O núcleo dorsal da rafe é a principal fonte de projeções serotonérgicas que inervam áreas límbicas implicadas na modulação de diferentes funções comportamentais e/ou neurovegetativas. Disfunções neste núcleo têm sido associadas à gênese de transtornos psiquiátricos. Estudos recentes apontam para a heterogeneidade morfológica e funcional do NDR, com destaque para evidências que sugerem a participação seletiva da sub-região denominada asas laterais nos mecanismos fisiopatológicos do transtorno de pânico. Dentre os diversos neurotransmissores presentes nas asas laterais, o papel desempenhado pelo fator liberador de corticotrofina (CRF) na modulação dos neurônios serotonérgicos presentes nesta área tem ganhado amplo destaque. Com base nestas evidências, o objetivo deste trabalho foi o de avaliar o envolvimento da neurotransmissão mediada pelo CRF nas asas laterais de ratos machos Wistar na expressão do comportamento de fuga avaliado no labirinto em T elevado (LTE). Os resultados obtidos mostram que administração local de CRF na dose de 100 ng atenuou a expressão do comportamento de fuga, enquanto que a dose de 0,3 ng facilitou a expressão desse comportamento, sugerindo assim um efeito do tipo panicolítico e panicogênico, respectivamente. A injeção de CRF nas asas laterais não afetou a aquisição da resposta de esquiva inibitória também medida no LTE. Este comportamento defensivo tem sido associado à ansiedade. Além disso, a administração de antalarmina, um antagonista seletivo de CRF1, previamente à dose de 0,3 ng bloqueou o efeito facilitador do CRF sobre a expressão da resposta da fuga, sugerindo então que os receptores de CRF1 estejam envolvidos no efeito panicogênico deste peptídeo. Assim sendo, o efeito do CRF sobre a resposta de fuga no LTE parece ser dependente da dose administrada. Os resultados obtidos, juntamente com dados prévios da literatura, indicam que diferentes subtipos de receptores de CRF sejam recrutados na mediação destes efeitos opostos causados pelo peptídeo. / The dorsal raphe nucleus (DRN) is the main source of serotonergic projections that innervate limbic areas involved in the modulation of different behavioral and/or neurovegetative functions. Dysfunctions in this nucleus have been associated with the genesis of psychiatric disorders. Recent studies point to the morphological and functional heterogeneity of NDR. There is evidence to suggest that the sub-region called lateral wings is involved in the physiopathological mechanisms of panic disorder. Among the several neurotransmitters present in the lateral wings, the role played by the corticotrophin releasing factor (CRF) in the modulation of the serotonergic neurons present in this area has raised attention. Based on these evidences, the objective of this work was to evaluate the involvement of CRFmediated neurotransmission in the lateral wings of male Wistar rats in the expression of the escape behavior evaluated in the elevated T maze test (ETM). The results showed that local administration of CRF at the dose of 100 ng attenuated the expression of escape behavior, whereas the dose of 0.3 ng facilitated the expression of this behavior, thus suggesting a panicolytic- and panicogenic-like effects, respectively. Injection of CRF in the lateral wings did not affect the acquisition of the inhibitory avoidance response, also measured in ETM. This defensive behavior has been associated with anxiety. In addition, the administration of antalarmine, a CRF1 receptor antagonist, prior to the 0.3 ng dose blocked the facilitatory effect of CRF on the expression of the escape response, thus suggesting that CRF1 receptors are involved in the panicogenic effect of this peptide. Thus, the effect of CRF on escape response in the ETM seems to be dose dependent. The results obtained, together with previous literature data, indicate that different subtypes of CRF receptors are recruited in the mediation of these opposite effects caused by the peptide.

O núcleo dorsal da rafe é a principal fonte de projeções serotonérgicas que inervam áreas límbicas implicadas na modulação de diferentes funções comportamentais e/ou neurovegetativas. Disfunções neste núcleo têm sido associadas à gênese de transtornos psiquiátricos. Estudos recentes apontam para a heterogeneidade morfológica e funcional do NDR, com destaque para evidências que sugerem a participação seletiva da sub-região denominada asas laterais nos mecanismos fisiopatológicos do transtorno de pânico. Dentre os diversos neurotransmissores presentes nas asas laterais, o papel desempenhado pelo fator liberador de corticotrofina (CRF) na modulação dos neurônios serotonérgicos presentes nesta área tem ganhado amplo destaque. Com base nestas evidências, o objetivo deste trabalho foi o de avaliar o envolvimento da neurotransmissão mediada pelo CRF nas asas laterais de ratos machos Wistar na expressão do comportamento de fuga avaliado no labirinto em T elevado (LTE). Os resultados obtidos mostram que administração local de CRF na dose de 100 ng atenuou a expressão do comportamento de fuga, enquanto que a dose de 0,3 ng facilitou a expressão desse comportamento, sugerindo assim um efeito do tipo panicolítico e panicogênico, respectivamente. A injeção de CRF nas asas laterais não afetou a aquisição da resposta de esquiva inibitória também medida no LTE. Este comportamento defensivo tem sido associado à ansiedade. Além disso, a administração de antalarmina, um antagonista seletivo de CRF1, previamente à dose de 0,3 ng bloqueou o efeito facilitador do CRF sobre a expressão da resposta da fuga, sugerindo então que os receptores de CRF1 estejam envolvidos no efeito panicogênico deste peptídeo. Assim sendo, o efeito do CRF sobre a resposta de fuga no LTE parece ser dependente da dose administrada. Os resultados obtidos, juntamente com dados prévios da literatura, indicam que diferentes subtipos de receptores de CRF sejam recrutados na mediação destes efeitos opostos causados pelo peptídeo. / The dorsal raphe nucleus (DRN) is the main source of serotonergic projections that innervate limbic areas involved in the modulation of different behavioral and/or neurovegetative functions. Dysfunctions in this nucleus have been associated with the genesis of psychiatric disorders. Recent studies point to the morphological and functional heterogeneity of NDR. There is evidence to suggest that the sub-region called lateral wings is involved in the physiopathological mechanisms of panic disorder. Among the several neurotransmitters present in the lateral wings, the role played by the corticotrophin releasing factor (CRF) in the modulation of the serotonergic neurons present in this area has raised attention. Based on these evidences, the objective of this work was to evaluate the involvement of CRFmediated neurotransmission in the lateral wings of male Wistar rats in the expression of the escape behavior evaluated in the elevated T maze test (ETM). The results showed that local administration of CRF at the dose of 100 ng attenuated the expression of escape behavior, whereas the dose of 0.3 ng facilitated the expression of this behavior, thus suggesting a panicolytic- and panicogenic-like effects, respectively. Injection of CRF in the lateral wings did not affect the acquisition of the inhibitory avoidance response, also measured in ETM. This defensive behavior has been associated with anxiety. In addition, the administration of antalarmine, a CRF1 receptor antagonist, prior to the 0.3 ng dose blocked the facilitatory effect of CRF on the expression of the escape response, thus suggesting that CRF1 receptors are involved in the panicogenic effect of this peptide. Thus, the effect of CRF on escape response in the ETM seems to be dose dependent. The results obtained, together with previous literature data, indicate that different subtypes of CRF receptors are recruited in the mediation of these opposite effects caused by the peptide.

Approximately 1 in 6 infants are born prematurely each year. Typically, these infants spend 25 days in the Neonatal Intensive Care Unit (NICU) where they experience 10-18 painful and inflammatory procedures each day. Remarkably, pre-emptive analgesics and/or anesthesia are administered less than 30% of the time. Unalleviated pain during the perinatal period is associated with permanent decreases in pain sensitivity, blunted cortisol responses and high rates of neuropsychiatric disorders. To date, the mechanism(s) by which these long-term changes in stress and pain behavior occur, and whether such alterations can be prevented by appropriate analgesia at the time of injury, remains unclear. We have previously reported in rats that inflammation experienced on the day of birth permanently upregulates central opioid tone, resulting in a significant reduction in adult pain sensitivity. However, the impact on early life pain on anxiety- and stress-related behavior and HPA axis regulation is not known. Therefore the goal of this dissertation was to determine the long-term impact of a single neonatal inflammatory pain experience on adult anxiety- and stress-related responses. Neuroanatomical changes in stress-associated neurocircuits were also examined. As the endogenous pain control system and HPA axis are in a state of exaggerated developmental plasticity early in postnatal life, and these systems work in concert to respond to noxious or aversive stimuli, this dissertation research aimed to answer the following questions: (1) Does neonatal injury produce deficits in adult stress-related behavior and alter stress-related neuroanatomy through an opioid-dependent mechanism? (2) Does neonatal injury alter receptor systems regulating the activation and termination of the stress response in adulthood? (3) Are stress- and pain-related neurotransmitters altered within the first week following early life pain? (4) Is early activation of the pain system necessary for the long-term changes in anxiety- and stress-related behavior? Together these studies demonstrate the degree, severity and preventability of the long-term deficits in stress responding associated with a single painful experience early in life. The goal of this research is to promote change in the treatment of infant pain in the NICU to reduce long-term sensory and mental health complications associated with prematurity.

Approximately 1 in 6 infants are born prematurely each year. Typically, these infants spend 25 days in the Neonatal Intensive Care Unit (NICU) where they experience 10-18 painful and inflammatory procedures each day. Remarkably, pre-emptive analgesics and/or anesthesia are administered less than 30% of the time. Unalleviated pain during the perinatal period is associated with permanent decreases in pain sensitivity, blunted cortisol responses and high rates of neuropsychiatric disorders. To date, the mechanism(s) by which these long-term changes in stress and pain behavior occur, and whether such alterations can be prevented by appropriate analgesia at the time of injury, remains unclear. We have previously reported in rats that inflammation experienced on the day of birth permanently upregulates central opioid tone, resulting in a significant reduction in adult pain sensitivity. However, the impact on early life pain on anxiety- and stress-related behavior and HPA axis regulation is not known. Therefore the goal of this dissertation was to determine the long-term impact of a single neonatal inflammatory pain experience on adult anxiety- and stress-related responses. Neuroanatomical changes in stress-associated neurocircuits were also examined. As the endogenous pain control system and HPA axis are in a state of exaggerated developmental plasticity early in postnatal life, and these systems work in concert to respond to noxious or aversive stimuli, this dissertation research aimed to answer the following questions: (1) Does neonatal injury produce deficits in adult stress-related behavior and alter stress-related neuroanatomy through an opioid-dependent mechanism? (2) Does neonatal injury alter receptor systems regulating the activation and termination of the stress response in adulthood? (3) Are stress- and pain-related neurotransmitters altered within the first week following early life pain? (4) Is early activation of the pain system necessary for the long-term changes in anxiety- and stress-related behavior? Together these studies demonstrate the degree, severity and preventability of the long-term deficits in stress responding associated with a single painful experience early in life. The goal of this research is to promote change in the treatment of infant pain in the NICU to reduce long-term sensory and mental health complications associated with prematurity.