title: Opiorphin causes a panicolytic-like effect in rat panic models mediated by μ-opioid receptors in the dorsal periaqueductal gray.
abstract: Reported evidence indicates that endogenous opioid peptides regulate the expression of escape behavior in rats, a panic-related defensive response, through μ-opioid receptors (MORs) in the dorsal periaqueductal gray (dPAG). These peptides are rapidly catabolized by degrading enzymes, including neutral endopeptidase (NEP) and aminopeptidase N (APN). Opiorphin is a peptide inhibitor of both NEP and APN and potentiates the action of endogenous enkephalins. This study evaluated the effects of intravenous and intra-dPAG administration of opiorphin on escape responses in the elevated T-maze and in a dPAG electrical stimulation test in rats. We also evaluated the involvement of MORs in the effects of opiorphin using the selective MOR antagonist CTOP. A dose of 2.0 mg/kg, i.v., of opiorphin impaired escape performance in both tests. Similar effects were observed with intra-dPAG administration of 5.0 nmol of opiorphin. Local pretreatment with 1.0 nmol CTOP antagonized the anti-escape effects of intra-dPAG opiorphin in both tests, as well as the effect of systemically administered opiorphin (2.0 mg/kg, i.v.) in the electrical stimulation test. These results indicate that opiorphin has an antipanic-like effect that is mediated by MORs in the dPAG. They may open new perspectives for the development of opiorphin analogues with greater bioavailability and physicochemical characteristics in the pursuit of new medications for the treatment of panic disorder.
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil. Electronic address: jhonatanmaraschin@gmail.com.
authors.forename: Jhonatan Christian
authors.initials: JC
authors.lastname: Maraschin
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil.
authors.forename: Marcel Pereira
authors.initials: MP
authors.lastname: Rangel
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil.
authors.forename: Antonio Joaquim
authors.initials: AJ
authors.lastname: Bonfim
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil.
authors.forename: Mariana
authors.initials: M
authors.lastname: Kitayama
authors.affiliation: Institute of Neuroscience and Behavior (INeC), Ribeirão Preto, Brazil; Neurobiology of Emotion Research Centre (NAP-NuPNE), University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Frederico Guilherme
authors.initials: FG
authors.lastname: Graeff
authors.affiliation: Institute of Neuroscience and Behavior (INeC), Ribeirão Preto, Brazil; Neurobiology of Emotion Research Centre (NAP-NuPNE), University of São Paulo, Ribeirão Preto, Brazil; Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Hélio
authors.initials: H
authors.lastname: Zangrossi
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Brazil; Institute of Neuroscience and Behavior (INeC), Ribeirão Preto, Brazil; Neurobiology of Emotion Research Centre (NAP-NuPNE), University of São Paulo, Ribeirão Preto, Brazil. Electronic address: elisabethaudi8@gmail.com.
authors.forename: Elisabeth Aparecida
authors.initials: EA
authors.lastname: Audi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004924:Escape Reaction / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology*; D010200:Panic / Q000187:drug effects*; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012471:Salivary Proteins and Peptides / Q000494:pharmacology*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D012471:Salivary Proteins and Peptides; C517879:glutaminyl-arginyl-phenylalanyl-seryl-arginine; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D013004:Somatostatin
keywords: CTOP (PubChem CID: 5311058); Dorsal periaqueductal gray; Endogenous opioids; Escape panic models; Oligopeptidase inhibitor; Opiorphin; Opiorphin (PubChem CID: 25195667); μ-opioid receptor