Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models

Oscar Sasso,Guillermo Moreno-Sanz,Cataldo Martucci,Natalia Realini,Mauro Dionisi,Luisa Mengatto,Andrea Duranti,Glauco Tarozzo,Giorgio Tarzia,Marco Mor,Rosalia Bertorelli,Angelo Reggiani,Daniele Piomelli

doi:10.1016/j.pain.2012.10.018

Abstract

Fatty acid ethanolamides (FAEs), which include palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), are endogenous agonists of peroxisome proliferator-activated receptor-α (PPAR-α) and important regulators of the inflammatory response. They are degraded in macrophages by the lysosomal cysteine amidase, N-acylethanolamine acid amidase (NAAA). Previous studies have shown that pharmacological inhibition of NAAA activity suppresses macrophage activation in vitro and causes marked anti-inflammatory effects in vivo, which is suggestive of a role for NAAA in the control of inflammation. It is still unknown, however, whether NAAA-mediated FAE deactivation might regulate pain signaling. The present study examined the effects of ARN077, a potent and selective NAAA inhibitor recently disclosed by our group, in rodent models of hyperalgesia and allodynia caused by inflammation or nerve damage. Topical administration of ARN077 attenuated, in a dose-dependent manner, heat hyperalgesia and mechanical allodynia elicited in mice by carrageenan injection or sciatic nerve ligation. The antinociceptive effects of ARN077 were prevented by the selective PPAR-α antagonist GW6471 and did not occur in PPAR-α–deficient mice. Furthermore, topical ARN077 reversed the allodynia caused by ultraviolet B radiation in rats, and this effect was blocked by pretreatment with GW6471. Sciatic nerve ligation or application of the proinflammatory phorbol ester 12-O-tetradecanoylphorbol 13-acetate decreased FAE levels in sciatic nerve and skin tissue, respectively. ARN077 reversed these biochemical effects. The results identify ARN077 as a potent inhibitor of intracellular NAAA activity, which is active in vivo by topical administration. The findings further suggest that NAAA regulates peripheral pain initiation by interrupting endogenous FAE signaling at PPAR-α.

Highlights

The amides of fatty acids with ethanolamine are a family of lipid-derived messengers that participate in the control of multiple physiological functions, including pain and inflammation [18, 19, 22]
The actions of these lipid messengers are terminated by enzyme-mediated hydrolysis, which is catalyzed by two intracellular lipid amidases: N-acylethanolamine acid amidase (NAAA) [31] and fatty acid amide hydrolase (FAAH) [8, 9]
NAAA appears to be primarily localized to the lysosomal compartment of macrophages [32], whereas FAAH is found on the outer face of mitochondria and endoplasmic reticulum of most mammalian cells [12]

Summary

Introduction

The amides of fatty acids with ethanolamine (fatty acid ethanolamides, FAEs) are a family of lipid-derived messengers that participate in the control of multiple physiological functions, including pain and inflammation [18, 19, 22]. Saturated or mono-unsaturated members of this family, such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), are produced in innate immune and neural cells by the action of a selective phospholipase, N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD), and exert anti-nociceptive and antiinflammatory effects in experimental animals and humans [6, 19, 24, 29] Such effects are primarily, albeit not exclusively [1, 19], due to the ability of PEA and OEA to engage the ligand-activated transcription factor, peroxisome proliferatoractivated receptor- (PPAR- ) [18, 19], to which they bind with high affinity [11]. NAAA appears to be primarily localized to the lysosomal compartment of macrophages [32], whereas FAAH is found on the outer face of mitochondria and endoplasmic reticulum of most mammalian cells [12]

Methods

Results

Conclusion