title: Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model.
abstract: Since herkinorin is the first non-opioid mu agonist derived from salvinorin A that has the ability to induce cerebral vascular dilatation, we hypothesized that herkinorin could have similar vascular dilatation effect via the mu and kappa opioid receptors and the cAMP pathway. The binding affinities of herkinorin to kappa and mu opioid receptors were determined by in-vitro competition binding assays. The cerebral arteries were monitored in piglets equipped with a closed cranial window and the artery responses were recorded before and every 30s after injection of artificial cerebrospinal fluid (CSF) in the presence or absence of the investigated drugs: herkinorion, norbinaltorphimine (NTP), a kappa opioid receptor antagonist, β-funaltrexamine (β-FNA), a mu opioid receptor antagonist, or Rp-8-Br-cAMPS (Rp-cAMPS), an inhibitor of protein kinase A (PKA). CSF samples were collected before and 10 min after herkinorin and NTP administration for the measurement of cAMP levels. Data were analyzed by repeated-measures analysis of variance. Our results show that herkinorin binds to both kappa and mu opioid receptors. Its vasodilation effect is totally abolished by NTP, but is not affected by β-FNA. The levels of cAMP in the CSF elevate after herkinorin administration, but are abolished with NTP administration. The cerebral vasodilative effect of herkinorin is also blunted by Rp-cAMPS. In conclusion, as a non-opioid kappa and mu opioid receptor agonist, herkinorin exhibits cerebral vascular dilatation effect. The dilatation is mediated though the kappa opioid receptor rather than the mu opioid receptor. cAMP signaling also plays an important role in this process.
authors.affiliation: Department of Anesthesiology, Beijing Tong Ren Hospital, Capital Medical University, Beijing, China. jifang@trhos.com
authors.forename: Fang
authors.initials: F
authors.lastname: Ji
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Nan
authors.initials: N
authors.lastname: Ma
authors.forename: John
authors.initials: J
authors.lastname: Riley
authors.forename: William M
authors.initials: WM
authors.lastname: Armstead
authors.forename: Renyu
authors.initials: R
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D002536:Cerebral Arteries / Q000187:drug effects*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D000242:Cyclic AMP / Q000502:physiology*; D045785:Diterpenes, Clerodane / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D011619:Psychotropic Drugs / Q000494:pharmacology; D011753:Pyrones / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000187:drug effects* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D013552:Swine; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C502982:9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho(2,1-c)pyran-7-carboxylic acid methyl ester; D045785:Diterpenes, Clerodane; D005663:Furans; D011619:Psychotropic Drugs; D011753:Pyrones; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D014665:Vasodilator Agents; D000242:Cyclic AMP; C090499:salvinorin A