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

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