References of "Hanesch, Ulrike 50001937"
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See detailEarly life stress reduces neuropathic pain in adulthood -is alteration of spinal microglial reactivity critically involved?
Genty, Julien UL; Tetsi Nomigni, Milène UL; Anton, Fernand UL et al

Poster (2017, November 14)

Growing evidence underlines the association between early life adversity and persistent alterations of neural, endocrine and immune functions that may be accompanied by a host of disease patterns such as ... [more ▼]

Growing evidence underlines the association between early life adversity and persistent alterations of neural, endocrine and immune functions that may be accompanied by a host of disease patterns such as chronic pain in later life. Neuropathy is a debilitating condition presenting a substantial cooccurrence with stress related disorders. Despite the established overlapping of biochemical pathways involved in the etiology of these disorders, the intricacy of their mutual interdependence remains. In this context, immunocompetent cells are largely affected during chronic stress and are a key factor in the sensitization of nociceptive dorsal horn neurons. The goal of the present study was to investigate the impact of maternal separation (MS), a wellestablished model of early life stress in rodents, on chronic constriction injury (CCI)induced neuropathic pain and to reveal the relevance of spinal microglia activation and proinflammatory cytokine regulation. For this purpose 12 groups of rats were exposed to different combinations of stress condition, CCIinjury and pharmacological treatment. Noxious sensitivity was tested during baseline conditions as well as during subsequent neuropathic and pharmacological treatment conditions. Von Frey hair and the cold plate tests were used for the assessment of mechanical and cold hyperalgesia/allodynia. Amphotericin B, a substance known to activate monocytes and macrophages in the periphery and microglial cells in the CNS was administered to subgroups of animals. At the end of the protocol, rats were sacrificed to assess microglial activation using qPCR and immunohistochemistry. Our main finding was that maternal separation led to a reduction of CCIrelated pain hypersensitivity (thermal and mechanical hyperalgesia/allodynia). We concomitantly observed a downregulation of Iba 1, mRNA a marker of microglial cells, and of IL1β mRNA, a proinflammatory cytokine that may be released by microglia. According to preliminary results, Amphotericin B in turn seemed to enhance CCI related pain sensitivity, possibly via an activation of microglia. Our results show that MS may lead to a reduction of neuropathy relatedpain in adult age. Stress related dampening of spinal microglial reactivity may play a critical role in this context. [less ▲]

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See detailChronic Social Stress Time-Dependently Affects Neuropathic Pain-Related Cold Allodynia and Leads to Altered Expression of Spinal Biochemical Mediators
Le Coz, Glenn Marie; Genty, Julien UL; Anton, Fernand UL et al

in Frontiers in Behavioral Neuroscience (2017), 11

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 ... [more ▼]

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 mechanicallyinduced pain remains unchanged. [less ▲]

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See detailPeripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to maternal separation
Juif, Piere-Eric; Salio, Chiara; Zell, Vivien et al

in European Journal of Neuroscience (2016)

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See detailPeripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to neonatal maternal deprivation
Juif, Pierre-Eric; Salio, Chiara; Zell, Vivien UL et al

in European Journal of Neuroscience (2016)

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See detailCorticosterone analgesia is mediated by the spinal production of neuroactive metabolites that enhance GABAergic inhibitory transmission on dorsal horn rat neurons.
Zell, Vivien; Juif, Pierre-Eric; Hanesch, Ulrike UL et al

in The European journal of neuroscience (2015)

Corticosterone (CORT) is a glucocorticoid produced by adrenal glands under the control of the hypothalamic-pituitary-adrenal axis. Circulating CORT can enter the central nervous system and be reduced to ... [more ▼]

Corticosterone (CORT) is a glucocorticoid produced by adrenal glands under the control of the hypothalamic-pituitary-adrenal axis. Circulating CORT can enter the central nervous system and be reduced to neuroactive 3alpha5alpha-reduced steroids, which modulate GABAA receptors. In the dorsal spinal cord, GABAergic transmission modulates integration of nociceptive information. It has been shown that enhancing spinal inhibitory transmission alleviates hyperalgesia and allodynia. Therefore, the spinal neuronal network is a pivotal target to counteract pain symptoms. Thus, any increase in spinal 3alpha5alpha-reduced steroid production enhancing GABAergic inhibition should reduce nociceptive message integration and the pain response. Previously, it has been shown that high levels of plasma glucocorticoids give rise to analgesia. However, to our knowledge, nothing has been reported regarding direct non-genomic modulation of neuronal spinal activity by peripheral CORT. In the present study, we used combined in vivo and in vitro electrophysiology approaches, associated with measurement of nociceptive mechanical sensitivity and plasma CORT level measurement, to assess the impact of circulating CORT on rat nociception. We showed that CORT plasma level elevation produced analgesia via a reduction in C-fiber-mediated spinal responses. In the spine, CORT is reduced to the neuroactive metabolite allotetrahydrodeoxycorticosterone, which specifically enhances lamina II GABAergic synaptic transmission. The main consequence is a reduction in lamina II network excitability, reflecting a selective decrease in the processing of nociceptive inputs. The depressed neuronal activity at the spinal level then, in turn, leads to weaker nociceptive message transmission to supraspinal structures and hence to alleviation of pain. [less ▲]

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See detailPlasma glucocorticoids differentially modulate phasic and tonic GABA inhibition during early postnatal development in rat spinal lamina II.
Zell, Vivien; Hanesch, Ulrike UL; Poisbeau, Pierrick et al

in Neuroscience letters (2014), 578

Nociceptive processing is tuned by GABAA receptor-mediated inhibition in the spinal cord dorsal horn that undergoes postnatal maturation in rodents. These GABAergic inhibitory postsynaptic currents (IPSCs ... [more ▼]

Nociceptive processing is tuned by GABAA receptor-mediated inhibition in the spinal cord dorsal horn that undergoes postnatal maturation in rodents. These GABAergic inhibitory postsynaptic currents (IPSCs) are modulated by 3alpha5alpha-reduced steroids during early postnatal development in spinal cord lamina II. Thus an enhanced phasic inhibition is present in neonates and decreases over time. GABA can also activate extrasynaptic receptors, giving rise to tonic inhibition. In this study, we characterized the contribution of plasma corticosterone (CORT) to postnatal maturation of spinal phasic and, for the first time, tonic GABAergic inhibitions. We used Fisher and Lewis rat strains displaying respectively high and low hypothalamic-pituitary-adrenal axis reactivity, compared to control Sprague-Dawley rats. Measured plasma CORT levels were significantly higher in Fisher rats, which also displayed significantly higher mechanical nociceptive thresholds, supporting the hypothesis of an antinociceptive action of CORT. Recorded GABAA IPSCs shortened during maturation in all strains while remaining larger in Fisher rats. Blocking the 5alpha-reduction of steroids in Fisher rats produced a further decrease of IPSC deactivation time constant. In contrast, GABAA tonic inhibition progressively increased during maturation, without any difference among strains. In conclusion, we show that both phasic and tonic GABAergic inhibitions undergo postnatal maturation in lamina II. Moreover spinal production of 3alpha5alpha-reduced steroids that presumably derive from plasma CORT is correlated to spinal GABAA phasic (but not tonic) inhibition and to mechanical nociceptive thresholds. [less ▲]

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See detailGlucocorticoid-Mediated Enhancement of Glutamatergic Transmission May Outweigh Anti-Inflammatory Effects under Conditions of Neuropathic Pain.
Le Coz, Glenn-Marie UL; Anton, Fernand UL; Hanesch, Ulrike UL

in PloS one (2014), 9(3), 91393

At the clinical level comorbidity between chronic pain and dysfunctional hypothalamus-pituitary-adrenal (HPA) axis is well established. We aimed to identify causal relationships in a model of neuropathic ... [more ▼]

At the clinical level comorbidity between chronic pain and dysfunctional hypothalamus-pituitary-adrenal (HPA) axis is well established. We aimed to identify causal relationships in a model of neuropathic pain (chronic constriction injury, CCI) by studying the effects of glucocorticoid receptor agonist (dexamethasone) and antagonist (RU-486) administration on pain behavior and spinal biochemical mediators. Daily injections were performed in Sprague Dawley rats. Weight, plasma corticosterone levels and mechanical pain thresholds were assessed before and during 21 days post-CCI. At days four and 21 we investigated the mRNA expression of spinal mediators. In the dexamethasone-injected group, we observed a diminution of body weight and plasma corticosterone levels during the 21 days post surgery period and a more pronounced pain sensitivity until day 7 post-CCI. This enhanced pain sensitivity in the early period following nerve injury was accompanied by a transient increase of the glutamate receptors mGluR5 and NMDA at day 4. However, at this time point we did not observe any effect of the agonist/antagonist injections on the mRNA expression of pro-inflammatory cytokines. The RU-486-injected rats showed a slight mechanical hypoalgesia until 7 days post-CCI, but without any significant correlation with the expression of the measured markers. Our results indicate that glucocorticoid-related modulations of neuropathic pain processing may rather depend on a modification of glutamatergic transmission than on a change in pro-inflammatory cytokine expression. [less ▲]

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See detailDifferential neuropathic pain sensitivity and expression of spinal mediators in Lewis and Fischer 344 rats.
Le Coz, Glenn-Marie UL; Fiatte, Cathy; Anton, Fernand UL et al

in BMC neuroscience (2014), 15(1), 35

BACKGROUND: Altered hypothalamo-pituitary-adrenal (HPA) axis activity may be accompanied by a modulation of pain sensitivity. In a model of neuropathic pain (chronic constriction injury, CCI) we ... [more ▼]

BACKGROUND: Altered hypothalamo-pituitary-adrenal (HPA) axis activity may be accompanied by a modulation of pain sensitivity. In a model of neuropathic pain (chronic constriction injury, CCI) we investigated the onset and maintenance of mechanical allodynia/hyperalgesia and the expression of biochemical mediators potentially involved in spinal cell modulation in two rat strains displaying either hypo- (Lewis-LEW) or hyper- (Fischer 344-FIS) reactivity of the HPA axis. RESULTS: Mechanical pain thresholds and plasmatic corticosterone levels were assessed before and during periods of 4 or 21 days following CCI surgery. At the end of the respective protocols, the mRNA expression of glial cell markers (GFAP and Iba1) and glutamate transporters (EAAT3 and EAAT2) were examined. We observed a correlation between the HPA axis reactivity and the pain behavior but not as commonly described in the literature; LEW rats seemed to be less sensitive than FIS from 4 to 14 days after the CCI surgery when looking at the mechanical allodynia/hyperalgesia. However, the biochemical spinal markers expression we observed is conflicting. CONCLUSION: We did not find a specific causal relation between the pain behavior and the glial cell activation or the expression of the glutamate transporters, suggesting that the interaction between the HPA axis and the spinal activation pattern is more complex in a context of neuropathic pain. [less ▲]

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See detailNeonatal maternal separation stress alters neuropathic pain behaviour and spinal nociceptive processing in rats
Genty, Julien UL; Le Coz, Glenn-Marie UL; Anton, Fernand UL et al

Scientific Conference (2014)

Aims Early life stress enhances vulnerability to metabolic and mental disorders in adulthood. Altered pain sensitivity and dysfunctional emotional processing have been described in this context. We ... [more ▼]

Aims Early life stress enhances vulnerability to metabolic and mental disorders in adulthood. Altered pain sensitivity and dysfunctional emotional processing have been described in this context. We assessed the impact of neonatal maternal separation (MS) on chronic constriction injury (CCI) induced neuropathic pain behavior and biochemical spinal processing in early adulthood. Methods Four groups of rats were tested: Controls, MS, CCI, MS+CCI. For MS, pups were separated from the dam from postnatal day 2 to 12 for 3 hours per day. At an age of 7 weeks mechanical and thermal pain thresholds where assessed by the von Frey and the cold plate test. CCI surgery was performed in two of the experimental groups and behavioural measurements were continued until day 21 post surgery. After decapitation spinal cord levels L4/L5 were removed and total RNA was extracted to perform qPCR. Results MS alone did not affect pain thresholds. Surprisingly, MS+CCI rats were less sensitive to mechanical and thermal stimuli compared to CCI. Regarding the biochemical data, MS as well as MS+CCI led to an upregulation of glial markers, cytokines and growth factors and to a downregulation of glutamate receptors and transporters. Conclusion Behavioral and biochemical data are conflicting. The reduced pain sensitivity in MS animals is in contrast to activation of glia and enhanced expression of cytokines but in line with reduced glutamatergic signalling. Since MS and MS+CCI groups did not differ, pain-related processing may have been outweighed by stress-related programming of biochemical reactivity. [less ▲]

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See detailMaternal separation delays the functional establishment of ascending and descending nociceptive circuits in the rat spinal cord.
Juif, Pierre-Eric UL; Petit-Demoulière, Nathalie; Lacaud, Adrien et al

in FENS Abstr., vol.6, p326, 57.11, 2012 (2012)

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See detailCirculating Glucocorticoids Shape Phasic and Tonic GABA Inhibition in Lamina II of Rat Spinal Cord.
Zell, Vivien UL; Anton, Fernand UL; Hanesch, Ulrike UL et al

in FENS Abstr., vol. 6, p153, 6.22, 2012 (2012)

Detailed reference viewed: 35 (3 UL)