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Background  Stress-induced analgesia (SIA) is an evolutionarily conserved phenomenon during stress. Neuropeptide S (NPS), orexins, substance P, glutamate and endocannabinoids are known to be involved in stress and/or SIA, however their causal links remain unclear. Here, we reveal an unprecedented sequential cascade involving these mediators in the lateral hypothalamus (LH) and ventrolateral periaqueductal gray (vlPAG) using a restraint stress-induced SIA model.    Methods  Male C57BL/6 mice of 8–12 week-old were subjected to intra-cerebroventricular ( i.c.v. ) and/or intra-vlPAG ( i.pag. ) microinjection of NPS, orexin-A or substance P alone or in combination with selective antagonists of NPS receptors (NPSRs), OX 1  receptors (OX 1 Rs), NK 1  receptors (NK 1 Rs), mGlu 5  receptors (mGlu 5 Rs) and CB 1  receptors (CB 1 Rs), respectively. Antinociceptive effects of these mediators were evaluated via the hot-plate test. SIA in mice was induced by a 30-min restraint stress. NPS levels in the LH and substance P levels in vlPAG homogenates were compared in restrained and unrestrained mice.    Results  NPS ( i.c.v.,  but not  i.pag. ) induced antinociception. This effect was prevented by  i.c.v.  blockade of NPSRs. Substance P ( i.pag. ) and orexin-A ( i.pag. ) also induced antinociception. Substance P ( i.pag. )-induced antinociception was prevented by  i.pag.  Blockade of NK 1 Rs, mGlu 5 Rs or CB 1 Rs. Orexin-A ( i.pag. )-induced antinociception has been shown previously to be prevented by  i.pag.  blockade of OX 1 Rs or CB 1 Rs, and here was prevented by NK 1 R or mGlu 5 R antagonist ( i.pag. ). NPS ( i.c.v. )-induced antinociception was prevented by  i.pag.  blockade of OX 1 Rs, NK 1 Rs, mGlu 5 Rs or CB 1 Rs. SIA has been previously shown to be prevented by  i.pag.  blockade of OX 1 Rs or CB 1 Rs. Here, we found that SIA was also prevented by  i.c.v.  blockade of NPSRs or  i.pag.  blockade of NK 1 Rs or mGlu 5 Rs. Restrained mice had higher levels of NPS in the LH and substance P in the vlPAG than unrestrained mice.    Conclusions  These results suggest that, during stress, NPS is released and activates LH orexin neurons via NPSRs, releasing orexins in the vlPAG. Orexins then activate OX 1 Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK 1 Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu 5 Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.

Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia