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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-HT1A receptor (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.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil. Electronic address: jhonatanmaraschin@gmail.com.

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    Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil.

    ,

    Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil.

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    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.

    ,

    Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, 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; 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.

    ,

    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.

    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.

    Source

    Behavioural brain research 327: 2017 06 01 pg 75-82

    MeSH

    8-Hydroxy-2-(di-n-propylamino)tetralin
    Animals
    Dose-Response Relationship, Drug
    Escape Reaction
    Male
    Models, Animal
    Naltrexone
    Narcotic Antagonists
    Panic
    Periaqueductal Gray
    Piperazines
    Pyridines
    Rats, Wistar
    Receptor, Serotonin, 5-HT1A
    Receptors, Opioid, kappa
    Receptors, Opioid, mu
    Serotonin 5-HT1 Receptor Agonists
    Serotonin 5-HT1 Receptor Antagonists
    Somatostatin
    Tranquilizing Agents

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    28347824

    Citation

    Maraschin, Jhonatan Christian, et al. "Participation of Dorsal Periaqueductal Gray 5-HT1A Receptors in the Panicolytic-like Effect of the Κ-opioid Receptor Antagonist Nor-BNI." Behavioural Brain Research, vol. 327, 2017, pp. 75-82.
    Maraschin JC, Almeida CB, Rangel MP, et al. Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI. Behav Brain Res. 2017;327:75-82.
    Maraschin, J. C., Almeida, C. B., Rangel, M. P., Roncon, C. M., Sestile, C. C., Zangrossi, H., ... Audi, E. A. (2017). Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI. Behavioural Brain Research, 327, pp. 75-82. doi:10.1016/j.bbr.2017.03.033.
    Maraschin JC, et al. Participation of Dorsal Periaqueductal Gray 5-HT1A Receptors in the Panicolytic-like Effect of the Κ-opioid Receptor Antagonist Nor-BNI. Behav Brain Res. 2017 06 1;327:75-82. PubMed PMID: 28347824.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Participation of dorsal periaqueductal gray 5-HT1A receptors in the panicolytic-like effect of the κ-opioid receptor antagonist Nor-BNI. AU - Maraschin,Jhonatan Christian, AU - Almeida,Camila Biesdorf, AU - Rangel,Marcel Pereira, AU - Roncon,Camila Marroni, AU - Sestile,Caio César, AU - Zangrossi,Hélio,Jr AU - Graeff,Frederico Guilherme, AU - Audi,Elisabeth Aparecida, Y1 - 2017/03/24/ PY - 2016/12/06/received PY - 2017/03/15/revised PY - 2017/03/21/accepted PY - 2017/3/30/pubmed PY - 2017/12/20/medline PY - 2017/3/29/entrez KW - 8-OH-DPAT hydrobromide (PubChem CID: 6917794) KW - CTOP (PubChem CID: 5311058) KW - Dorsal periaqueductal gray KW - Elevated T-maze KW - Panic disorder KW - WAY-100635 maleate salt (PubChem CID: 11957721) KW - dPAG electrical stimulation KW - nor-binaltorphimine dihydrochloride (PubChem CID: 11957626) KW - κ-opioid receptor 5-HT(1A) receptor SP - 75 EP - 82 JF - Behavioural brain research JO - Behav. Brain Res. VL - 327 N2 - 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-HT1A receptor (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. SN - 1872-7549 UR - https://www.unboundmedicine.com/medline/citation/28347824/Participation_of_dorsal_periaqueductal_gray_5_HT1A_receptors_in_the_panicolytic_like_effect_of_the_κ_opioid_receptor_antagonist_Nor_BNI_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-4328(16)31211-6 DB - PRIME DP - Unbound Medicine ER -