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

British Journal of Pharmacology, ISSN: 1476-5381, Vol: 154, Issue: 2, Page: 480-492
2008
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Background and purpose: The endogenous cannabinoid anandamide (AEA) acts at cannabinoid (CB) and vanilloid (TRPV) receptors. AEA also shows antinociceptive properties; although the underlying mechanism for this is not fully understood, both CB and TRPV may be involved. Voltage-activated Ca 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 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 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 Ca transients. The insensitivity of these responses to the CB receptor antagonist rimonabant (100 nM) and preincubation of DRG neurons with pertussis toxin suggested that these actions are not CB 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 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. © 2008 Nature Publishing Group All rights reserved.

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