Chronic exposure of sensory neurones to increased levels of nerve growth factor modulates CB1/TRPV1 receptor crosstalk

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Abstract
Anandamide (AEA) activates both cannabinoid CB(1) and TRPV1 receptors, which are expressed on cultured dorsal root ganglion neurones. Increased levels of nerve growth factor (NGF) are associated with chronic pain states. The aim of this study was to compare of the effects of AEA on CB(1) receptor signalling and TRPV1-CB(1) crosstalk in low and high concentrations of NGF, using voltage-clamp electrophysiology and Fura-2 calcium imaging. Chronic exposure to high NGF (200 ng ml(-1)) as compared to low NGF (20 ng ml(-1)) increases the proportion of neurones that exhibit an inward current in response to AEA (1 microM), from 7 to 29%. In contrast, inhibition of voltage-gated calcium currents by AEA is not significantly different in low NGF (33+/-9%, compared to high NGF 28+/-6%). Crosstalk between CB and TRPV1 receptors is modulated by exposure to high NGF. In low NGF, exposure to the CB(1) receptor antagonist, SR141716A, (100 nM) increases the percentage of neurones in which AEA elicits an increase in [Ca(2+)](i), from 10 to 23%. In high NGF, the antagonist does not alter the percentage of responders (33 to 30%). In low NGF, exposure to the CB receptor agonist, WIN55 (1 microM) reduces capsaicin-mediated increases in [Ca(2+)](i) to 28+/-8% of control as compared to an enhancement to 172+/-26% of control observed in high NGF. We conclude that cannabinoid-mediated modulation of TRPV1 receptor activation is altered after exposure to high NGF.