Mice lacking the endocannabinoid-synthesizing enzyme NAPE-PLD exhibit sex-dependent dysregulations in responsiveness to oxycodone and a natural reward.

The endogenous cannabinoid (endocannabinoid) and opioid systems are highly interconnected in the context of drug reward. Bioactive lipids known as N-acylethanolamines (NAEs), and, specifically, anandamide (AEA), influence several unwanted side effects of opioids, including dependence and tolerance. AEA undergoes degradation catalyzed by the enzyme fatty-acid amide hydrolase (FAAH), whereas the biosynthesis of AEA in vivo is catalyzed by the enzyme N-acyl phosphatidylethanolamine phospholipase-D (NAPE-PLD). AEA and FAAH are implicated in opioid reward, but the impact of genetic deletion of NAPE-PLD on responsiveness to opioids remains unknown. Here we explored the role of NAPE-PLD in behavioral sensitivity to the opioid analgesic oxycodone. We evaluated NAPE-PLD knockout (KO) and wild type (WT) mice of both sexes in assays that assess opioid-induced psychomotor responses and voluntary oral consumption of oxycodone. In our studies, genetic deletion of NAPE-PLD produced a shift in sexually dimorphic responses to oxycodone. Psychomotor response to oxycodone was reduced in female but not male NAPE-PLD KO mice. Female NAPE-PLD KO mice consumed more oral oxycodone that female WT mice, while no genotypic differences in consumption were observed in males. Oxycodone consumption also increased the number of striatal ΔFosB positive cells in female WT mice, but not in male WT mice or NAPE-PLD KO mice of either sex. Additionally, NAPE-PLD KO mice of both sexes consumed more sucrose than WT mice. Together, these findings suggest that NAPE-PLD may regulate responses to opioids in a sexually dimorphic manner as the impact of genetic deletion of NAPE-PLD was greater in females than males.