title: µ- and κ-Opioid receptor activation in the dorsal periaqueductal grey matter differentially modulates panic-like behaviours induced by electrical and chemical stimulation of the inferior colliculus.
abstract: It has been shown that electrical stimulation of the mesencephalic tectum (MT) provokes defensive responses in both humans and rodents. During an emotional aversive state, some convergent studies have also demonstrated the existence of a complex interaction between endogenous opioid peptide- and γ-aminobutyric acid (GABA)-containing connections during fear-induced responses. It has been proposed that opioid neurons exert an influence on GABAergic interneurons, which, in turn, exert inhibitory tonic control on the mesencephalic excitatory pathways. Thus, opioid peptides can disinhibit neurons that are tonically inhibited by GABA, therefore, modulating the expression of defensive behavioural reactions. In the present work, we used both electric stimulation and microinjections of the GABAA receptor antagonist bicuculline in the inferior colliculus (IC) of Wistar rats in combination with microinjections of µ- and κ-opioid receptor selective agonists into the dorsal columns of periaqueductal grey matter (dPAG) to evaluate the effects on panic-like behaviours elicited by IC electrical and chemical stimulation. The present results showed that neurochemical lesions of the dPAG caused a significant impairment in the organisation of defensive responses by IC neurons, reducing the duration [t(14)=3.0; p<0.01] of defensive immobility and the duration [t(14)=2.8; p<0.05] and frequency [t(14)=2.5; p<0.05] of escape. Paradoxically, treating the dPAG with the µ-opioid receptor agonist met-enkephalin caused a significant reduction of panic-like behaviours induced by both electrical and chemical stimulation of the IC, increasing the escape behaviour threshold [F(2,23)=13.5; p<0.001] and decreasing the frequency [F(3,36)=11.7; p<0.001] and duration [F(3,36)=11.6; p<0.001] of escape and the duration of defensive immobility [F(3,36)=16.1; p<0.05]. In contrast, treating the dPAG with the κ-opioid receptor agonist salvinorin-A increased the frequency [F(3,36)=12.4; p<0.01] and duration [F(3,34)=16.1; p<0.01] of defensive immobility induced by GABAA receptor blockade in the IC. The present results suggest the existence of a complex neuronal network in the MT in which endogenous opioid peptides and GABAergic pathways interact in the control of fear-related behavioural responses.
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Twardowschy
authors.affiliation: Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP), Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil; Institute for Neuroscience and Behaviour (INeC), Av. do Café, Monte Alegre, Ribeirão Preto, São Paulo, 14050-220, Brazil; NAP-USP-Neurobiology of Emotions (NuPNE) Research Centre, FMRP-USP, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, 14049-900, Brazil. Electronic address: nccoimbr@fmrp.usp.br.
authors.forename: Norberto Cysne
authors.initials: NC
authors.lastname: Coimbra
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D045785:Diterpenes, Clerodane / Q000494:pharmacology; D004558:Electric Stimulation; D004744:Enkephalin, Methionine / Q000494:pharmacology; D004924:Escape Reaction / Q000502:physiology; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D007051:Ibotenic Acid; D007245:Inferior Colliculi / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010200:Panic / Q000502:physiology*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000502:physiology*; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D045785:Diterpenes, Clerodane; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D007051:Ibotenic Acid; D004744:Enkephalin, Methionine; C090499:salvinorin A; D001640:Bicuculline
keywords: Bicuculline; Electric stimulation; Inferior colliculus; Met-enkephalin; Panic-like behaviour; Periaqueductal grey matter; Salvinorin-A