The effect of NmU on stress and pain perception pathways has been demonstrated using mice. In contrast to NmU peptide-deficient mice, NmUR2 knockout (KO) mice appeared normal with regard to stress, anxiety, body weight regulation, and food consumption. However, the NmUR2 KO mice exhibit reduced pain sensitivity in both hot plate test and the chronic phase of the formalin test. Furthermore, facilitated excitatory synaptic transmission in spinal dorsal horn neurons, a mechanism by which NmU stimulates pain, did not occur in NmUR2 KO mice. Both NmUR2 expression and NmU-23 binding sites are highly localized to the outer layers of the spinal dorsal horn, and administration of NmU via intracerebroventricular (ICV) injections usually increases pain sensitivity in rats and mice.