Juliana Almeida da Silva1,2, Audrey Franceschi Biagioni1, Rafael Carvalho Almada1,2, Renato Leonardo de Freitas1,2,3,4, Norberto Cysne Coimbra5,6,7,8. 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. 2. Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo, 14050-220, Brazil. 3. 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. 4. 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. 5. 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. nccoimbr@fmrp.usp.br. 6. Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo, 14050-220, Brazil. nccoimbr@fmrp.usp.br. 7. 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. nccoimbr@fmrp.usp.br. 8. 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. nccoimbr@fmrp.usp.br.
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.
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.
Entities:
Keywords:
Deep layers of the superior colliculus; GABAergic nigrotectal pathways; Nociceptin/Orphanin FQ; Tectonigral opioid pathways
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