N-(2-HYDROXYETHYL)HEXADECANAMIDE IS ORALLY-ACTIVE IN REDUCING EDEMA FORMATION AND INFLAMMATORY HYPERALGESIA BY DOWN-MODULATING MAST-CELL ACTIVATION

Mast cells play a key role in inflammatory reactions triggered by tiss ue injury or immune perturbations. Little is known about endogenous mo lecules and mechanisms capable of modulating inappropiate mast cell ac tivity. N-(2-Hydroxyethyl)hexadecanamide (palmitoylethanolamide), foun d in peripheral tissues, has been proposed to act as a local autacoid capable of negatively regulating mast cell activation and inflammation - hence the acronym Autacoid Local Inflammation Antagonism (ALIA). Re cently, N-(2-hydroxyethyl)hexadecanamide (LG 2110/1) has been reported to down-modulate mast cell activation in vitro by behaving as an agon ist at the peripheral cannabinoid CB2 receptor. Here, we have characte rized and functionally correlated the anti-inflammatory actions of LG 2110/1 with its ability to control mast cell activation, when given or ally in a battery of rodent models of inflammation. LG 2110/1 diminish ed, in a dose-dependent and correllated manner, the number of degranul ated mast cells and plasma extravasation induced by substance P inject ion in the mouse ear pinna. In addition, LG 2110/1 reduced dose depend ently plasma extravasation induced by passive cutaneous anaphylaxis re action. In adult rats LG 2110/1 decreased, in a dose-dependent manner, carrageenan-induced hindpaw edema and hyperalgesia, but not phospholi pase A,-induced hindpaw edema. Further, anti-edema effects were observ ed when utilizing dextran and formalin, known to also cause mast cell activation. Locally administered LG 2110/1 was likewise effective in m inimizing dextran-induced hind paw edema. In contrast equivalent amoun ts of palmitic acid plus ethanolamine were ineffective against plasma extravasation provoked by substance P. LG 2110/1 did not decrease plas ma extravasation induced by the substance P fragment, substance P-(6-1 1), known to be inactive on mast cells. These results indicate that or ally administered N-(2-hydroxyethyl)hexadecanamide is effective in: (a ) directly down-modulating mast cell activation in vivo; (b) suppressi ng pathological consequences initiated by mast cell activation indepen dently of the activating stimuli; (c) exerting an anti-inflammatory ac tion distinguishable from that of classical steroidal and non-steroida l anti-inflammatory agents. These findings raise the possibility that N-(2-hydroxyethyl)hexadecanamide and related saturated N-acylamides (' ALIAmides') represent novel therapeutic agents useful in the managemen t of inflammatory disease conditions.