Investigação do efeito de nanocápsulas de Polyε-caprolactona contendo artemisinina e da participação do receptor Toll like 4 e de células da glia espinais em um modelo de dor crônica pós-operatória em camundongos

Abstract

Chronic postoperative pain is defined as a chronic pain that develops or increases in intensity after a surgical procedure or a tissue injury, persists beyond the healing process and lasts for at least 3 months. The glial cells express the Toll Like Receptor 4 (TLR4) and activation thereof plays an important role in the modulation of DCPO. Artemisinin (ART) shows to be an effective drug in inhibiting the TLR4-related pathway. However, ART has a short half-life and low solubility in water and to aid in the process of improving drug delivery and facilitating its action, nanotechnology is an advantageous strategy. Thus, the objective of the present study was to investigate the effect of ART nanocapsule on DCPO in mice, evaluating the involvement of spinal glial cells and the participation of spinal TLR4. For this, male Swiss mice weighing between 30 and 35 g were used. The skin and muscle incision and retraction model (IRPM) was used and adapted for mice. A 1 cm incision was made in the medial region of the thigh of the animal and another incision of 7 mm in the muscular layer of the medial thigh. The superficial region of the muscle was removed by insertion of the microtractor at the incision site where they were then retracted by 10 mm, revealing the fascia of the underlying adductor muscles. The free ART and nanocapsule ART drugs were administered intrathecally (it) on the 3rd and 28th postoperative day (PO) and minocycline (microglial inhibitor), fluorocitrate (astrocyte inhibitor) and lipopolysaccharide of Rhodobacter sphaeroides (LPS-RS, TLR4 antagonist) were only administered in the 3rd PO. The nociception evaluation was done by nociceptive test of von Frey filaments. The results showed that the IRPM surgery induced hyperalgesia, which was verified from the 1st to the 28th postoperative day. The free ART promoted antinociception only on the 3rd postoperative day, which lasted for 1 hour, which could not be observed in the evaluation of the same 28th PO The nanocapsule of ART promoted an antinociception after 3 and 28 days of IRPM surgery, having a longer effect (up to 7 hours on the 3rd day) in relation to the time of effectiveness than ART in its free form The fluorocitrate did not alter the nociception induced by IRPM surgery. On the other hand, pre-treatment with minocycline or with LPS-RS reversed the antinociception found after the 3rd PO day. Thus, the present study concluded that nanocapsule ART was more effective in relation to the time of effectiveness than free ART in the control of pain induced by IRPM surgery in both an acute and chronic phase. In addition, it was found that spinal microglia as well as TLR4 may be involved in the acute phase of postoperative pain induced by the IRPM model. Keywords: Chronic postoperative pain. Artemisinin. Nanocapsules. Microglia