Pain Perception and Stress Response
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.
The expression of NmUR2 in the paraventricular nucleus of hypothalamus (PVN), a major site for the release of Corticotropin-releasing hormone (CRH), suggests an alternative role in mediating stress response. NmU and its receptors are also abundantly expressed in nociceptive sensory pathways, including the dorsal root ganglia (DRG), spinal cord, and brainstem. In particular, NmU induces hyperalgesia, allodynia, and increased persistent pain after formalin injection. ICV injections of NmU in rats and mice induce behavior responses associated with activation of the nociceptive pathways, for example it will increase plasma levels of corticosterone, and stimulates the release of CRH from hypothalamic explants in vitro. Central administration of NmU also induces expression of key genes in hypothalamic areas associated with stress, as well as stress-related behaviours that can be blocked by CRH antagonist (this is absent from CRH knockout mice).
Certain stress responses are abolished in NmU knockout mice. These results suggest that NmU significantly modulates nociceptive sensory transmission.
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