or the cited doses of CP55,940 30 min prior to a 10 Gy radiation exposure. Emetic parameters were recorded for 30 min postradiation. Graph A depicts attenuation in the frequency (mean ± S.E.M.) of emesis whereas graph B shows reduction in the percentage of shrews vomiting. ^*Significantly different from vehicle control at P < 0.05.

Fig. 7

The ability of the cannabinoid CB₁ receptor antagonist SR141716A (0, 1, 5 and 10 mg/kg, s.c.) to reverse the antiemetic effects of a fully effective dose of either Δ⁹ –THC (20 mg/kg, s.c., solid line) or CP55,940 (0.3 mg/kg, s.c., dashed line) to protect shrews from radiation (10 Gy) - induced emesis. SR141716A reversed the induced reductions in emesis frequency (graph A) and blocked the ability of both Δ⁹ –THC and CP55,940 to protect shrews from vomiting caused by radiation exposure (graph B). At 0 time, different groups of shrews received either vehicle or the cited doses of SR141716A s.c. and at 30 min Δ⁹ –THC or CP55,940. At 60 min shrews were exposed to 10 Gy radiation and emesis parameters were recorded for 30 min following the radiation exposure. ^*Significantly different from corresponding control at P < 0.05.

Fig. 8

This figure indicates a lack of additive or synergistic emetic interactive effects of the cannabinoid CB₁receptor antagonist SR141716A with a 10 Gy dose of radiation. The cited nonemetic s.c. doses of SR141716A were administered to different groups of shrews 60 min prior to a 10 Gy dose of radiation. Emetic parameters were recorded (graphs A and B) for 30 min after the last injection.

Fig. 9

The inhibitory effects of the cited doses of total body radiation on both the spontaneous locomotor activity (total distance moved, mean ± S.E.M. in meters) and the frequency of rearing behavior (mean ± S.E.M.) in the least shrew. The motor behaviors were recorded for a 10 min observation period between 5-15 min (graphs A and B) or at 10 min observation periods during the 5-15, 50-60 and 110-120 min post-radiation exposure intervals (graphs C and D) on different groups of shrews. The motor behaviors were recorded by a computerized video tracking, motion analysis, and behavior recognition system (EthoVision). ^*Significantly different from sham-treated control group at P < 0.05.