NAPE-PLD regulates specific baseline affective behaviors but is dispensable for inflammatory hyperalgesia

Irene Chen; Laura B Murdaugh; Cristina Miliano; Yuyang Dong; Ann M Gregus; Matthew W Buczynski

doi:10.1016/j.ynpai.2023.100135

NAPE-PLD regulates specific baseline affective behaviors but is dispensable for inflammatory hyperalgesia

Neurobiol Pain. 2023 Jun 14:14:100135. doi: 10.1016/j.ynpai.2023.100135. eCollection 2023 Aug-Dec.

Authors

Irene Chen¹, Laura B Murdaugh^{1

2}, Cristina Miliano¹, Yuyang Dong¹, Ann M Gregus¹, Matthew W Buczynski^{1

3}

Affiliations

¹ School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
² Translational Biology, Medicine, and Health, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
³ Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.

Abstract

N-acyl-ethanolamine (NAEs) serve as key endogenous lipid mediators as revealed by manipulation of fatty acid amide hydrolase (FAAH), the primary enzyme responsible for metabolizing NAEs. Preclinical studies focused on FAAH or NAE receptors indicate an important role for NAE signaling in nociception and affective behaviors. However, there is limited information on the role of NAE biosynthesis in these same behavioral paradigms. Biosynthesis of NAEs has been attributed largely to the enzyme N-acylphosphatidylethanolamine Phospholipase D (NAPE-PLD), one of three pathways capable of producing these bioactive lipids in the brain. In this report, we demonstrate that Nape-pld knockout (KO) mice displayed reduced sucrose preference and consumption, but other baseline anxiety-like or depression-like behaviors were unaltered. Additionally, we observed sex-dependent responses in thermal nociception and other baseline measures in wildtype (WT) mice that were absent in Nape-pld KO mice. In the Complete Freund's Adjuvant (CFA) model of inflammatory arthritis, WT mice exhibited sex-dependent changes in paw edema that were lost in Nape-pld KO mice. However, there was no effect of Nape-pld deletion on arthritic pain-like behaviors (grip force deficit and tactile allodynia) in either sex, indicating that while NAPE-PLD may alter local inflammation, it does not contribute to pain-like behaviors associated with inflammatory arthritis. Collectively, these findings indicate that chronic and systemic NAPE-PLD inactivation will likely be well-tolerated, warranting further pharmacological evaluation of this target in other disease indications.

Keywords: Arthritis; Depression; Endocannabinoids; Hyperalgesia; Lipids; Sex difference.

Abstract

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