Prior chronic stress induces persistent polyI:C-induced allodynia and depressive-like behavior in rats: Possible involvement of glucocorticoids and microglia

Abstract

When animals suffer from viral infections, they develop a set of symptoms known as the "sickness response." Recent studies suggest that psychological stress can modulate the sickness response. However, it remains uncertain whether acute and chronic psychosocial stresses have the same effect on viral infection-induced sickness responses. To address this question, we compared changes in polyI:C-induced sickness responses, such as fever, change of body weight and food intake, mechanical allodynia, and depressive-like behavior, in rats that had been pre-exposed to single and repeated social defeat stresses. Intraperitoneal injection of polyI:C induced a maximal fever of 38.0°C 3h after injection. Rats exposed to prior social defeat stress exhibited blunted febrile responses, which were more pronounced in the repeated stress group. Furthermore, only the repeated stress group showed late-onset and prolonged mechanical allodynia lasting until 8days after injection in the von Frey test and prolonged immobility time in the forced swim test 9days post-injection. To assess the role of glucocorticoids and microglia in the delayed and persistent development of these sickness responses in rats exposed to repeated stress, we investigated the effect of pretreatment with RU486, a glucocorticoid receptor antagonist, and minocycline, an inhibitor of microglial activation, on polyI:C-induced allodynia and depressive-like behavior. Pretreatment with either drug inhibited both the delayed allodynia and depressive-like behavior. The present study demonstrates that repeated, but not single, social defeat stress followed by systemic polyI:C administration induced prolonged allodynia and depressive-like behavior in rats. Our results show that even though a single-event psychosocial stress does not have any effect by itself, animals may develop persistent allodynia and depressive-like behavior when they suffer from an infectious disease if they are pre-exposed to repeated or chronic psychosocial stress. Furthermore, this study suggests that stress-induced corticosterone and microglial activation play a pivotal role in this phenomenon.

Stress-induced neuroinflammatory priming is time of day dependent

“…Substantial evidence indicates that glucocorticoids are the proximal signal through which acute and chronic stress primes microglia and neuroinflammatory responses (Frank et al, 2010, Frank et al, 2012, Frank et al, 2014, Chijiwa et al, 2015). Indeed, blocking the glucocorticoid response to stress (pharmacologically or surgically) prevents neuroinflammatory priming (Frank et al, 2012, Chijiwa et al, 2015).…”

“…Indeed, blocking the glucocorticoid response to stress (pharmacologically or surgically) prevents neuroinflammatory priming (Frank et al, 2012, Chijiwa et al, 2015). Moreover, acute and chronic glucocorticoid administration at doses that mimic the rises produced by stress primes microglia to pro-inflammatory stimuli (Frank et al, 2010, Frank et al, 2014).…”

Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal

“…In addition, stimulating stress-exposed microglia with an immune challenge reduces social interaction and open field exploration (Wohleb, Fenn et al 2012 which is prevented by minocycline treatment (Chijiwa, Oka et al 2015). Therefore, microglia are a key cell population that responds to stress exposure by increasing neuroinflammatory signaling to influence the behavioral response of stress.…”

FAAH inhibition attenuates TLR3-mediated hyperthermia, nociceptive- and anxiety-like behaviour in female rats

“…The arena used for the von Frey test (VFT) and acetone drop test (ADT) consisted of a sixcompartment Perspex arena (11cm × 20cm × 15cm) with wire mesh flooring as previously described [36][37][38]. A modified von Frey behavioural testing was performed to assess mechanical allodynia as previously described [14]. In brief, rats were habituated to the arena for at least 15min after which time an 8g von Frey filament (Touch-Test® Sensory Evaluators, North Coast Medical, Inc., Gilroy, CA, USA) was applied perpendicular to the mid-plantar surface of the hindpaw, for up to a maximum of 5 seconds or until flinching, licking or withdrawal of the paw occurred.…”

“…Recent data has highlighted that FAAH inhibition attenuates the TLR3-mediated increase in the expression of IFN-inducible genes and pro-inflammatory cytokines in brain regions such as the hippocampus and hypothalamus, without altering peripheral immune responses [8,9]. The behavioural and physiological consequences of TLR3 activation include the induction of sickness behaviours such as fever/hypothermia, hypoactivity and anorexia [8,[10][11][12][13] and enhanced pain sensitivity [14] which represents a highly adaptive coping mechanism by the CNS to fight viral infection.…”