The plant cannabinoids (phytocannabinoids), cannabidiol (CBD), and Δ⁹-tetrahydrocannabinol (THC) were previously shown to activate transient receptor potential channels of both vanilloid type 1 (TRPV1) and ankyrin type 1 (TRPA1), respectively. Furthermore, the endocannabinoid anandamide is known to activate TRPV1 and was recently found to antagonize the menthol- and icilin-sensitive transient receptor potential channels of melastatin type 8 (TRPM8). In this study, we investigated the effects of six phytocannabinoids [i.e., CBD, THC, CBD acid, THC acid, cannabichromene (CBC), and cannabigerol (CBG)] on TRPA1- and TRPM8-mediated increase in intracellular Ca²⁺ in either HEK-293 cells overexpressing the two channels or rat dorsal root ganglia (DRG) sensory neurons. All of the compounds tested induced TRPA1-mediated Ca²⁺ elevation in HEK-293 cells with efficacy comparable with that of mustard oil isothiocyanates (MO), the most potent being CBC (EC₅₀ = 60 nM) and the least potent being CBG and CBD acid (EC₅₀ = 3.4–12.0 μM). CBC also activated MO-sensitive DRG neurons, although with lower potency (EC₅₀ = 34.3 μM). Furthermore, although none of the compounds tested activated TRPM8-mediated Ca²⁺ elevation in HEK-293 cells, they all, with the exception of CBC, antagonized this response when it was induced by either menthol or icilin. CBD, CBG, THC, and THC acid were equipotent (IC₅₀ = 70–160 nM), whereas CBD acid was the least potent compound (IC₅₀ = 0.9–1.6 μM). CBG inhibited Ca²⁺ elevation also in icilin-sensitive DRG neurons with potency (IC₅₀ = 4.5 μM) similar to that of anandamide (IC₅₀ = 10 μM). Our findings suggest that phytocannabinoids and cannabis extracts exert some of their pharmacological actions also by interacting with TRPA1 and TRPM8 channels, with potential implications for the treatment of pain and cancer.

Background and purpose: The phytocannabinoid, Δ⁹‐tetrahydrocannabivarin (THCV), can block cannabinoid CB₁receptors. This investigation explored its ability to activate CB₂receptors, there being evidence that combined CB₂activation/CB₁blockade would ameliorate certain disorders.Experimental approach: We tested the ability of THCV to activate CB₂receptors by determining whether: (i) it inhibited forskolin‐stimulated cyclic AMP production by Chinese hamster ovary (CHO) cells transfected with human CB₂(hCB₂) receptors; (ii) it stimulated [³⁵S]GTPγS binding to hCB₂CHO cell and mouse spleen membranes; (iii) it attenuated signs of inflammation/hyperalgesia induced in mouse hind paws by intraplantar injection of carrageenan or formalin; and (iv) any such anti‐inflammatory or anti‐hyperalgesic effects were blocked by a CB₁or CB₂receptor antagonist.Key results: THCV inhibited cyclic AMP production by hCB₂CHO cells (EC₅₀= 38 nM), but not by hCB₁or untransfected CHO cells or by hCB₂CHO cells pre‐incubated with pertussis toxin (100 ng·mL⁻¹) and stimulated [³⁵S]GTPγS binding to hCB₂CHO and mouse spleen membranes. THCV (0.3 or 1 mg·kg⁻¹i.p.) decreased carrageenan‐induced oedema in a manner that seemed to be CB₂receptor‐mediated and suppressed carrageenan‐induced hyperalgesia. THCV (i.p.) also decreased pain behaviour in phase 2 of the formalin test at 1 mg·kg⁻¹, and in both phases of this test at 5 mg·kg⁻¹; these effects of THCV appeared to be CB₁and CB₂receptor mediated.Conclusions and implications: THCV can activate CB₂receptorsin vitroand decrease signs of inflammation and inflammatory pain in mice partlyviaCB₁and/or CB₂receptor activation.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visithttp://dx.doi.org/10.1111/j.1476‐5381.2010.00831.x

Background and purpose: Salvinorin A, the active component of the hallucinogenic herbSalvia divinorum, inhibits intestinal motility through activation of κ‐opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A‐induced delay in motility in the inflamed gut.Experimental approach: Motilityin vivowas measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.Key results: Salvinorin A as well as the KOR agonist U‐50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U‐50488 was counteracted by the KOR antagonist nor‐binaltorphimine and by the cannabinoid CB₁receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB₁and CB₂and no inhibitory effect on 2‐arachidonoylglycerol and anandamide hydrolysis and cellular uptake.Conclusions and implications: The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB₁receptors and KORs in the inflamed—but not in the normal—gutin vivo.British Journal of Pharmacology(2008)155, 681–689; doi:10.1038/bjp.2008.294; published online 14 July 2008

N‐oleoylethanolamine (OEA) and N‐palmitoylethanolamine (PEA) are endogenous lipids that activate peroxisome proliferator–activated receptor‐α with high and intermediate potency, and exert anorectic and anti‐inflammatory actions in rats, respectively. We investigated OEA and PEA tissue level regulation by the nutritional status in lean and obese rats. OEA and PEA levels in the brainstem, duodenum, liver, pancreas, and visceral (VAT) or subcutaneous (SAT) adipose tissues of 7‐week‐old wild‐type (WT) and Zucker rats, fed ad libitum or following overnight food deprivation, with and without refeeding, were measured by liquid chromatography–mass spectrometry. In WT rats, duodenal OEA, but not PEA, levels were reduced by food deprivation and restored by refeeding, whereas the opposite was observed for OEA in the pancreas, and for both mediators in the liver and SAT. In ad lib fed Zucker rats, PEA and OEA levels were up to tenfold higher in the duodenum, slightly higher in the brainstem, and lower in the other tissues. Fasting/refeeding‐induced changes in OEA levels were maintained in the duodenum, liver, and SAT, and lost in the pancreas, whereas fasting upregulated this compound also in the VAT. The observed changes in OEA levels in WT rats are relevant to the actions of this mediator on satiety, hepatic and adipocyte metabolism, and insulin release. OEA dysregulation in Zucker rats might counteract hyperphagia in the duodenum, but contribute to hyperinsulinemia in the pancreas, and to fat accumulation in adipose tissues and liver. Changes in PEA levels might be relevant to the inflammatory state of Zucker rats.