Neuropeptide W

NPW binds NPBWR1 (GPR7) and NPBWR2 (GPR8) with high affinity, coupling through Gi/o to reduce adenylate cyclase activity and lower cAMP. MAPK/ERK and PI3K/Akt pathways are also activated. NPW-30 generally shows higher potency at NPBWR1 than NPW-23, while relative potencies at NPBWR2 vary. The non-brominated tryptophan at position 1 (versus brominated in NPB) means NPW may have slightly different receptor conformation and possibly different signaling bias between the two receptor subtypes.

ICV NPW consistently increases food intake in rodents across multiple studies. NPBWR1 knockout mice develop late-onset obesity and hyperleptinemia, particularly on normal chow, a relatively unusual phenotype suggesting tonic NPW/NPB signaling normally suppresses excessive weight gain over time despite acute orexigenic effects. NPW may regulate meal size via distinct circuits than those mediating longer-term energy balance.

NPW activates the HPA axis, stimulating CRH release from the hypothalamus and acth/" class="wiki-internal-link">ACTH from pituitary corticotrophs, ultimately raising corticosterone. Conversely, glucocorticoids upregulate NPW expression in the hypothalamus, creating a positive feedback loop during stress. In immune cells, NPBWR1 is expressed on macrophages and NK cells, where NPW suppresses cytokine production and NK cell cytotoxicity, potentially dampening excessive inflammatory responses during stress.

ICV NPW-30 at 1-10 nmol reliably increases 1-hour food intake in satiated rodents by 50-150%. The effect is blunted by NPBWR1 antagonism and absent in NPBWR1 knockout mice. Peripheral SC administration of NPW also increases feeding but at much higher doses, suggesting partial CNS penetration. The orexigenic circuits mediating NPW effects overlap with those of NPY and orexin.

Like NPB, NPW reduces thermal and inflammatory hyperalgesia after ICV administration. The analgesic effect is partially opioid-mediated. Spinal cord NPBWR1 expression suggests NPW may also modulate dorsal horn pain transmission. The stress-pain interface (cortisol activating NPW; NPW reducing pain) may represent an endogenous stress analgesia pathway.

NPBWR1 knockout mice show increased anxiety-like behavior in conflict-based tests, with elevated basal corticosterone and exaggerated stress responses. NPW ICV reduces anxiety in some paradigms. These observations suggest NPW normally buffers the HPA stress response and exerts anxiolytic effects, possibly through interactions with CRF receptor signaling.