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.
Albuterol samples collected in the inhalation filter, nebulizer, T-piece, and corrugated tubing were eluted with distilled water and analyzed with a spectrophotometer. RESULTS: The inhaled drug, as a percentage of total dose in both lung models, was 5.1-7.5%, without statistical significance among the 3 modes. Median nebulization times for IIM, CM, and EIM were 38.9, 14.3, and 17.7 min, respectively, and nebulization time for the 3 modes significantly differed (P < .001). The inhaled drug mass for the 3 modes with the adult lung model was similar to that with the pediatric lung model (7.39 ؎ 0.76 vs 6.27 ؎ 0.69%, P ؍ .77). CONCLUSIONS: Aerosol drug delivery with a jet nebulizer placed proximal to the ventilator was not dependent on nebulization mode during simulated pediatric and adult conventional mechanical ventilation. Use of expiratory intermittent mode and continuous nebulization should be considered to reduce treatment time.
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