title: Morphine upregulates functional expression of neurokinin-1 receptor in neurons.
abstract: Neuronkinin-1 receptor (NK-1R), the neuropeptide substance P (SP) preferring receptor, is highly expressed in areas of the central nervous system (CNS) that are especially implicated in depression, anxiety, and stress. Repeated exposure to opioids may sensitize neuronal systems involved in stress response. We examined the effects of morphine, the principal metabolite of heroin, on the functional expression of NK-1R in the cortical neurons. NK-1R and mu-opioid receptor (MOR) are co-expressed in the cortical neurons. Morphine enhanced NK-1R expression in the cortical neurons at both the mRNA and protein levels. The upregulated NK-1R by morphine had functional activity, because morphine-treated cortical neurons had greater SP-induced Ca(2+) mobilization than untreated neurons. Blocking opioid receptors on the cortical neurons by naltrexone or CTAP (a mu-opioid receptor antagonist) abolished the morphine action. Investigation of the mechanism(s) responsible for the morphine action showed that morphine activated NK-1R promoter and induced the phosphorylation of p38 MAPK protein in the cortical neurons. These in vitro data provide a plausible cellular mechanism for opioid-mediated neurological disorders.
authors.affiliation: Division of Allergy and Immunology, Joseph Stokes Jr. Research Institute at The Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, Pennsylvania.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
authors.forename: Steven D
authors.initials: SD
authors.lastname: Douglas
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kolson
authors.forename: Lauren A
authors.initials: LA
authors.lastname: O'Donnell
authors.forename: Wen-Zhe
authors.initials: WZ
authors.lastname: Ho
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects*; D010446:Peptide Fragments; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013004:Somatostatin; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C529311:CTAP octapeptide; D004791:Enzyme Inhibitors; D009292:Narcotic Antagonists; D009294:Narcotics; D010446:Peptide Fragments; D010455:Peptides; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D017450:Receptors, Opioid, mu; D013004:Somatostatin; D009271:Naltrexone; D009020:Morphine; D048051:p38 Mitogen-Activated Protein Kinases; D002118:Calcium