Early life stress induces sex‐dependent increases in phosphorylated extracellular signal‐regulated kinase in brains of mice with neuropathic pain

Nishinaka, Takashi; Nakamoto, Kazuo; Tokuyama, Shogo

doi:10.1002/ejp.860

Cited by 13 publications

(9 citation statements)

References 49 publications

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“…Studies on humans and rodents strongly suggest that males and females show different sensitivity to pain and differences in peripheral or spinal processing of painful stimuli 64,65 . Women show stronger activation of the mPFC than men in response to subthreshold and strong painful stimuli, which could be linked to increased self-related attention in response to pain 66 and only female mice show differential pERK activation in mPFC in a partial nerve ligation model 67 . In the current investigation all recordings were performed in male mice since male SNI mice are significantly more impaired in a set-shifting task for prefrontal cortex dysfunction than female mice 56 .…”

Section: Discussionmentioning

confidence: 99%

Layer- and subregion-specific electrophysiological and morphological changes of the medial prefrontal cortex in a mouse model of neuropathic pain

Mitrić

Seewald

Moschetti

et al. 2019

Sci Rep

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Chronic neuropathic pain constitutes a serious public health problem, but the disease mechanisms are only partially understood. The involvement of different brain regions like the medial prefrontal cortex has already been established, but the comparison of the role of different subregions and layers is still inconclusive. In the current study, we performed patch-clamp recordings followed by anatomical reconstruction of pyramidal cells from different layers of the prelimbic and infralimbic subregions of the medial prefrontal cortex in neuropathic (spared nerve injury, SNI) and control mice. We found that in the prelimbic cortex, layer 2/3 pyramidal cells from SNI mice exhibited increased excitability compared to sham controls, whereas prelimbic layer 5 pyramidal neurons showed reduced excitability. Pyramidal cells in both layer 2/3 and layer 5 of the infralimbic subregion did not change their excitability, but layer 2/3 pyramidal cells displayed increased dendritic length and branching. Our findings support the view that chronic pain is associated with subregion- and layer-specific changes in the medial prefrontal cortex. They therefore provide new insights into the mechanisms underlying the chronification of pain.

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Section: Discussionmentioning

confidence: 99%

Layer- and subregion-specific electrophysiological and morphological changes of the medial prefrontal cortex in a mouse model of neuropathic pain

Mitrić

Seewald

Moschetti

et al. 2019

Sci Rep

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“…This would especially be true for developmental and high plasticity periods such as gestation ( Lupien et al, 2009 , Weinstock, 2008 ). Nevertheless, several studies showing an increased sensitivity following early life stress were performed in the offspring of females that were pregnant at the time point of shipment ( Alvarez et al, 2013 , Chung et al, 2007 , Green et al, 2011 , Kalinichev et al, 2001 , Nishinaka et al, 2016 , Tsang et al, 2012 ). The animals to be tested could hence have accumulated pre- and post-natal stress.…”

Section: Discussionmentioning

confidence: 99%

Maternal separation stress leads to resilience against neuropathic pain in adulthood

Genty

Nomigni

Anton

et al. 2018

Neurobiology of Stress

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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.

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“…We previously studied the effects of MS, an established ELS paradigm on the development of neuropathic [ 10 ] and inflammatory pain [ 11 ] in adult age. While these studies revealed that MS may be beneficial, in the sense that it promotes a form of resilience against pain hypersensitivity, other studies showed that MS can lead to an enhanced vulnerability to chronic pain conditions [ 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

The combination of postnatal maternal separation and social stress in young adulthood does not lead to enhanced inflammatory pain sensitivity and depression-related behavior in rats

et al. 2018

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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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Early life stress induces sex‐dependent increases in phosphorylated extracellular signal‐regulated kinase in brains of mice with neuropathic pain

Cited by 13 publications

References 49 publications

Layer- and subregion-specific electrophysiological and morphological changes of the medial prefrontal cortex in a mouse model of neuropathic pain

Layer- and subregion-specific electrophysiological and morphological changes of the medial prefrontal cortex in a mouse model of neuropathic pain

Maternal separation stress leads to resilience against neuropathic pain in adulthood

The combination of postnatal maternal separation and social stress in young adulthood does not lead to enhanced inflammatory pain sensitivity and depression-related behavior in rats

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