Synergistic antinociceptive effects of concomitant NAAA and peripheral FAAH inhibition

Alex Mabou Tagne; Yannick Fotio; Parwinder Singh Uppal; Daniele Piomelli

doi:10.1016/j.expneurol.2022.114194

Synergistic antinociceptive effects of concomitant NAAA and peripheral FAAH inhibition

Exp Neurol. 2022 Nov:357:114194. doi: 10.1016/j.expneurol.2022.114194. Epub 2022 Aug 4.

Authors

Alex Mabou Tagne¹, Yannick Fotio², Parwinder Singh Uppal², Daniele Piomelli³

Affiliations

¹ Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA. Electronic address: amabouta@hs.uci.edu.
² Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA.
³ Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA; Department of Biological Chemistry, University of California, Irvine, CA 92697-4625, USA; Department of Pharmaceutical Sciences, University of California Irvine, CA 92697-4625, USA. Electronic address: piomelli@hs.uci.edu.

PMID: 35932800
DOI: 10.1016/j.expneurol.2022.114194

Abstract

The intracellular lipid amidases, fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA), terminate the actions of anandamide and palmitoylethanolamide (PEA), two antinociceptive and anti-inflammatory lipid-derived mediators. Here we show, confirming prior research, that small-molecule inhibitors of peripheral FAAH (compound URB937) and systemic NAAA (compound ARN19702) individually attenuate, in male CD-1 mice, pain-related behaviors and paw inflammation in the formalin and carrageenan tests. More importantly, isobolographic analyses revealed that the combination of URB937 and ARN19702 produced substantial synergistic (greater than additive) antinociceptive effects in both models as well as additive anti-inflammatory effects in the carrageenan test. Together, the findings uncover a functional interplay between FAAH and NAAA substrates in the control of nociception, which might be exploited clinically to develop safe and effective pain management strategies.

Keywords: ARN19702; FAAH; Isobolographic analysis; NAAA; Pain; URB937.

MeSH terms

Amidohydrolases*
Analgesics / pharmacology
Analgesics / therapeutic use
Animals
Anti-Inflammatory Agents* / pharmacology
Carrageenan
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Male
Mice

Substances

Analgesics
Anti-Inflammatory Agents
Enzyme Inhibitors
Carrageenan
Amidohydrolases
fatty-acid amide hydrolase
amidase