N-Acylethanolamine acid amidase (NAAA) is an Nterminal cysteine hydrolase primarily found in the endosomal− lysosomal compartment of innate and adaptive immune cells. NAAA catalyzes the hydrolytic deactivation of palmitoylethanolamide (PEA), a lipid-derived peroxisome proliferator-activated receptor-α (PPAR-α) agonist that exerts profound anti-inflammatory effects in animal models. Emerging evidence points to NAAAregulated PEA signaling at PPAR-α as a critical control point for the induction and the resolution of inflammation and to NAAA itself as a target for anti-inflammatory medicines. The present Perspective discusses three key aspects of this hypothesis: the role of NAAA in controlling the signaling activity of PEA; the structural bases for NAAA function and inhibition by covalent and noncovalent agents; and finally, the potential value of NAAA-targeting drugs in the treatment of human inflammatory disorders.

Fatty acid amide hydrolase (FAAH) is an enzyme that prominently degrades the major endocannabinoid N-arachidonoylethanolamine (anandamide). Inhibition of this enzyme leads to increased anandamide levels in brain regions that modulate stress and anxiety. Recently, we found that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats display hyperactive FAAH in amygdalar regions that was associated with increased stress sensitivity and a hyper-anxious phenotype. Our previous work has also demonstrated that msPs display an innate preference for and excessive consumption of alcohol, potentially reflecting a form of self-medication to gain relief from hyper-anxious states. Here, we expand on our previous work by microinjecting the selective FAAH inhibitor URB597 (vehicle, 0.03, 0.1 and 1.0 μg per rat) into the central amygdala (CeA) and basolateral amygdala in msP versus non-selected Wistar rats to evaluate the effects of localized FAAH inhibition on operant alcohol self-administration and restraint-induced anxiety using the elevated plus maze. Intra-CeA URB597 significantly reduced alcohol self-administration in msP but not in Wistar rats. Intra-basolateral amygdala URB597 also attenuated alcohol drinking in msPs, although the effect was less pronounced relative to CeA treatment. In contrast, control experiments administering URB597 into the ventral tegmental area produced no genotypic differences in drinking. We also found that URB597 treatment in the CeA significantly reduced the anxiogenic effects of restraint stress in msPs, although no effects were detected in Wistars. Dysregulation of FAAH regulated systems in the major output region of the amygdala may drive the propensity for co-morbid expression of anxiety and excessive alcohol use.

Background and Purpose Nociceptin/orphanin FQ (N/OFQ) peptide and its cognate receptor (NOP) are widely expressed in mesolimbic brain regions where they play an important role in modulating reward and motivation. Early evidence suggested that NOP receptor activation attenuates the rewarding effects of drugs of abuse, including alcohol. However, emerging data indicate that NOP receptor blockade also effectively attenuates alcohol drinking and relapse. To advance our understanding of the role of the N/OFQ‐NOP receptor system in alcohol abuse, we examined the effect of NOP receptor blockade on voluntary alcohol drinking at the neurocircuitry level. Experimental Approach Using male and female genetically selected alcohol‐preferring Marchigian Sardinian (msP) rats, we initially evaluated the effects of the selective NOP receptor antagonist LY2817412 (3, 10, and 30 mg·kg−1, p.o.) on alcohol consumption in a two‐bottle free‐choice paradigm. We then microinjected LY2817412 (3 and 6 μg·μl−1 per rat) in the central nucleus of the amygdala (CeA), ventral tegmental area (VTA), and nucleus accumbens (NAc). Key Results Peripheral LY2817412 administration dose‐dependently and selectively reduced voluntary alcohol intake in male and female msP rats. Central injections of LY2817412 markedly attenuated voluntary alcohol intake in both sexes following administration in the CeA and VTA but not in the NAc. Conclusion and Implications The present results revealed that the CeA and VTA are neuroanatomical substrates that mediate the effects of NOP receptor antagonism on alcohol consumption. Overall, our findings support the potential of NOP receptor antagonism as a treatment strategy to attenuate alcohol use and addiction.

The enzyme NAAA is a critical control node that offers a druggable target to prevent the transition from acute to chronic pain.

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