Desenvolvimento de um modelo de dor persistente induzido por carragenina na pata de ratos

Abstract

Introduction: Non-communicable chronic diseases (NCDs), according to the World Health Organization [WHO], between 2000 and 2019 were the cause of 74% of global deaths. Often, NCDs are related to chronic pain, which causes suffering, physical stress, emotional stress, and loss of quality of life for about 35.7% of adults and 47.32% of elderly Brazilians. Inflammatory pain is marked by the sensitization of nociceptors after prolonged exposure to inflammatory mediators. Prostaglandins (PGE2) cause primary hyperalgesia at the injury site, which increases the response to infraliminal stimuli and reduces the nociceptive excitability threshold. The animal model of chronic or nociplastic pain, initially described by Ferreira et al. (1990), induced a state of persistent inflammatory hyperalgesia by daily subcutaneous injection of PGE2 for 14 days. λ-carrageenan (CGN) is a polysaccharide extracted from the cell wall of marine algae used to trigger local acute inflammatory response under experimental conditions. Objectives: Develop a model of persistent peripheral hypersensitivity induced by inflammation of the rat’s paw by CGN injections. Evaluate the effect of maintaining inflammatory hyperalgesia for 7 or 14 days on mechanical sensitivity and edema in the rat’s paw and evaluate the resting potential and activation of TRPV1 receptors in neuron cultures obtained from control animals and animals with persistent hyperalgesia. Methodology: Male Wistar rats weighing 180 to 250g were used and distributed into three experimental groups: 14-day control, 7- day inflammation, and 14-day inflammation. The animals were subjected to intraplantar injections of CGN or saline solution in the right hind paw to induce or not a low to moderate intensity inflammation. Edema and mechanical sensitivity were evaluated by plethysmography and electronic Von Frey, respectively, during treatment and up to 14 days after the end of the injections. The animals were euthanized, and the dorsal root ganglia were harvested for primary neuron cultures. The cultures were used to evaluate the resting potential and capsaicin-induced depolarization to TRPV1 through confocal microscopy. Results: The results show that the animals treated with CGN for 7 days (30,81± 2,04) or 14 days (25,87± 1,5) had a significant reduction in the nociceptive withdrawal threshold of the paw (14,34%), and an increase in inflammatory edema (11,11%), compared to the control animals (39,91± 0,87). The inflammatory hyperalgesia of the 14-day CGN group persisted up to 14 days after the end of the injections, indicating the chronification of hyperalgesia dependent on the duration of treatment. The neuron cultures of the animals with persistent hyperalgesia for 14 days showed a decreased resting potential compared to the cultures of the control animals (16,69%), suggesting greater excitability and sensitization of the nociceptors. Conclusion: The results show that the persistent peripheral hypersensitivity model induced by CGN in the rat’s paw can reproduce clinical and histological aspects of chronic or nociplastic pain. The work also highlights the importance of studying the events and changes that cause the chronification of pain, aiming at developing preventive strategies and more effective public health interventions.