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

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Abstract
Background and purpose: The endogenous cannabinoid anandamide (AEA) acts at cannabinoid (CB1) and vanilloid (TRPV1) receptors. AEA also shows antinociceptive properties; although the underlying mechanism for this is not fully understood, both CB1 and TRPV1 may be involved. Voltage‐activated Ca2+ 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 Ca2+ 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 Ca2+ 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 μM AEA attenuated voltage‐activated K+ currents and the recovery of KCl‐evoked Ca2+ transients. The insensitivity of these responses to the CB1 receptor antagonist rimonabant (100 nM) and preincubation of DRG neurons with pertussis toxin suggested that these actions are not CB1 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 Ca2+ 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