Efeito anti-hiperalgésico do óleo essencial de Lippia grata livre e complexado em β-ciclodextrina em modelos animais de dor crônica não inflamatória e dor neuropática

Abstract

Chronic pain associated with non-inflammatory and neuropathic states is prevalent and debilitating, and still remains without an efficient and safe treatment. For this purpose, this study was designed to investigate the antihyperalgesic effect of free and complexed Lippia grata essential oil on β-cyclodextrin (OEL/βCD) in animal models of chronic noninflammatory pain (fibromyalgia) and neuropathic pain. In this study, it was possible to demonstrate strong experimental evidence of how β-cyclodextrin can act as a safe and low cost drug complexation system, improving the pharmacological properties of terpenes, transforming these natural products into an attractive choice for pharmacological use. In a systematic review, selecting the species of Lippia with properties on the central nervous system, this study observed that although several species present analgesic activity few studies have explored the mechanism of action responsible for these effects or have made a detailed phytochemical description or even investigated the toxicity and/or therapeutic safety of continued use of these drugs. Despite this, the results of the extracts and oils analyzes were consistent with most reports of ethnopharmacological studies reaffirming the importance of folk medicine as a guide for such studies. Using a non-inflammatory muscle pain model, this study demonstrated that OEL/βCD reduced primary and secondary hyperalgesia without altering muscle strength. It attributed these effects to the possible involvement of opiodergic and serotonergic receptors, corroborating the hypothesis of involvement of the pain inhibitory descending pathway supported by in silico study and the expression of the Fos protein in the dorsal horn of the medulla, in addition to the antioxidant activity demonstrated by OEL and OEL/βCD. The mechanical and thermal anti-hyperalgesic action of OEL and OEL/βCD (24mg / kg) in neuropathic pain (partial sciatic nerve ligation) and persistent inflammatory pain (CFA) models was also investigated. The attenuated migration of leukocytes associated with reduced levels of TNF-α and IL-1β observed in the pleurisy model may suggest the reduction of hyperalgesia and edema caused by the intraplantar injection of CFA observed after oral treatment with OEL and OEL/βCD. This treatment also reduced the development of mechanical and thermal hyperalgesia unleashed by the partial sciatic nerve ligation. Reduction of TNF-α levels in the sciatic nerve and medulla as well as phosphorylation of NFκB and PKA in these same tissues suggest a positive correlation between the action of the oil and the reduction of the algic effect of these mediators. The OEL (24mg/kg) and OEL/βCD (24mg/kg) did not inhibit the intraplantar injection-induced nociception of cinnamaldehyde (TRPA1 agonist) and menthol (TRPM8 agonist). The acute and prolonged oral treatment OEL and OEL-βCD (24 mg / kg) did not alter the motor activity of the animals. The results indicated that OEL/βCD (24mg/kg) may be potentially interesting for the development of drugs clinically relevant for the treatment of chronic pain disorders.