Systemic and intra-amygdala administrations of midazolam reverse anxiety-like behavior induced by cohabiting with a cagemate in chronic pain condition

Abstract

The affective component of pain may be shared among conspecifics through emotional contagion, a form of empathic expression. In this sense, reverberation of negative emotions could generate distress behavioral responses, such as pathological anxiety. Evidences reported that amygdala and its benzodiazepine receptors are involved in perception of pain in others. However, relatively little is known about the neural processes underlying emotional contagion induced by pain observation. In the present study, we investigated the effects of midazolam, an allosteric GABAergic receptor agonist, in anxiety-like behaviors induced by cohabitation with cagemate submitted to sciatic nerve constriction. For this purpose, we administrated systemic (0.5, 1.0 and 2.0 mg/kg) and intra-amygdala midazolam injections (3.0 and 30.0 nmol) in observer cagemates before elevated plus-maze (EPM) evaluation. We found that mice subjected to nerve constriction and their observer cagemates increased anxiety-like behavior in the EPM. Further, systemically (1.0 and 2.0 mg/kg) and intra-amygdala administration of midazolam (3.0 and 30 nmol) reverse this anxiogenic effect. Collectively, these results suggest that social interaction with a cagemate under chronic pain produces anxiety-like responses that could be blocked through midazolam application.

Mice cohabiting with familiar conspecific in chronic stress condition exhibit methamphetamine-induced locomotor sensitization and augmented consolation behavior.

“…Moreover, our previous findings also reported emotional contagion in mice provoked by neuropathic pain. In these studies, cohabitation with a mouse subjected to chronic pain diminished the exploration of open arms in the EPM (Baptista- de-Souza et al, 2015;Carmona et al, 2016;Benassi-Cezar et al, 2020) and caused hypersensitivity to visceral pain (Baptista-de-Souza et al, 2015Zaniboni et al, 2018;Tavares et al, 2021). Taken together, our data corroborate studies from literature showing emotional contagion through approaches that the cagemate witnesses or shares aversive stimuli.…”

“…Regarding empathy for pain, a body of evidence, including data from our group, has shown the effects of emotional contagion of pain-promoting alterations in anxiety-like behaviors of cagemates. Using a model of chronic neuropathic pain, researchers from our laboratory demonstrated anxiogenic-related behaviors in mouse cages tested in EPM and open fields (Baptista- de-Souza et al, 2015;Carmona et al, 2016;Benassi-Cezar et al, 2020). In approaches where cagemates live with conspecifics in other kinds of pain conditions, such as melanoma-bearer mice (Tomiyoshi et al, 2009), formalin-induced paw inflammation (Parent et al, 2012;Mohammadi et al, 2019;Nazeri et al, 2019), and neuropathy (Wallace et al, 2008) augmented anxiety through tests conducted in EPM and open field models was also observed.…”

“…In previous studies from our laboratory, we investigated the consequences of living with a conspecific subjected to chronic restraint stress (Carneiro de Oliveira et al, 2017) or chronic neuropathic pain (Baptista- de-Souza et al, 2015Carmona et al, 2016;Zaniboni et al, 2018;Benassi-Cezar et al, 2020;Tavares et al, 2021) for 14 days. In these studies, mice were kept in dyads for 14 days before the beginning of stress sessions or sciatic nerve constriction to establish familiarity, as proposed by Langford et al (2006).…”

“…Due to its importance, animal models have been developed to understand the neurobiological basis of empathy-like behaviors, such as emotional contagion, consolation, and helping activity (Knapska et al, 2006;Langford et al, 2006;Bartal et al, 2011;Mogil, 2015;Burkett et al, 2016;Karakilic et al, 2018). Studies from our laboratory, for example, observed anxiogeniclike behaviors and anhedonia in mice living with a conspecific subjected to chronic restraint stress (Carneiro de Oliveira et al, 2017) and neuropathic conditions (Baptista-de-Souza et al, 2015Carmona et al, 2016;Benassi-Cezar et al, 2020). In this sense, through emotional contagion, researchers have emphasized that distress-induced psychiatric disorders, such as anxiety and depression, can occur vicariously.…”

Anterior cingulate cortex, but not amygdala, modulates the anxiogenesis induced by living with conspecifics subjected to chronic restraint stress in male mice

“…Overall, to investigate the basis of empathy in animals, rodent models apply emotional stress or nociceptive stimuli to change behavioral responses in the observer partner (Baptista-de-Souza et al, 2015;Carneiro de Oliveira et al, 2017, 2022Zaniboni et al, 2018;Benassi-Cezar et al, 2020;Tavares et al, 2021). For instance, besides inducing anxiety, nerve constriction, a procedure that produces neurophatic pain by itself (Benbouzid et al, 2008;Yalcin et al, 2014), also induced anxiogenic-like behaviors in mice living with a conspecific in chronic pain (Baptista- de-Souza et al, 2015;Carmona et al, 2016;Benassi-Cezar et al, 2020).…”