Early life stress (ELS) leads to a permanent reprogramming of biochemical stress response cascades that may also be relevant for the processing of chronic pain states such as neuropathy. Despite clinical evidence, little is known about ELS-related vulnerability for neuropathic pain and the possibly underlying etiology.In the framework of experimental studies aimed at investigating the respective relationships we used the established ELS model of maternal separation (MS). Rat dams and neonates were separated for 3 h/day from post-natal day 2–12. At adulthood, noxious mechanical and thermal thresholds were assessed before and during induction of neuropathic pain by chronic constriction injury (CCI). The potential involvement of spinal glutamatergic transmission, glial cells, pro-inflammatory cytokines and growth factors was studied by using qPCR.MS per se did not modify pain thresholds. But, when exposed to neuropathic pain, MS rats exhibited a marked reduction of thermal sensitivity and a delayed development of mechanical allodynia/hyperalgesia when compared to control animals. Also, MS did not alter glucocorticoid receptor mRNA levels, but prevented the CCI-induced down-regulation of NR1 and NR2 sub-units of the NMDA receptor and of the glutamate transporter EAAT3 as observed at 21 days post-surgery. Additionally, CCI-provoked up-regulation of glial cell markers was either prevented (GFAP for astrocytes) or dampened (Iba1 for microglia) by MS. Pro-inflammatory cytokine mRNA expression was either not affected (IL-6) or reduced (IL-1β) by MS shortly after CCI. The growth factors GDNF and NGF were only slightly downregulated 4 days after CCI in the MS-treated animals. The changes in glutamatergic signaling, astroglial and cytokine activation as well as neurotrophin expression could, to some extent, explain these changes in pain behavior. Taken together, the results obtained in the described experimental conditions support the mismatch theory of chronic stress where an early life stress, rather than predisposing individuals to certain pathologies, renders them resilient.

Clinical data have shown that chronic exposure to stress may be accompanied by an enhancement of inflammation-related pain sensitivity. In this context, little is however known on the impact of stress on neuropathic pain. In the present study we addressed this issue by combining the chronic constriction injury (CCI) model with an ongoing social stress (OSS) paradigm. Cold plate and von Frey tests were performed in 48 rats divided into four groups: OSS exposed to OSS, CCI subjected to chronic nerve constriction, OSS+CCI with a combination of neuropathy and stress and CON, a control group lacking any manipulation. While we did not observe any stress-related differences in mechanical sensitivity throughout the observation period, CCI rats were more sensitive to cold stimulation than OSS+CCI in the initial phase of neuropathy. A switch was observed at a later stage, leading to a hypersensitivity of the OSS+CCI compared to the CCI rats. At this time point we investigated the spinal mRNA expression of neuron and glia related molecules potentially involved in neuropathic pain and stress. The combination of psychosocial stress and neuropathic pain seemed to enhance glial cell activation, pro-inflammatory cytokine and neurotrophic factor mRNA levels, rather than glutamatergic transmission. Our data show that long lasting social stress may lead to time-dependent alteration of neuropathy-related cold pain sensitivity while mechanically-induced pain remains unchanged.

The cumulative and match/mismatch hypotheses of stress are still under discussion regarding the effects of early life stress (ELS) on the vulnerability or resilience to psychopathology. In this context, an additional stress in later life (second hit) often leads to stress-related disorders that frequently include comorbid pain states. We previously observed that maternal separation (MS), a model of ELS, reduces vulnerability to neuropathic and inflammatory pain in rats. In the present study, we investigated the effects of an additional later stressor on the vulnerability to inflammatory pain. Sprague Dawley pups were divided into 4 groups: controls (CON, no stress), MS, social stress (SS) and MS+SS. At young adult age (from 7 to 15 weeks), stress- as well as pain-related parameters were evaluated prior and during 21 days following the induction of paw inflammation with complete Freund’s adjuvant (CFA). Finally spinal glutamatergic transmission, immunocompetent cells, pro-inflammatory cytokines and growth factors were examined using qPCR. None of the stress conditions had a significant impact on corticosterone levels and anhedonia. In the forced swim test, MS and SS displayed increased passive coping whereas the combination of both stressors revoked this effect. The different stress conditions had no influence on basal mechanical thresholds and heat sensitivity. At 4 days post-inflammation all stress groups displayed lower mechanical thresholds than CON but the respective values were comparable at 7, 10, and 14 days. Only on day 21, MS rats were more sensitive to mechanical stimulation compared to the other groups. Regarding noxious heat sensitivity, MS+SS animals were significantly less sensitive than CON at 10 and 21 days after CFA-injection. qPCR results were mitigated. Despite the finding that stress conditions differentially affected different players of glutamatergic transmission, astrocyte activity and NGF expression, our biochemical results could not readily be related to the behavioral observations, precluding a congruent conclusion. The present results do neither confirm the cumulative nor corroborate or disprove the match/mismatch hypothesis.

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Autism Spectrum Disorders (ASD) are neuro-developmental pathologies characterized by social communication and interaction deficiency, and repetitive and restricted behaviors. The social motivation network, notably the nucleus accumbens (NAc), is dysfunctional in these disorders. We previously showed that pharmacological treatment facilitating the activity of the mGlu4 glutamate receptor relieves autistic symptoms in the Oprm1 -/- mouse model of autism. Interestingly, we also evidenced that mGlu4 can modulate the activity of the amygdala, a critical brain region for emotional responses and social behavior. Aim: Our hypothesis is mGlu Autism Spectrum Disorders (ASD) are neuro-developmental pathologies characterized by social communication and interaction deficiency, and repetitive and restricted behaviors. The social motivation network, notably the nucleus accumbens (NAc), is dysfunctional in these disorders. We previously showed that pharmacological treatment facilitating the activity of the mGlu4 glutamate receptor relieves autistic symptoms in the Oprm1 -/- mouse model of autism. Interestingly, we also evidenced that mGlu4 can modulate the activity of the amygdala, a critical brain region for emotional responses and social behavior. Aim: Our hypothesis is mGlu4 in the NAc and the basolateral amygdala (BLA) plays a critical role in modulating autism-sensitive symptoms, namely social motivation and stereotyped behaviors. Methods : In order to test this, we performed the knockdown of the gene coding for mGlu4, Grm4 , in the nucleus accumbens or the basolateral amygdala of wild-type mice using bilateral stereotaxic injections of shRNA-expressing AAVs. We tested them in several behavioral tests to evaluate the presence or not of autistic symptoms. In the end, we conducted qRT-PCR analysis in several structures of reward circuit in these same mice. Results: Knocking down (KD) of Grm4 expression in NAc neurons induces autistic-like symptoms such as impaired social interactions and social preference, and impacts gene expression in several brain regions. In contrast, we expect that knocking down Grm4 expression in BLA neurons will elicit modifications in social anxiety levels. Conclusions : These results suggest that mGlu4 receptors expressed in the NAc and BLA neurons play a major role in modulating sociability in mice.4 in the NAc and the basolateral amygdala (BLA) plays a critical role in modulating autism-sensitive symptoms, namely social motivation and stereotyped behaviors. Methods : In order to test this, we performed the knockdown of the gene coding for mGlu4, Grm4 , in the nucleus accumbens or the basolateral amygdala of wild-type mice using bilateral stereotaxic injections of shRNA-expressing AAVs. We tested them in several behavioral tests to evaluate the presence or not of autistic symptoms. In the end, we conducted qRT-PCR analysis in several structures of reward circuit in these same mice. Results: Knocking down (KD) of Grm4 expression in NAc neurons induces autistic-like symptoms such as impaired social interactions and social preference, and impacts gene expression in several brain regions. In contrast, we expect that knocking down Grm4 expression in BLA neurons will elicit modifications in social anxiety levels. Conclusions : These results suggest that mGlu4 receptors expressed in the NAc and BLA neurons play a major role in modulating sociability in mice.