title: Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI.
abstract: Panic patients may have abnormalities in serotonergic and opioidergic neurotransmission. The dorsal periaqueductal gray (dPAG) plays an important role in organizing proximal defense, related to panic attacks. The 5-HT1Areceptor (5-HT1A-R) is involved in regulating escape behavior that is organized in the dPAG. Activation of κ-opioid receptor (KOR) in this region causes anxiogenic effects. In this study, we investigated the involvement of KOR in regulating escape behavior, using systemic and intra-dPAG injection of the KOR antagonist Nor-BNI. As panic models, we used the elevated T-maze (ETM) and the dPAG electrical stimulation test (EST). We also evaluated whether activation of the 5-HT1A-R or the μ-opioid receptor (MOR) in the dPAG contributes to the Nor-BNI effects. The results showed that systemic administration of Nor-BNI, either subcutaneously (2.0 and 4.0mg/kg) or intraperitoneally (2.0mg/kg), impaired escape in the EST, indicating a panicolytic-like effect. Intra-dPAG injection of this antagonist (6.8nmol) caused the same effect in the EST and in the ETM. Association of ineffective doses of Nor-BNI and the 5-HT1A-R agonist 8-OH-DPAT caused panicolytic-like effect in these two tests. Previous administration of the 5-HT1A-R antagonist WAY-100635, but not of the MOR antagonist CTOP, blocked the panicolytic-like effect of Nor-BNI. These results indicate that KOR enhances proximal defense in the dPAG through 5-HT1A-R modulation, independently of MOR. Because former results indicate that the 5-HT1A-R is involved in the antipanic action of antidepressants, KOR antagonists may be useful as adjunctive or alternative drug treatment of panic disorder.
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, 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, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil.
authors.forename: Camila Biesdorf
authors.initials: CB
authors.lastname: Almeida
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil.
authors.forename: Marcel Pereira
authors.initials: MP
authors.lastname: Rangel
authors.affiliation: Neurobiology of Emotions Research Centre (NAP-USP-NuPNE), School of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirao Preto, São Paulo 14049-900, Brazil; Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Camila Marroni
authors.initials: CM
authors.lastname: Roncon
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil.
authors.forename: Caio César
authors.initials: CC
authors.lastname: Sestile
authors.affiliation: Neurobiology of Emotions Research Centre (NAP-USP-NuPNE), School of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirao Preto, São Paulo 14049-900, Brazil; Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Hélio
authors.initials: H
authors.lastname: Zangrossi
authors.affiliation: Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil; Neurobiology of Emotions Research Centre (NAP-USP-NuPNE), School of Medicine of Ribeirão Preto, University of São Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeirao Preto, São Paulo 14049-900, Brazil.
authors.forename: Frederico Guilherme
authors.initials: FG
authors.lastname: Graeff
authors.affiliation: Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil. Electronic address: elisabethaudi8@gmail.com.
authors.forename: Elisabeth Aparecida
authors.initials: EA
authors.lastname: Audi
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D008297:Male; D023421:Models, Animal; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010200:Panic / Q000187:drug effects* / Q000502:physiology; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D014149:Tranquilizing Agents / Q000494:pharmacology*
chemical_list: D009292:Narcotic Antagonists; D010879:Piperazines; D011725:Pyridines; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D014149:Tranquilizing Agents; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D044282:Receptor, Serotonin, 5-HT1A; C051844:norbinaltorphimine; D013004:Somatostatin; D009271:Naltrexone; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin
keywords: 8-OH-DPAT hydrobromide (PubChem CID: 6917794); CTOP (PubChem CID: 5311058); Dorsal periaqueductal gray; Elevated T-maze; Panic disorder; WAY-100635 maleate salt (PubChem CID: 11957721); dPAG electrical stimulation; nor-binaltorphimine dihydrochloride (PubChem CID: 11957626); κ-opioid receptor 5-HT(1A) receptor