Modulation of sensory neuron potassium conductances by anandamide indicates roles for metabolites

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+ 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+ 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+ imaging were used to characterize the actions of AEA on action potential firing and voltage‐activated K + 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 μ M AEA attenuated voltage‐activated K + currents and the recovery of KCl‐evoked Ca 2+ transients. The insensitivity of these responses to the CB 1 receptor antagonist rimonabant (100 n M ) 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 + currents and Ca 2+ influx. Conclusion and implications: These data suggest that the products of AEA metabolism by FAAH contribute to the attenuation of K + conductances and altered excitability of cultured sensory neurons. British Journal of Pharmacology (2008) 154 , 480–492; doi: 10.1038/bjp.2008.93 ; published online 31 March 2008