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 unpreced...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-01-01
|
| Series: | Journal of Biomedical Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12929-019-0590-1 |
| _version_ | 1828932622330363904 |
|---|---|
| author | Ming Tatt Lee Yu-Ting Chiu Yu-Chun Chiu Chia Chun Hor Hsin-Jung Lee Remo Guerrini Girolamo Calo Lih-Chu Chiou |
| author_facet | Ming Tatt Lee Yu-Ting Chiu Yu-Chun Chiu Chia Chun Hor Hsin-Jung Lee Remo Guerrini Girolamo Calo Lih-Chu Chiou |
| author_sort | Ming Tatt Lee |
| collection | DOAJ |
| description | 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), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), 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 NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. 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 OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia. |
| first_indexed | 2024-12-14T01:05:03Z |
| format | Article |
| id | doaj.art-53f537b86a584716bdf814fb935a0b18 |
| institution | Directory Open Access Journal |
| issn | 1423-0127 |
| language | English |
| last_indexed | 2024-12-14T01:05:03Z |
| publishDate | 2020-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj.art-53f537b86a584716bdf814fb935a0b182022-12-21T23:23:00ZengBMCJournal of Biomedical Science1423-01272020-01-0127111510.1186/s12929-019-0590-1Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesiaMing Tatt Lee0Yu-Ting Chiu1Yu-Chun Chiu2Chia Chun Hor3Hsin-Jung Lee4Remo Guerrini5Girolamo Calo6Lih-Chu Chiou7Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan UniversityGraduate Institute of Pharmacology, College of Medicine, National Taiwan UniversityGraduate Institute of Pharmacology, College of Medicine, National Taiwan UniversityGraduate Institute of Pharmacology, College of Medicine, National Taiwan UniversityDepartment of Pharmacology, College of Medicine, National Taiwan UniversityDepartment of Chemical and Pharmaceutical Sciences, Laboratorio per le Tecnologie delle Terapie Avanzate (LTTA)Department of Medical Sciences and National Institute of Neurosciences, Section of Pharmacology, University of FerraraGraduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan UniversityAbstract 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), OX1 receptors (OX1Rs), NK1 receptors (NK1Rs), mGlu5 receptors (mGlu5Rs) and CB1 receptors (CB1Rs), 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 NK1Rs, mGlu5Rs or CB1Rs. Orexin-A (i.pag.)-induced antinociception has been shown previously to be prevented by i.pag. blockade of OX1Rs or CB1Rs, and here was prevented by NK1R or mGlu5R antagonist (i.pag.). NPS (i.c.v.)-induced antinociception was prevented by i.pag. blockade of OX1Rs, NK1Rs, mGlu5Rs or CB1Rs. SIA has been previously shown to be prevented by i.pag. blockade of OX1Rs or CB1Rs. Here, we found that SIA was also prevented by i.c.v. blockade of NPSRs or i.pag. blockade of NK1Rs or mGlu5Rs. 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 OX1Rs on substance P-containing neurons in the vlPAG to release substance P that subsequently. Activates NK1Rs on glutamatergic neurons to release glutamate. Glutamate then activates perisynaptic mGlu5Rs to initiate the endocannabinoid retrograde inhibition of GABAergic transmission in the vlPAG, leading to analgesia.https://doi.org/10.1186/s12929-019-0590-1Neuropeptide SOrexinSubstance PMetabotropic glutamate receptorEndocannabinoidPeriaqueductal gray |
| spellingShingle | Ming Tatt Lee Yu-Ting Chiu Yu-Chun Chiu Chia Chun Hor Hsin-Jung Lee Remo Guerrini Girolamo Calo Lih-Chu Chiou Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia Journal of Biomedical Science Neuropeptide S Orexin Substance P Metabotropic glutamate receptor Endocannabinoid Periaqueductal gray |
| title | Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia |
| title_full | Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia |
| title_fullStr | Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia |
| title_full_unstemmed | Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia |
| title_short | Neuropeptide S-initiated sequential cascade mediated by OX1, NK1, mGlu5 and CB1 receptors: a pivotal role in stress-induced analgesia |
| title_sort | neuropeptide s initiated sequential cascade mediated by ox1 nk1 mglu5 and cb1 receptors a pivotal role in stress induced analgesia |
| topic | Neuropeptide S Orexin Substance P Metabotropic glutamate receptor Endocannabinoid Periaqueductal gray |
| url | https://doi.org/10.1186/s12929-019-0590-1 |
| work_keys_str_mv | AT mingtattlee neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia AT yutingchiu neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia AT yuchunchiu neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia AT chiachunhor neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia AT hsinjunglee neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia AT remoguerrini neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia AT girolamocalo neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia AT lihchuchiou neuropeptidesinitiatedsequentialcascademediatedbyox1nk1mglu5andcb1receptorsapivotalroleinstressinducedanalgesia |