The Blockade of µ₁- and κ-Opioid Receptors in the Inferior Colliculus Decreases the Expression of Panic Attack-Like Behaviours Induced by Chemical Stimulation of the Dorsal Midbrain

Abstract

<b><i>Background:</i></b> Gamma-aminobutyric acid (GABA)ergic and opioid systems play a crucial role in the neural modulation of innate fear organised by the inferior colliculus (IC). In addition, the IC is rich in GABAergic fibres and opioid neurons, which are also connected to other mesencephalic structures, such as the superior colliculus and the substantia nigra. However, the contribution of distinct opioid receptors (ORs) in the IC during the elaboration and expression of innate fear and panic-like responses is unclear. The purpose of the present work was to investigate a possible integrated action exerted by ORs and the GABA<sub>A</sub> receptor-mediated system in the IC on panic-like responses. <b><i>Methods:</i></b> The effect of the blockade of either µ<sub>1</sub>- or κ-ORs in the IC was evaluated in the unconditioned fear-induced responses elicited by GABA<sub>A</sub> antagonism with bicuculline. Microinjections of naloxonazine, a µ<sub>1</sub>-OR antagonist, or nor-binaltorphimine (nor-BNI), a κ-OR antagonist, were made into the IC, followed by intramesencephalic administration of the GABA<sub>A</sub>-receptor antagonist bicuculline. The defensive behaviours elicited by the treatments in the IC were quantitatively analysed, recording the number of escapes expressed as running (crossing), jumps, and rotations, over a 30-min period in a circular arena. The exploratory behaviour of rearing was also recorded. <b><i>Results:</i></b> GABA<sub>A</sub>-receptor blockade with bicuculline in the IC increased defensive behaviours. However, pretreatment of the IC with higher doses (5 µg) of naloxonazine or nor-BNI followed by bicuculline resulted in a significant decrease in unconditioned fear-induced responses. <b><i>Conclusions:</i></b> These findings suggest a role played by µ<sub>1</sub>- and κ-OR-containing connexions and GABA<sub>A</sub> receptor-mediated neurotransmission on the organisation of panic attack-related responses elaborated by the IC neurons.

Rodent Brain Pathology, Audiogenic Epilepsy

“…The naturally occurring panic attacks (provoked in rats by ultrasonic stimulation) are the valid model of the respective human disorder [ 37 ]. Of course, panic behavior is the phenomenon which is not homogenous, and this was demonstrated by the effects of experimental interventions into the function of GABAergic and opioid systems in corpora quarigemina, substantia nigra, and other structures ([ 31 , 38 , 39 , 40 , 41 ], as the examples). The data obtained also demonstrated that forebrain excitation exert the plausible impact in panic-like behavior of different origin [ 42 ].…”

CB1 receptor signalling mediates cannabidiol-induced panicolytic-like effects and defensive antinociception impairment in mice threatened by Bothrops jararaca lancehead pit vipers

“…The neural bases of non-oriented panic-like responses include mesencephalic tectum structures, such as the dorsal columns of the periaqueductal grey matter and corpora quadrigemina (Calvo et al, 2019a(Calvo et al, , 2019b(Calvo et al, , 2019cCoimbra et al, 2006;Lovick and Adamec, 2009;Lovick et al, 2000). However, more elaborate defensive behaviours, such as oriented escape behaviour to safe places, involves other diencephalic and prosencephalic structures, such as the hypothalamus (Canteras, 2002;dos Anjos-Garcia and Coimbra, 2020;dos Anjos-Garcia et al, 2017;Falconi-Sobrinho et al, 2017;Freitas et al, 2009;Ullah et al, 2015Ullah et al, , 2017.…”

A diminuição de atividades de receptores µ no hipotálamo medial causa efeito panicolítico em presas ameaçadas por serpentes cascaveis

“…O tratamento intra-hipotalâmico com CTOP também diminuiu a incidência (na dose de 1 nmol) e na duração de eliciação de fuga orientada (nas doses de 0,1, i e 10 nmol), assim como na incidência de fuga não orientada (nas doses de 0,1, 1 e de 10 nmol), o que sugere um claro efeito panicolítico. Um efeito similar foi obtido em ratos tratados com microinjeções ou de naloxonazine, um antagonista seletivo de receptores µ1-opioide, ou com nor-binaltorfimina, um antagonista seletivo de receptores opioides do tipo kappa, em concentrações elevadas (5 µg/0,2 µL) no colículo inferior, o qual foi ativado com administrações in situ de bicuculina, um antagonista seletivo de receptores GA-BAérgicos do tipo A, sendo que ambos os antagonistas opioides causaram um efeito panicolítico (Calvo et al, 2019a). Ratos tratados no colículo inferior com naloxone ou naloxonazine e confrontados com cascaveis também apresentaram um comportamento de defesa arrefecido, reforçando o efeito panicolícito desse tratamento farmacológico (CALVO et al, 2019b,c).…”