Transtorno do estresse pós-traumático aumenta a sensibilidade à dor por reduzir a modulação descendente serotoninérgica e noradrenérgica

Abstract

Chronic psychological stresses have affected a large part of the world's population, promoting negative changes in the short and long term. One type of stress that has been studied is PTSD (Post Traumatic Stress Disorder), characterized by chronic psychiatric changes triggered after a traumatic experience. Among the main clinical characteristics of this disorder are fear, social isolation, depression and anxiety, reducing in some way the nociceptive sensitivity. The pathophysiology of these manifestations involves deficits of serotonin and noradrenalin, also responsible for modulation in the modulatory descending path of pain. Thus, the present work aimed to verify the development of PTSD in animals exposed to shock, to evaluate the nociceptive response of these animals and to investigate the involvement and participation of the modulatory pathway of pain. Before starting the experiments, the experimental procedures were previously forwarded and obtained approval from the CEUA of UNIFAL-MG with protocol no50/2016. Male Wistar rats were used, submitted to 0.8 mA shock for 5 random times followed by social isolation. For PTSD induction, the animals were re-exposed to the shock inducing box under restraint and social isolation for 7, 14 and 21 days, divided into different groups. To confirm the development of PTSD, the behavior in freezing was evaluated and open field tests, high cross labyrinth, social interaction, memory, evaluation of the number of fecal cakes and weight of adrenal glands were performed. For evaluation of the nociceptive and mechanical threshold, formalin and Von Frey tests with filaments were performed. For the study of the participation of the descending inhibitory pain system, Fluoxetine and Desipramine administered intratecal before the formalin test were used. After the tests, the animals were perfused and the Dorsal Nucleus of Rafe, Locus Coeruleus (LC) and spinal cord (L4-L6) were dissected for immunohistochemistry to evaluate the

number of immunoreactive neurons for c-Pos, tryptophan hydroxylase c- Pos/triptophan hydroxylase, c-Pos/tyrosine hydroxylase respectively. Our results

showed an increase in freezing time of animals exposed to shock when compared to those not exposed, an increase in the time spent in closed arms in front of the high cross labyrinth test, a reduction in social interaction, damage in short and long lasting memories, an increase in the number of adrenal glands weight and in the number of fecal cakes when compared to the group not exposed to shock. We also observed a reduction in the distance traveled in animals exposed to shock under 21 days of

retention when compared to those not exposed. The animals with PTSD showed a decrease in the mechanical threshold and increased sensitivity to pain in all retention periods in the Von Frey tests with filaments and formalin respectively, when compared to their respective controls. It was observed that the animals with PTSD showed a decrease in the number of serotonergic and noradrenergic neurons and c-fos immunoreactive protein in the Dorsal Nucleus of Rafe and Locus Coeruleus respectively. In addition, the number of neuronal activations in the dorsal spinal cord was evaluated and a reduction in the number of activated c-FOS was observed. In view of all the data presented, it was concluded that Post-traumatic Stress Disorder (PTSD) increased pain sensitivity by reducing the activity of serotonergic and noradrenergic neurons in the Dorsal Nucleus of Rafe and Locus Coeruleus respectively and by reducing neuronal activation (c-FOS in the dorsal horn of the spinal cord, possibly influencing the modulatory descending pathway of pain.