Actions of two naturally occurring saturated N-acyldopamines on transient receptor potential vanilloid 1 (TRPV1) channels

摘要

class="enumerated" style="list-style-type:decimal">Four long-chain, linear fatty acid dopamides (N-acyldopamines) have been identified in nervous bovine and rat tissues. Two unsaturated members of this family of lipids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine, were shown to potently activate the transient receptor potential channel type V1 (TRPV1), also known as the vanilloid receptor type 1 for capsaicin. However, the other two congeners, N-palmitoyl- and N-stearoyl-dopamine (PALDA and STEARDA), are inactive on TRPV1. We have investigated here the possibility that the two compounds act by enhancing the effect of NADA on TRPV1 (‘entourage' effect).When pre-incubated for 5 min with cells, both compounds dose-dependently enhanced NADA's TRPV1-mediated effect on intracellular Ca²⁺ in human embryonic kidney cells overexpressing the human TRPV1. In the presence of either PALDA or STEARDA (0.1–10 μM), the EC50 of NADA was lowered from ∼90 to ∼30 nM.The effect on intracellular Ca²⁺ by another endovanilloid, N-arachidonoyl-ethanolamine (anandamide, 50 nM), was also enhanced dose-dependently by both PALDA and STEARDA. PALDA and STEARDA also acted in synergy with low pH (6.0–6.7) to enhance intracellular Ca²⁺ via TRPV1.When co-injected with NADA (0.5 μg) in rat hind paws, STEARDA (5 μg) potentiated NADA's TRPV1-mediated nociceptive effect by significantly shortening the withdrawal latencies from a radiant heat source. STEARDA (1 and 10 μg) also enhanced the nocifensive behavior induced by carrageenan in a typical test of inflammatory pain.These data indicate that, despite their inactivity per se on TRPV1, PALDA and STEARDA may play a role as ‘entourage' compounds on chemicophysical agents that interact with these receptors, with possible implications in inflammatory and neuropathic pain.