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

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.