CONSEQUENCES OF EARLY LIFE STRESS FOR PAIN PROCESSING AND COPING WITH STRESS IN LATER LIFE: BEHAVIOURAL AND BIOCHEMICAL STUDIES IN THE RAT

Doctoral thesis (2018)

Stress is commonly defined as the response to a non-specific situation presenting a psychological and/or physical challenge. In order to react in an appropriate manner to environmental threats the body ... [more ▼]

Stress is commonly defined as the response to a non-specific situation presenting a psychological and/or physical challenge. In order to react in an appropriate manner to environmental threats the body will trigger a wide range of defence mechanisms. However cases where challenges are sustained and the individual does not have the ability to cope with the stress are nowadays believed to be a main factor for the onset and exacerbation of a broad range of disorders. Among these are psychiatric disorders such as depression but also pain affections. Pain is described by the International Association for the study of Pain (IASP) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. As for stress, this system aiming at preserving the body integrity can become defective and enhance pain sensitivity or foster the development of chronic pain. These two health problems categories each represent a considerable issue of public health. Indeed the World Health Organization (WHO) estimates that 27% of the European adult population had experienced at least one episode of mental disorder and the IASP reported that 19% of the pan-European population experienced chronic pain (Macfarlane, Pain 2016). Furthermore, chronic pain and stress-related disorders are greatly comorbid, having deleterious effects on the efficacy of treatments. Despite the raising awareness of clinical and pre-clinical research on their overlapping pathways, common mediators and interactions, the nature of the relationship between chronic pain conditions and stress-related disorders is not yet elucidated. The studies I undertook during my Ph.D. aimed to understand how chronic stress, with an emphasis on early-life stress, is linked to altered nociceptive transmission and to modified chronic pain vulnerability. Early life stress (ELS) was of particular interest as this period of life is subjected to an intense neuronal plasticity of notably stress and pain systems. Furthermore it is increasingly accepted that early life factors are linked to the susceptibility to develop chronic pain conditions in adulthood. As pain is a multidimensional system, I had to restrict my studies to one of the relay stations for the transmission of pain. In the context of chronic stress, most of the work was done on the brain circuits underlying the affective part of pain but little is known about the effect of chronic pain on spinal nociceptive processes. Since chronic stress is a broad phenomenon altering not only processing at the brain level, I focused my studies on spinal dorsal horn noxious transmission. The first stage of my work was to assess the impact of ELS on neuropathic pain, a type of chronic pain arising from nerve lesions. In a second step, I sought to determine if the results obtained in this first study were specific to the type of pain (neuropathic) or also were valid for another type of chronic pain, e.g. chronic inflammatory pain. The third study aimed to determine if ELS would predispose to enhanced vulnerability to stress exposure later in life and to concomitant alterations of chronic pain. To finish, during the last year of my Ph.D. I investigated the possible mechanisms underlying the behavioural results using pharmacological manipulations and initiated a separate project devoted to in vivo electrophysiological characterization of the response behaviour of nociceptive spinal dorsal horn neurons. In the following introduction, I will give an overview of the stress systems, focusing on the hypothalamo-pituitary adrenal (HPA) axis and early life stress. Then I will outline the different part of the pain system and concepts of central sensitization involved in chronic pain. [less ▲]

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

in PLoS ONE (2018), 13(8), 0202599

Early life stress reduces neuropathic pain in adulthood -is alteration of spinal microglial reactivity critically involved?

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 ▲]

Impact of neonatal maternal separation on neuropathic pain behavior and spinal nociceptive procesing - a support of the mismatch hypothesis?

Scientific Conference (2016)

Neonatal maternal separation stress alters neuropathic pain behaviour and spinal nociceptive processing in rats

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 ▲]