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. 2023 May 31;28(11):4465.
doi: 10.3390/molecules28114465.

Antinociceptive Effect of a p-Cymene/β-Cyclodextrin Inclusion Complex in a Murine Cancer Pain Model: Characterization Aided through a Docking Study

Wagner B R Santos  1 , Lícia T S Pina  1 , Marlange A de Oliveira  2 , Lucas A B O Santos  3 , Marcus V A Batista  3 , Gabriela G G Trindade  1 , Marcelo C Duarte  1 , Jackson R G S Almeida  4 , Lucindo J Quintans-Júnior  2 , Jullyana S S Quintans  2 , Mairim R Serafini  1 , Henrique D M Coutinho  5 , Grażyna Kowalska  6 , Tomasz Baj  7 , Radosław Kowalski  8 , Adriana G Guimarães  1
Affiliations

Antinociceptive Effect of a p-Cymene/β-Cyclodextrin Inclusion Complex in a Murine Cancer Pain Model: Characterization Aided through a Docking Study

Wagner B R Santos et al. Molecules. .

Abstract

Pain is one of the most prevalent and difficult to manage symptoms in cancer patients, and conventional drugs present a range of adverse reactions. The development of β-cyclodextrins (β-CD) complexes has been used to avoid physicochemical and pharmacological limitations due to the lipophilicity of compounds such as p-Cymene (PC), a monoterpene with antinociceptive effects. Our aim was to obtain, characterize, and measure the effect of the complex of p-cymene and β-cyclodextrin (PC/β-CD) in a cancer pain model. Initially, molecular docking was performed to predict the viability of complex formation. Afterward, PC/β-CD was obtained by slurry complexation, characterized by HPLC and NMR. Finally, PC/β-CD was tested in a Sarcoma 180 (S180)-induced pain model. Molecular docking indicated that the occurrence of interaction between PC and β-CD is favorable. PC/β-CD showed complexation efficiency of 82.61%, and NMR demonstrated PC complexation in the β-CD cavity. In the S180 cancer pain model, PC/β-CD significantly reduced the mechanical hyperalgesia, spontaneous nociception, and nociception induced by non-noxious palpation at the doses tested (p < 0.05) when compared to vehicle differently from free PC (p > 0.05). Therefore, the complexation of PC in β-CD was shown to improve the pharmacological effect of the drug as well as reducing the required dose.

Keywords: cancer pain; inclusion complex; monoterpenes; natural products.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of p-cymene (a) and β-cyclodextrin (b).
Figure 2
Figure 2
Representation of the binding mode of p-cymene (PC) in beta-cyclodextrin (β-CD). Blue represents the PC molecule, green represents the carbon atoms, and red represents the oxygen atoms. The dipole-induced dipole interactions are represented as dashed lines, and the values indicate the distances in Angstrom (Å).
Figure 3
Figure 3
1H NMR spectra of free PC (a), β-CD (b), and the SC inclusion complex (c) in DMSO-d6.
Figure 4
Figure 4
Effect of β-CD/PC complexes (1.2, 2.4, and 4.8 mg/kg, p.o.) and isolated PC (50 mg/kg, p.o.) on mechanical hyperalgesia ((A1): 10th to 15th day; (A2): areas under the curve from the 10th to the 15th day), spontaneous nociception ((B1): 10th to 15th day; (B2): areas under the curve from the 10th to the 15th day), and palpation ((C1): 10th to 15th day; (C2): areas under the curve from the 10th to the 15th day) induced by S180. The values are presented as mean ± S.E.M., * p < 0.05, ** p < 0.01, and *** p < 0.001 vs. vehicle group (two-way ANOVA followed by Tukey’s post hoc test).
Figure 5
Figure 5
Mechanism of action of the β-CD/PC complex against cancer pain.
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