title: Cisplatin causes over-expression of tachykinin NK(1) receptors and increases ERK1/2- and PKA- phosphorylation during peak immediate- and delayed-phase emesis in the least shrew (Cryptotis parva) brainstem.
abstract: Scant information is available regarding the effects of cisplatin on the expression profile of tachykinin NK(1) receptors and downstream signaling during cisplatin-induced emesis. Cisplatin causes peak early- and delayed-phase emesis in the least shrew at 1-2 and 33 h post-injection. To investigate the expression profile of NK(1) receptor during both emetic phases, we cloned the cDNA corresponding to a ~700 base pairs of mRNA flanked by two stretches of nucleotides conserved among different species and demonstrated that the shrew NK(1) receptor nucleotide sequence shares ~90% sequence identity with the human NK(1) receptor. Of the 12 time-points tested, significant increases in expression levels of NK(1) receptor mRNA in the shrew brainstem occurred at 2 and 28 h post-cisplatin injection, whereas intestinal NK(1) receptor mRNA was increased at 28 h. Shrew brainstem and intestinal substance P mRNA levels also tended to increase during the two phases. Furthermore, expression levels of NK(1) receptor protein were significantly increased in the brainstem at 2, 8, and 33 h post-cisplatin. No change in brainstem 5-HT(3) receptor protein expression was observed. The temporal enhancements in NK(1) receptor protein expression were mirrored by significant increases in the phosphorylation status of the brainstem ERK1/2 at 2, 8, and 33 h post-cisplatin. Phosphorylation of PKA significantly increased at 33rd and 40th hour. Our results indicate associations between cisplatin's peak immediate- and delayed-phase vomiting frequency with increased: (1) expression levels of NK(1) receptor mRNA and its protein level, and (2) downstream NK(1) receptor-mediated phosphorylation of ERK1/2 and PKA signaling.
authors.affiliation: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 E Second Street, Pomona, CA 91766, USA. ndarmani@westernu.edu
authors.forename: Nissar A
authors.initials: NA
authors.lastname: Darmani
authors.forename: Dilip
authors.initials: D
authors.lastname: Dey
authors.forename: Seetha
authors.initials: S
authors.lastname: Chebolu
authors.forename: Barry
authors.initials: B
authors.lastname: Amos
authors.forename: Raj
authors.initials: R
authors.lastname: Kandpal
authors.forename: Tursun
authors.initials: T
authors.lastname: Alkam
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000009:adverse effects*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism; D012788:Shrews; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000235:genetics*; D014839:Vomiting / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D011985:Receptors, Serotonin; C078730:serotonin 5 receptor; D013373:Substance P; D011494:Protein Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002945:Cisplatin