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.