Blockade of nociceptin/orphanin FQ receptor signaling reverses LPS-induced depressive-like behavior in mice

Nociceptin/orphanin FQ is the natural ligand of a Gi-protein coupled receptor named NOP. This peptidergic system is involved in the regulation of mood states and inflammatory responses. The present study aimed to investigate the consequences of blocking NOP signaling in lipopolysaccharide (LPS)-induced sickness and depressive-like behaviors in mice. LPS 0.8 mg/kg, ip, significantly induced sickness signs such as weight loss, decrease of water and food intake and depressive-like behavior in the tail suspension test. Nortriptyline (ip, 60 min prior the test) reversed the LPS-induced depressive states. The NOP receptor antagonist SB-612111, 30 min prior LPS, did not modify LPS-induced sickness signs and depressive-like behavior. However, when injected 24 h after LPS, NOP antagonists (UFP-101, icv, and SB-612111, ip) significantly reversed the mood effects of LPS. LPS evoked similar sickness signs and significantly increased tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) plasma levels 6 h post-injection in wild-type ((NOP(+/+)) and NOP knockout ((NOP(−/−)) mice. However, LPS treatment elicited depressive-like effects in NOP(+/+) but not in NOP(−/−) mice. In conclusion, the pharmacological and genetic blockade of NOP signaling does not affect LPS evoked sickness signs while reversing depressive-like behavior.