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

Abstract

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.

Stress induces reinstatement of extinguished cocaine conditioned place preference by a sequential signaling via neuropeptide S, orexin, and endocannabinoid

“…Besides, NPSR blockade prevented the reinstatement of cocaine CPP induced by either NPS (Figure 1C) or a restraint stress (Figure 4B) in mice, suggesting stress reinstates cocaine CPP via activation of the NPS system. Previously, we have demonstrated that the same restraint stressor in mice induced an elevation of NPS levels in the LH 14 . Here, we further demonstrated that exogenous NPS can activate orexin neurons in the LH, and increase orexin levels in the VTA (Figure 3).…”

“…Taken together, previous findings show that (i) stress activates the NPS‐containing neurons in the peri‐LC and PBN, 12 (ii) restraint stress increases the NPS level in the mouse LH, 14 (iii) intra‐LH microinjection of NPS activates orexin neurons, 5,6 and (iv) intra‐VTA ( i.vta .) microinjection of orexin‐A reinstates extinguished cocaine CPP 4 .…”

“…In response to stress, NPS neurons in the peri‐LC and PBN of rats are activated, 12 similar to the finding that stress activates LH orexin neurons in mice 4,13 . We previously reported that acute restraint stress significantly increased NPS release in the mouse LH 14 . Interestingly, prior studies showed that intra‐LH 15 or i.c.v 16 .…”

“…injection of NPS (1 nmol) to reinstate cocaine CPP. Mice in the restraint group were put into a 50‐ml‐centrifuge tube for 30 min, whereas those in the nonrestrained group were remained in their home cages as reported in our previous study 4,13,14 . Then, mice received the CPP test for evaluating their reinstatement magnitudes.…”

Impact of improvement of sleep disturbance on symptoms and quality of life in patients with functional dyspepsia

“…An orexin receptor antagonist, suvorexant, may therefore inhibit gastric acid secretion, which could improve patients’ symptoms. However, orexin is also involved in stress-induced analgesia [ 52 – 54 ] and is involved in antinociceptive effects on visceral perception [ 55 ]. Therefore, suvorexant could worsen patients’ symptoms.…”