O papel dos receptores GABAA-benzodiazepínicos da amídala na modulação da antinocicepção e de comportamentos defensivos em camundongos submetidos ao teste de exposição ao rato
Girotti, Cilene Aparecida Barbalho
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Animal models have been widely used to investigate the neurobiology of anxiety, fear and to evaluate the antinociception-induced by anxiety/fear. In this sense, the mice (prey) exposed to a predator (rat) exhibit intense defensive response, avoidance and antinociception. Several studies have demonstrated that intra-amygdala injection of midazolam, agonist of GABAAbenzodiazepine, can modulate antinociception-induced by anxiety/fear and defense reactions in rodents. However, it remains unknown what role of GABAA-benzodiazepine receptors in amygdala modulation of antinociception induced in mice exposed to a predator (rat). For this adult male Swiss mice (n= 6-11/group) received intra-amygdala injection of drugs followed by intraperitoneal (i.p.) injection of acetic acid 0.6%, 0.1 ml/10g weight (a nociceptive stimulus that induces abdominal writhes, Writhing test) and were exposed to a Long Evans rat (R) or to a toy rat (TR). The exposure cage was divided into 3 compartments [side A: home cage (protected compartment, 10 x 29 x 18 cm), side B: surface (unprotected compartment, 29 x 29 x 18 cm) and side C: the predator compartment (20 x 29 x 18 cm), which was separated from the surface with a wire mesh]. Mice had free access between the home cage and surface area through a door (5 x 8 cm). The following measures were recorded: (a) nociceptive response (total number of writhes and unprotected writhes) and (b) defensive behavior [total entries in surface (TE), % entries and % time spent in the protected area (%PE and %PT), stretched-attend postures (SAP), unprotected rear (UR) and time spent in contact with wire mesh. The results were analyzed by two-way analyses of variance (ANOVA), factor 1 [exposure (toy rat or rat)] and factor 2 (treatment), followed by Duncan's multiple range test as necessary. P values p≤ 0.05 were considered significant. The mice were divided into two experiments. Experiment 1, the exposure of mice to the rat reduced the nociceptive response (total number of writhes and unprotected writhes) and TE, SAP, UR and time spent in contact with wire mesh, while increased the %PE and %PT in intra-amydala saline-injected mice. Intra-amygdala injection of midazolam (3.0 and 30 nmol/0.1 μl) increased the nociceptive response (total number of writhes and unprotected writhes) and TE, SAP, UR and time spent in contact with wire mesh and decreased %PE and %PT in animals exposed to the rat. In Experiment 2, mice received combined intra-amygdala injection of flumazenil, antagonist of benzodiazepine receptor (saline + 2.0 nmol/0.1 μl) and midazolam (saline + 30 nmol/0.1 μl) on behavior of mice exposed to the rat. Midazolam alone (saline + 30 nmol) replicated the results obtained in Experiment 1. However, flumazenil (2.0 nmol) antagonized the effects of midazolam on nociception and on defensive behavior of mice. The exposure of mice to a predator (rat) elicits defensive response as well as attenuates nociceptive response. Activation of GABAA-benzodiazepine receptors within the amygdala produced anxiolytic-like effects and intensified the nociceptive response in mice. These results suggest that the GABAA receptors located within the amygdala are recruited to modulate both antinociception and emotional behavior of mice front a natural predator (rat).