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 [Δ⁹‐THC, (delta‐9‐tetrahydrocannabinol); (Δ⁸‐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) = Δ⁸‐THC (4.36 (3.05–6.22) mg/kg) > Δ⁹‐THC (6.76 (5.22–8.75) mg/kg). Although the greater antiemetic potency and efficacy of Δ⁸‐THC relative to its isomer Δ⁹‐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 Δ⁸‐THC. This effect has not been clinically observed for Δ⁹‐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 Δ⁹‐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.

Introduction

Chemotherapy, radiotherapy and surgery are the main modalities of cancer treatment. In contrast to chemotherapy, radiotherapy and surgery are generally for local treatment. Vomiting and nausea are among the most distressing aspects of cancer treatment Griffin et al., 1996, Kayl and Meyers, 2006, which impair patients’ quality of life (Osoba et al., 1996). Numerous published clinical trials as well as reviews have dealt with the problems, possible solutions and mechanisms by which highly emetogenic chemotherapeutics such as cisplatin induce nausea and vomiting (e.g. Hesketh et al., 2003; Veyrat‐Follet et al., 1997). Although not all patients tend to vomit following radiotherapy, a significant proportion do experience emesis following total body or upper abdominal irradiation (Maranzano, 2001). Effective control of radiation‐induced emesis is important since emesis persisting throughout radiotherapy can cause dehydration, electrolyte imbalance and malnutrition (Jereczek‐Fossa et al., 2001).

Relatively few randomized clinical trials have evaluated the efficacy of various antiemetic drugs preventing radiation‐induced emesis Maranzano, 2001, Feyer et al., 2005, Scarantino et al., 1994. Dopamine D₂‐receptor antagonists are effective in only about 50% of patients, whereas serotonin 5‐HT₃‐receptor antagonists, either alone or in combination with a glucocorticoid such as dexamethasone, appear to be more, but not completely, effective antiemetics against highly emetogenic regimens such as total body irradiation. A small number of available clinical studies also suggest that cannabinoids (e.g. delta‐9‐tetrahydrocannabinol, nabilone or levonantradol) can be useful for the prevention of radiation‐induced emesis Ungerleider et al., 1982, Priestman et al., 1987, Lucraft and Palmer, 1982. The D₂‐ and 5‐HT₃‐receptor antagonists’ antiemetic efficacies have been suggested to be dependent upon selective blockade of corresponding specific dopaminergic‐ and serotonergic‐receptor subtypes (Maranzano et al., 2005). However, the receptor mechanism by which cannabinoid agonists prevent radiation‐induced emesis remains unknown. Four chemically diverse groups of cannabinoid receptor agonists exist (Pertwee, 1999). Delta‐9‐tetrahydrocannabinol (Δ⁹‐THC) and its isomer Δ⁸‐THC are members of the “classical cannabinoids”, whereas CP55,940 ([1α, 2β‐(R)‐5α]‐(−)‐5‐(1,1‐dimethyl)‐2‐[5‐hydroxy‐2 (3‐hydroxypropyl) cyclohexyl‐phenol]) represents the nonclassical cannabinoid group. The aminoalkylindole cannabinoids consist of the pravadoline derivatives such as WIN55,212‐2 [R (+)‐[2,3‐dihydro‐5‐methyl‐3‐[(morpholinyl)methyl] pyrolol [1,2,3‐de]‐1, 4‐benzoxazinyl]‐(1‐naphthalenyl) methanone mesylate]. The fourth group is endocannabinoids, which constitute arachidonic acid derivatives such as anandamide and 2‐arachidonoylglycerol. Exogenous cannabinoids (plant derived and synthetic) and endocannabinoids produce their effects mainly via the stimulation of at least two cannabinoid receptors called CB₁ and CB₂ (Onaivi et al., 2006). The cannabinoid CB₁ receptor is preferentially located in the brain, spinal cord and peripheral neurons, whereas the cannabinoid CB₂ receptor is mainly found on peripheral tissues. The clinical potential of antiemetic cannabinoids predates basic animal investigations (Darmani, 2002a). Recent animal studies have shown that cannabinoid CB₁‐ and CB₂‐ receptor agonists of diverse structure and activity prevent chemotherapy‐induced emesis via the activation of cannabinoid CB₁ receptors (Darmani, 2001a,Darmani, 2001b, Darmani et al., 2003, Van Sickle et al., 2001, Van Sickle et al., 2005; Kwiatkowska et al., 2004). Indeed, the cannabinoid CB₁‐receptor is present in several emetic nuclei in the brainstem Darmani et al., 2003, Van Sickle et al., 2003. A more recent study also indicates an expression of CB₂ receptor messenger RNA and its protein in such nuclei and suggests a possible modulatory role for CB₂ receptors in emesis (Van Sickle et al., 2005).

Preliminary studies indicated that exposure to radiation induces emesis in the least shrew (Cryptotis parva). This animal model has been extensively used in our laboratory for the characterization of emetic circuits (reviews: Darmani, 2002a, Darmani, 2006). The purpose of this investigation was to evaluate: 1) whether radiation‐induced emesis is dose‐related in the least shrew, 2) the antiemetic structure–activity relationship among the cited diverse cannabinoid CB₁/CB₂ receptor agonists against radiation‐induced emesis, 3) whether the antiemetic activity of cannabinoids against radiation‐induced emesis is a CB₁‐ or CB₂‐receptor‐mediated event, 4) if radiation exposure can alter motor behaviors in the least shrew since such treatment causes lethargy in patients (Jones et al., 2005) and can reduce locomotion in rodents (Van der Meeren and Lebaron‐Jacobs, 2001) and nonrodent emetic species (King and Landauer, 1990).