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Panicolytic-like effects caused by substantia nigra pars reticulata pretreatment with low doses of endomorphin-1 and high doses of CTOP or the NOP receptors antagonist JTC-801 in male Rattus norvegicus

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Abstract

Rationale

Gamma-aminobutyric acid (GABA)ergic neurons of the substantia nigra pars reticulata (SNpr) are connected to the deep layers of the superior colliculus (dlSC). The dlSC, in turn, connect with the SNpr through opioid projections. Nociceptin/orphanin FQ peptide (N/OFQ) is a natural ligand of a Gi protein-coupled nociceptin receptor (ORL1; NOP) that is also found in the SNpr. Our hypothesis is that tectonigral opioid pathways and intranigral orphanin-mediated mechanisms modulate GABAergic nigrotectal connections.

Objectives

Therefore, the aim of this work was to study the role of opioid and NOP receptors in the SNpr during the modulation of defence reactions organised by the dlSC.

Methods

The SNpr was pretreated with either opioid or NOP receptor agonists and antagonists, followed by dlSC treatment with bicuculline.

Results

Blockade of GABAA receptors in the dlSC elicited fear-related defensive behaviour. Pretreatment of the SNpr with naloxone benzoylhydrazone (NalBzoH), a μ-, δ-, and κ1-opioid receptor antagonist as well as a NOP receptor antagonist, decreased the aversive effect of bicuculline treatment on the dlSC. Either μ-opioid receptor activation or blockade by SNpr microinjection of endomorphin-1 (EM-1) and CTOP promoted pro-aversive and anti-aversive actions, respectively, that modulated the defensive responses elicited by bicuculline injection into the dlSC. Pretreatment of the SNpr with the selective NOP receptor antagonist JTC801 decreased the aversive effect of bicuculline, and microinjections of the selective NOP receptor agonist NNC 63-0532 promoted the opposite effect.

Conclusions

These results demonstrate that opioid pathways and orphanin-mediated mechanisms have a critical role in modulating the activity of nigrotectal GABAergic pathways during the organisation of defensive behaviours.

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Abbreviations

dlSC:

Deep layers of the superior colliculus

dPAG:

Dorsal columns of the periaqueductal grey matter

EM-1:

Endomorphin-1

GABA:

Gamma-aminobutyric acid

GPCR:

G protein-coupled nociceptin receptor

NalBzoH:

Naloxone benzoylhydrazone

N/OFQ:

Nociceptin/orphanin FQ

ORL1/NOP:

Nociceptin receptor

PAG:

Periaqueductal grey matter

SNpr:

Substantia nigra pars reticulata

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Acknowledgements

This study was supported by CNPq (process 483763/2010-1), FAEPA (processes 70/2002, 210/2005, and 345/2009), and FAPESP (processes 1995/3604-4, 1995/8418-4, 2007/01174-1, 2009/54014-7, 2012/03798-0, and 2017/11855-8). J.A. Silva was a recipient of a Scientific Initiation scholarship from CNPq (PIBIC process 2005.1.891.17.3) and was also supported by FAPESP and CNPq post-graduation fellowships (CNPq M.Sc. process 130170/2009-7; FAPESP M.Sc. process 2009/02458-9; CNPq Sc.D. process 142844/2011-0; FAPESP post-doctoral process 2015/10313-1). A.F. Biagioni was supported by FAPESP (Sc.D. process 2010/15140-4; post-doctorate process 2014/10742-7). R.C. Almada is a post-doctoral student supported by FAPESP (process 2012/22681-7). R.L. de Freitas was supported by FAPESP (Scientific Initiation Scholarship 01/03752-6, M.Sc. fellowship 03/05256-1, post-doctoral fellowship 2009/17258-5, Young Researchers in Emergent Centres Program fellowship 2013/12916-0, and research grant 2014/11869-0) and CAPES (Sc.D. Fellowship). Coimbra was granted a research fellowship (level 1A) from CNPq (processes 301905/2010-0 and 301341/2015-0). The authors are grateful to D.H. Elias-Filho for the expert technical assistance. D.H. Elias-Filho received a technician scholarship from FAPESP (TT-2, process 02/01497-1) and was the recipient of scholarships sponsored by CNPq (processes 501858/2005-9, 500896/2008-9, and 505461/2010-2).

Author information

Authors and Affiliations

  1. Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Av Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Juliana Almeida da Silva, Audrey Franceschi Biagioni, Rafael Carvalho Almada, Renato Leonardo de Freitas & Norberto Cysne Coimbra

  2. Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo, 14050-220, Brazil

    Juliana Almeida da Silva, Rafael Carvalho Almada, Renato Leonardo de Freitas & Norberto Cysne Coimbra

  3. NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto Medical School of the University of São Paulo, Av Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Norberto Cysne Coimbra

  4. Multiuser Centre of Neuroelectrophysiology, Department of Anatomy and Surgery, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Renato Leonardo de Freitas & Norberto Cysne Coimbra

  5. Laboratory of Pain and Emotions, Department of Anatomy and Surgery, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Renato Leonardo de Freitas

Authors
  1. Juliana Almeida da Silva
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  2. Audrey Franceschi Biagioni
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  3. Rafael Carvalho Almada
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  4. Renato Leonardo de Freitas
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  5. Norberto Cysne Coimbra
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Contributions

JA Silva performed the experiments, analysed and interpreted the data, wrote the manuscript, and designed the figures. AF Biagioni performed the experiments and analysed and interpreted the data. RC Almada analysed the data, designed the figures, and revised the manuscript. RL de Freitas performed the experiments, analysed the data, and revised the manuscript. NC Coimbra designed the experiments, analysed and interpreted the data, wrote the manuscript and approved the final manuscript. All authors have approved the final version of the manuscript.

Corresponding author

Correspondence to Norberto Cysne Coimbra.

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All experiments were performed in accordance with the recommendations of the Brazilian Society for Neuroscience and Behaviour (SBNeC). The study was approved by the FMRP-USP Ethics in Animal Research Committee (CETEA; process 112/2011).

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The authors declare that they have no conflicts of interest.

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da Silva, J.A., Biagioni, A.F., Almada, R.C. et al. Panicolytic-like effects caused by substantia nigra pars reticulata pretreatment with low doses of endomorphin-1 and high doses of CTOP or the NOP receptors antagonist JTC-801 in male Rattus norvegicus . Psychopharmacology 234, 3009–3025 (2017). https://doi.org/10.1007/s00213-017-4678-6

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  • DOI: https://doi.org/10.1007/s00213-017-4678-6

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