4 THCV also antagonized R-( þ )-WIN55212, anandamide, methanandamide and CP55940 in the vas deferens, but with lower apparent K B -values (1.5, 1.2, 4.6 and 10.3 nM, respectively). 5 THCV (100 nM) did not oppose clonidine, capsaicin or (À)-7-hydroxy-cannabidiol-dimethylheptyl-induced inhibition of electrically evoked contractions of the vas deferens. 6 Contractile responses of the vas deferens to phenylephrine hydrochloride or b,g-methylene-ATP were not reduced by 1 mM THCV or R-( þ )-WIN55212, suggesting that THCV interacts with R-( þ )-WIN55212 at prejunctional sites. 7 At 32 mM, THCV did reduce contractile responses to phenylephrine hydrochloride and b,gmethylene-ATP, and above 3 mM it inhibited electrically evoked contractions of the vas deferens in an SR141716A-independent manner. 8 In conclusion, THCV behaves as a competitive CB 1 and CB 2 receptor antagonist. In the vas deferens, it antagonized several cannabinoids more potently than THC and was also more potent against CP55940 and R-( þ )-WIN55212 in this tissue than in brain membranes. The bases of these agonist-and tissue-dependent effects remain to be established.

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Background and purpose: The endogenous cannabinoid anandamide (AEA) acts at cannabinoid (CB 1 ) and vanilloid (TRPV 1 ) receptors. AEA also shows antinociceptive properties; although the underlying mechanism for this is not fully understood, both CB 1 and TRPV 1 may be involved. Voltage-activated Ca 2 þ channels in rat-cultured dorsal root ganglion (DRG) neurons are modulated by AEA. However, AEA in different populations of neurons enhanced or attenuated KCl-evoked Ca 2 þ influx; these effects were linked with soma size. The aim of this study was to determine how AEA or its metabolites might produce these variable responses. Experimental approach: The whole cell patch-clamp technique and fura-2 Ca 2 þ imaging were used to characterize the actions of AEA on action potential firing and voltage-activated K þ currents and to determine whether AEA metabolism plays any role in its effects on cultured DRG neurons. Key results: AEA attenuated multiple action potential firing evoked by 300 ms depolarizing current commands in a subpopulation of DRG neurons. Application of 1 mM AEA attenuated voltage-activated K þ currents and the recovery of KClevoked Ca 2 þ transients. The insensitivity of these responses to the CB 1 receptor antagonist rimonabant (100 nM) and preincubation of DRG neurons with pertussis toxin suggested that these actions are not CB 1 receptor-mediated. Preincubating DRG neurons with the fatty acid amide hydrolase (FAAH) inhibitor phenylmethylsulphonyl fluoride (PMSF) attenuated the inhibitory actions of AEA on K þ currents and Ca 2 þ influx. Conclusion and implications: These data suggest that the products of AEA metabolism by FAAH contribute to the attenuation of K þ conductances and altered excitability of cultured sensory neurons.