Previous studies have shown that the exposure to an open elevated plus maze (oEPM, an EPM with all four open arms) elicits fear/anxiety-related responses in laboratory rodents. However, very little is known about the underlying neural substrates of these defensive behaviors. Accordingly, the present study investigated the effects of chemical inactivation of the amygdala [through local injection of cobalt chloride (CoCl: a nonspecific synaptic blocker)] on the behavior of oEPM-exposed mice. In a second experiment, the pattern of activation of the basolateral (BLA) and central (CeA) nuclei of the amygdala was assessed through quantification of Fos protein expression in mice subjected to one of several behavioral manipulations. To avoid the confound of acute handling stress, 4 independent groups of mice were habituated daily for 10days to an enclosed EPM (eEPM) and, on day 11 prior to immunohistochemistry, were either taken directly from their home cage (control) or individually exposed for 10min to a new clean holding cage (novelty), an eEPM, or the oEPM. An additional group of mice (maze-naïve) was not subjected to either the habituation or exposure phase but were simply chosen at random from their home cages to undergo an identical immunohistochemistry procedure. Results showed that amygdala inactivation produced an anxiolytic-like profile comprising reductions in time spent in the proximal portions of the open arms and total stretched attend postures (SAP) as well as increases in time spent in the distal portions of the open arms and total head-dipping. Moreover, Fos-positive labeled cells were bilaterally increased in the amygdaloid complex, particularly in the BLA, of oEPM-exposed animals compared to all other groups. These results suggest that the amygdala (in particular, its BLA nucleus) plays a key role in the modulation of defensive behaviors in oEPM-exposed mice.
Divergent results in pain management account for the growing number of studies aiming at elucidating the pharmacology of the endocannabinoid/endovanilloid anandamide (AEA) within several pain-related brain structures. For instance, the stimulation of both Transient Receptor Potential Vanilloid type 1 (TRPV1) and Cannabinoid type 1 (CB1) receptors led to paradoxical effects on nociception. Here, we attempted to propose a clear and reproducible methodology to achieve the antinociceptive effect of exogenous AEA within the dorsal periaqueductal gray (dPAG) of mice exposed to the tail-flick test. Accordingly, male Swiss mice received intra-dPAG injection of AEA (CB1/TRPV1 agonist), capsaicin (TRPV1 agonist), WIN (CB1 agonist), AM251 (CB1 antagonist), and 6-iodonordihydrocapsaicin (6-IODO) (TRPV1 selective antagonist) and their nociceptive response was assessed with the tail-flick test. In order to assess AEA effects on nociception specifically at vanilloid or cannabinoid (CB) substrates into the dPAG, mice underwent an intrinsically inactive dose of AM251 or 6-IODO followed by local AEA injections and were subjected to the same test. While intra-dPAG AEA did not change acute pain, local injections of capsaicin or WIN induced a marked TRPV1- and CB1-dependent antinociceptive effect, respectively. Regarding the role of AEA specifically at CB/vanilloid substrates, while the blockade of TRPV1 did not change the lack of effects of intra-dPAG AEA on nociception, local pre-treatment of AM251, a CB1 antagonist, led to a clear AEA-induced antinociception. It seems that the exogenous AEA-induced antinociception is unmasked when it selectively binds to vanilloid substrates, which might be useful to address acute pain in basic and perhaps clinical trials.
20, 30 and 40 minutes after intra-dPAG drug treatment. Two-way ANOVA (factor 1: treatment; factor 2: time) followed by Duncan post hoc test revealed that intra-dPAG injection of CsA 1 nmol increased TFL in animals [treatment factor (F3,15=28.39; p < 0.05); interaction (F18,90=3.23; p < 0.05)]. In Experiment 2; animals were intra-dPAG injected with AM251 (10 pmol; a cannabinoid receptor antagonist, in order to prevent AEA binding to the cannabinoid system) or vehicle followed ten minutes later by local injection of CsA 0.1 nmol (an intrinsically inactive dose on nociception). Five minutes later, each animal was placed into the homecage of an aggressive conspecific mouse for a social defeat stress. The aggressive interaction was interrupted when the intruder mouse exhibited a submissive posture (i.e., defensive upright posture for a 3-sec period). Then, the intruder mouse was placed inside a transparent and perforated plastic bottle (7 cm x 7 cm x 15 cm) and kept inside the aggressor's cage for further five minutes (psychological stress). After that, further five TFL measures were recorded at 0, 5, 10, 20 and 30 minutes post-stress. Two-way ANOVA followed by Duncan post hoc test revealed that animals pre-treated with AM251 followed by CsA had potentiated the social defeat stress-induced analgesia [treatment factor (F 1,8 = 11.08; p < 0.05); time factor (F 6,48 = 57.68; p < 0.05); interaction (F 6,48 = 3.92; p < 0.05)]. Intra-dPAG injection of CsA, at an intrinsically-inactive dose (0.1 nmol), potentiated and prolonged the social defeat stress-induced analgesia. Present results are suggestive that the role of vanilloid receptors located within the dPAG in the modulation of social defeat stress-induced analgesia in mice appears to be dependent on its phosphorylated state.
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