PMID- 26096126
OWN - NLM
STAT- MEDLINE
DCOM- 20160602
LR  - 20210223
IS  - 1872-6240 (Electronic)
IS  - 0006-8993 (Print)
IS  - 0006-8993 (Linking)
VI  - 1622
DP  - 2015 Oct 5
TI  - A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central 
      cannabinoid receptor 1-mediated pressor response in conscious rats.
PG  - 51-63
LID - S0006-8993(15)00482-5 [pii]
LID - 10.1016/j.brainres.2015.06.011 [doi]
AB  - Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) 
      modulation of feeding. Further, our studies established the dependence of the 
      central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) 
      and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the 
      RVLM. Here, we tested the novel hypothesis that brainstem orexin-A/OX1R signaling 
      plays a pivotal role in the central CB1R-mediated pressor response. Our multiple 
      labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and 
      the peptide orexin-A within the C1 area of the rostral ventrolateral medulla 
      (RVLM). Activation of central CB1R following intracisternal (i.c.) WIN55,212-2 
      (15mug/rat) in conscious rats caused significant increases in BP and orexin-A 
      level in RVLM neuronal tissue. Additional studies established a causal role for 
      orexin-A in the central CB1R-mediated pressor response because (i) selective 
      blockade of central CB1R (AM251, 30mug/rat; i.c.) abrogated WIN55,212-2-evoked 
      increases in RVLM orexin-A level, (ii) the selective OX1R antagonist SB-408124 
      (10nmol/rat; i.c.) attenuated orexin-A (3nmol/rat; i.c.) or WIN55,212-2 
      (15mug/rat; i.c.)-evoked pressor response while selective CB1R blockade (AM251) 
      had no effect on orexin-A (3nmol/rat; i.c.)-evoked pressor response, (iii) direct 
      CB1R activation in the RVLM (WIN55,212-2; 0.1mug/rat) increased RVLM orexin-A and 
      BP. Finally, SB-408124 attenuated WIN55,212-2-evoked increases in RVLM nNOS and 
      ERK1/2 phosphorylation and BP. Our findings suggest that orexin-A/OX1R dependent 
      activation of the RVLM nNOS/ERK1/2 cascade is essential neurochemical mechanism 
      for the central CB1R-mediated pressor response in conscious rats.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Ibrahim, Badr Mostafa
AU  - Ibrahim BM
AD  - Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina 
      University, 600 Moye Boulevard, Greenville, NC 27858, United States.
FAU - Abdel-Rahman, Abdel A
AU  - Abdel-Rahman AA
AD  - Department of Pharmacology & Toxicology, Brody School of Medicine, East Carolina 
      University, 600 Moye Boulevard, Greenville, NC 27858, United States. Electronic 
      address: ABDELRAHMANA@ecu.edu.
LA  - eng
GR  - R01 AA007839/AA/NIAAA NIH HHS/United States
GR  - R01 AA014441/AA/NIAAA NIH HHS/United States
GR  - 2R01AA07839-19/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150618
PL  - Netherlands
TA  - Brain Res
JT  - Brain research
JID - 0045503
RN  - 0 (Benzoxazines)
RN  - 0 (Cannabinoid Receptor Modulators)
RN  - 0 (Cardiovascular Agents)
RN  - 0 (Cnr1 protein, rat)
RN  - 0 (Hcrt protein, rat)
RN  - 0 (Hcrtr1 protein, rat)
RN  - 0 (Morpholines)
RN  - 0 (Naphthalenes)
RN  - 0 (Orexin Receptor Antagonists)
RN  - 0 (Orexin Receptors)
RN  - 0 (Orexins)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 0 (SB 408124)
RN  - 5H31GI9502 
      ((3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - EC 1.14.13.39 (Nos1 protein, rat)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
SB  - IM
MH  - Animals
MH  - Benzoxazines/pharmacology
MH  - Blood Pressure/drug effects/*physiology
MH  - Cannabinoid Receptor Modulators/pharmacology
MH  - Cardiovascular Agents/pharmacology
MH  - Heart Rate/drug effects/physiology
MH  - Male
MH  - Medulla Oblongata/drug effects/*metabolism
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Morpholines/pharmacology
MH  - Naphthalenes/pharmacology
MH  - Neurons/drug effects/*metabolism
MH  - Nitric Oxide Synthase Type I/metabolism
MH  - Orexin Receptor Antagonists/pharmacology
MH  - Orexin Receptors/*metabolism
MH  - Orexins/administration & dosage/*metabolism
MH  - Phenylurea Compounds/pharmacology
MH  - Phosphorylation/drug effects
MH  - Rats, Sprague-Dawley
MH  - Receptor, Cannabinoid, CB1/antagonists & inhibitors/*metabolism
MH  - Tyrosine 3-Monooxygenase/metabolism
PMC - PMC4562882
MID - NIHMS708071
OTO - NOTNLM
OT  - Blood pressure
OT  - Cannabinoid receptor 1
OT  - Orexin receptor 1
OT  - Rostral ventrolateral medulla
COIS- Conflict of interest The authors declare no conflict of interest.
EDAT- 2015/06/23 06:00
MHDA- 2016/06/03 06:00
PMCR- 2016/10/05
CRDT- 2015/06/23 06:00
PHST- 2015/02/17 00:00 [received]
PHST- 2015/06/11 00:00 [revised]
PHST- 2015/06/12 00:00 [accepted]
PHST- 2015/06/23 06:00 [entrez]
PHST- 2015/06/23 06:00 [pubmed]
PHST- 2016/06/03 06:00 [medline]
PHST- 2016/10/05 00:00 [pmc-release]
AID - S0006-8993(15)00482-5 [pii]
AID - 10.1016/j.brainres.2015.06.011 [doi]
PST - ppublish
SO  - Brain Res. 2015 Oct 5;1622:51-63. doi: 10.1016/j.brainres.2015.06.011. Epub 2015 
      Jun 18.