THU0452 ANTINOCICEPTIVE EFFECT OF Α-PHELLANDRENE IN CHRONIC PAIN: IN SILICO PHARMACOKINETIC, MOLECULAR DOCKING AND IN VIVO EVALUATION
Authors: Y. M. S. Pires, M. C. Leal de Moura, W. Amorim Dias, V. D. Pimentel
Journal: Annals of the Rheumatic Diseases (2020)

Background: The pharmacological approaches of chronic pain are a challenge in the clinical context. Currently, only palliative treatments are performed. The α-phellandrene (α-phel) is a cyclic monoterpene found in essential oils of aromatic plants, which presents several biological activities, such as antinociceptive, antihyperalgesic and immunostimulant.1,2 Objectives: This study aimed to investigate the action of α-phellandrene in chronic pain through in silico and in vivo approaches, aiming to develop a new therapeutic option for painful conditions, reducing analgesic doses and side effects. Methods: The pharmacokinetic analysis of α-phel was performed by PreADMET online server. The software ACD/ChemSketch 14.0 was used to optimize the 3D structure of α-phel. Molecular docking was performed with the software AutoDock Tools 1.5.6 to evaluate the pharmacodynamics interactions of α-phel and opioid receptors. The mechanism of action of α-phel in chronic pain was analyzed in vivo . Ethics Committee of UFPI approved this project (protocol n° 305/17). Female Swiss mice (25-30 g) underwent partial sciatic nerve ligation surgery to induce neuropathy. The neuropathic mice (N=6) were pre-treated with Naloxone (2 mg/kg, i.p.) or Saline (10 mL/kg, p.o.). After 20 minutes, they were treated with α-phel (6,25 mg/kg, p.o.) or morphine (5 mg/kg, i.p.) and evaluated by Von Frey test. Results: The predicted pharmacokinetic parameters (Table 1) suggest good intestinal absorption and good permeability. Plasma protein binding is elevated, however, it is reversible and technological alternatives, such as carrier systems, can improve it. The α-phel does not inhibit CYP3A4, it indicates a minimal possibility of interactions with others drugs and adverse reactions. Table 1. Pharmacokinetic parameters of α-phel ID VALUE BBB 7.17054 Buffer_solubility_mg_L 1227.08 Caco2 23.4164 CYP_2C19 and 2C9_inhibition Inhibitor CYP_2D6_inhibition_substrate Non CYP_3A4_inhibition Non CYP_3A4_substrate Weakly HIA 100.00000 MDCK 267.707 Pgp_inhibition Non Plasma_Protein_Binding 90.00000 Pure_water_solubility 141.466 The structure of α-phel binding opioid receptors is shown in Figure 1. The lowest ligand-receptor binding energies were, respectively: -6.0 kca/mol, -6.6 kcal/mol and -7.4 kcal/mol for the interaction of α-phel with Mu, Kappa and Delta receptors. It indicates that α-phel has high affinity for all three opioid receptors, binding in a strong and stable way. Figure 1. Graphical 3D representation of the binding modes of α-phellandrene with opioid receptors: A - Mu; B - Kappa; C – Delta The analgesic potential of the substance was tested in vivo as well. It was observed that Naloxone, an opioid antagonist, significantly reversed the effect of α-phel, indicating that it displays antinociceptive and antihyperalgesic activity through opioid system. Conclusion: The monoterpene α-phel presents antinociceptive activity and reduces the sensitivity in chronic pain through the activation of opioid receptors. Thus, in vivo and in silico results indicate that α-phel is an analgesic opioid agonist. This work may guide further preclinical studies, since α-phel may be an important strategy to treat chronic pain, with fewer side effects, dependence and tolerance than conventional drugs. References: [1]Nascimento AF, Camara CA, Moraes MM, Ramos CS. Essential oil composition and acaricidal activity of Schinusterebinthifolius from Atlantic Forest of Pernambuco, Brazil against Tetranychusurticae. Natural product communications. 2012 Jan:7(1):129-132. [2]Piccinelli AC, Santos JA, Konkiewitz EC, et al. Antihyperalgesic and antidepressive actions of (R)-(+)-limonene, α-phellandrene, and essential oil from Schinusterebinthifolius fruits in a neuropathic pain model. Nutritional neuroscience. 2015 Jul 1;18(5):217-24. Disclosure of Interests: : None declared