Envolvimento do sistema opioidérgico e SP-érgico na hiperalgesia induzida pela privação de sono paradoxal
Data
2006
Autores
Nascimento, Danielle da Cunha 
Orientadores
Tufik, Sergio
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Estudos têm demonstrado que sono fragmentado está relacionado à
alteração na sensibilidade dolorosa. Acredita-se que a hiperalgesia, induzida pela
privação de sono paradoxal (PSP), pode ser devido alterações na transmissão
opioidérgica e SP-érgica. Em vista de resultados contraditórios a respeito deste
assunto nos propusemos inicialmente a realizar um experimento com o objetivo de
observar o efeito longitudinal da PSP na sensibilidade dolorosa, após submeter
ratos Wistar a 24, 48, 72 e 96 horas de PSP, seguida de 24 e 48 horas de
recuperação de sono em duas diferentes condições, patas secas e úmidas. Após
estabelecer este efeito, animais controle (CTRL), PSP 96 horas, bem como
animais no período rebote de 24 horas após 96 horas de PSP (REB) receberam
salina, morfina, antagonista de neuroquinina 1 (NK1) ou neuroquinina 3 (NK3) e
em seguida foram submetidos ao teste da placa quente uma hora após a
administração dessas drogas na tentativa de avaliar o limiar de retirada da pata.
Ainda realizamos estudo autorradiográfico de receptores com o objetivo de
verificar uma possível alteração cerebral de ratos da ligação dos receptores µopióides, NK1 e NK3 nos grupos CTRL, PSP e REB. O presente estudo
demonstrou que a PSP promoveu mudanças hiperalgésicas na sensibilidade
dolorosa, da mesma intensidade, desde as primeiras 24 horas até 96 horas de
PSP, e que somente o rebote de sono de 48 horas, após 96 horas de PSP, foi
capaz de restaurar a latência para os valores basais. A condição da pata, seca ou
úmida, foi de extrema importância para avaliação da latência de retirada na pata
após um estímulo térmico, sendo que, o grupo que apresentou patas úmidas no
momento do teste demonstrou maiores latências em comparação com aquele com as patas secas. Somado a isso, quando foi verificado o efeito da privação total de
sono de 6 horas na sensibilidade dolorosa, não foi observada nenhuma alteração
significativa. Os estudos envolvendo as suposições dos mecanismos pelos quais a
PSP promove essas alterações demonstraram que a PSP reduziu o efeito
antinociceptivo da morfina, e dos antagonistas NK1 e NK3. No entanto, a
possibilidade desse efeito envolver alterações da ligação dos receptores
analisados denota que a ligação dos receptores µ-opióides, NK1 e NK3
permaneceram inalterados após a PSP de 96 horas, assim como, durante o
período rebote de 24 horas nas áreas analisadas. Nossos dados não permitem
excluir a participação do sistema opioidérgico e SP-érgico nesse processo, uma
vez que foi observada a redução da atividade analgésica desses compostos após
a privação de sono, e até mesmo após o período rebote. Porém conclui que
alterações na ligação desses receptores parecem não ser o principal mecanismo
Previous studies have established a relationship between sleep disruption and pain, and it has been suggested that hyperalgesia induced by paradoxical sleep deprivation (PSD) could be due to a reduction of opioidergic or SP-ergic neurotransmission in the brain. Despite the contradictory results observed until now regarding such effect, in this present study, we conducted initially an experiment in order to evaluate the longitudinal effect of PSD on pain, after submitting animals to 24, 48, 72 and 96 h to PSD followed by 24 or 48 h of sleep recovery in two different conditions, dry and wet paw. Established the PSD effect on pain, rats deprived of sleep for 96 h as well as rats allowed to recover for 24 h after PSD and normal controls received vehicle, morphine, neurokinin 1 (NK1) or neurokinin 3 (NK3) antagonists and were tested on a hotplate one hour later. Quantitative receptor autoradiography was used to map alterations in binding to brain µ-opioid, NK1 and NK3 receptors in separate groups. Results demonstrated that PSD induced a significant reduction in thermal pain threshold equally from 24 to 96 h, as measured by paw withdrawal latencies. This effect did not return to baseline control values after 24 h of sleep recovery, but after 48 h only in 96 h deprived animals. The paw condition was such important because animals with wet paw during the pain evaluation presented higher values of latency then those with dry paw. The usual analgesic effect of morphine was observed in the control group but not in PSD or rebound groups except at the highest dose (10 mg/kg). NK1 antagonist (L732,138) showed analgesic property by the dose of 10 mg/kg, although PSD antagonized such effect. The treatment with NK3 antagonist (SB218795) after 96 h of PSD did not present the analgesic effect observed in the control group in any doses used. Binding of [3 H]DAMGO to µ sites, [3 H][Sar9.Met(O2)11] substance P to NK1 sites and [3 H]senktide to NK3 sites did not differ significantly among the three groups in any of the analyzed regions. These results do not exclude the participation of these systems in PSD-induced pain hypersensitivity since sleep-deprived rats were clearly resistant to the used drugs. However, the fact no changes were seen in the binding assay indicates that mechanisms other than altered receptors binding must be sought to explain the phenomenon
Previous studies have established a relationship between sleep disruption and pain, and it has been suggested that hyperalgesia induced by paradoxical sleep deprivation (PSD) could be due to a reduction of opioidergic or SP-ergic neurotransmission in the brain. Despite the contradictory results observed until now regarding such effect, in this present study, we conducted initially an experiment in order to evaluate the longitudinal effect of PSD on pain, after submitting animals to 24, 48, 72 and 96 h to PSD followed by 24 or 48 h of sleep recovery in two different conditions, dry and wet paw. Established the PSD effect on pain, rats deprived of sleep for 96 h as well as rats allowed to recover for 24 h after PSD and normal controls received vehicle, morphine, neurokinin 1 (NK1) or neurokinin 3 (NK3) antagonists and were tested on a hotplate one hour later. Quantitative receptor autoradiography was used to map alterations in binding to brain µ-opioid, NK1 and NK3 receptors in separate groups. Results demonstrated that PSD induced a significant reduction in thermal pain threshold equally from 24 to 96 h, as measured by paw withdrawal latencies. This effect did not return to baseline control values after 24 h of sleep recovery, but after 48 h only in 96 h deprived animals. The paw condition was such important because animals with wet paw during the pain evaluation presented higher values of latency then those with dry paw. The usual analgesic effect of morphine was observed in the control group but not in PSD or rebound groups except at the highest dose (10 mg/kg). NK1 antagonist (L732,138) showed analgesic property by the dose of 10 mg/kg, although PSD antagonized such effect. The treatment with NK3 antagonist (SB218795) after 96 h of PSD did not present the analgesic effect observed in the control group in any doses used. Binding of [3 H]DAMGO to µ sites, [3 H][Sar9.Met(O2)11] substance P to NK1 sites and [3 H]senktide to NK3 sites did not differ significantly among the three groups in any of the analyzed regions. These results do not exclude the participation of these systems in PSD-induced pain hypersensitivity since sleep-deprived rats were clearly resistant to the used drugs. However, the fact no changes were seen in the binding assay indicates that mechanisms other than altered receptors binding must be sought to explain the phenomenon
Descrição
Citação
NASCIMENTO, Danielle da Cunha. Envolvimento do sistema opioidérgico e SP-érgico na hiperalgesia induzida pela privação de sono paradoxal. 2006. 93 f. Dissertação (Mestrado) - Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2006.