. 2022 Oct 26;11(21):2854.

doi: 10.3390/plants11212854.

Mechanisms of Actions Involved in The Antinociceptive Effect of Estragole and its β-Cyclodextrin Inclusion Complex in Animal Models

Roger Henrique Sousa da Costa¹, Anita Oliveira Brito Pereira Bezerra Martins¹, Renata Torres Pessoa¹, Saad Ali Alshehri², Shadma Wahab², Md Faruque Ahmad³, Muath Suliman⁴, Lucas Yure Santos da Silva¹, Isabel Sousa Alcântara¹, Andreza Guedes Barbosa Ramos¹, Maria Rayane Correia de Oliveira^{1

5}, Francisco Lucas Alves Batista¹, Gyllyandeson de Araújo Delmondes⁶, Pablo Antonio Maia de Farias⁷, Janaína Esmeraldo Rocha⁸, Henrique Douglas Melo Coutinho⁸, António Raposo⁹, Conrado Carrascosa¹⁰, José Raduan Jaber¹¹, Irwin Rose Alencar de Menezes⁸

Affiliations

¹ Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri-URCA, Pimenta 63.100-000, Ceará, Brazil.
² Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia.
³ Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia.
⁴ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia.
⁵ Graduate Program in Biotechnology-Northeast Biotechnology Network (RENORBIO), State University of Ceará (UECE), Fortaleza 60741-000, Ceará, Brazil.
⁶ Nursing Academic Collegiate, Federal University of Vale do São Francisco (UNIVASF), Petrolina 56330-400, Pernambuco, Brazil.
⁷ CECAPE College, Juazeiro do Norte-CE 63.024-015, Ceará, Brazil.
⁸ Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri-URCA, Pimenta 63.100-000, Ceará, Brazil.
⁹ CBIOS (Research Center for Biosciences and Health Technologies), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal.
¹⁰ Department of Animal Pathology and Production, Bromatology and Food Technology, Faculty of Veterinary, Universidad de Las Palmas de Gran Canaria, Trasmontaña s/n, 35413 Arucas, Spain.
¹¹ Departamento de Morfologia, Facultad de Veterinaria, Universidad de Las Palmas de Gran Canaria, 35413 Las Palmas de Gran Canaria, Spain.

PMID: 36365307
PMCID: PMC9654024
DOI: 10.3390/plants11212854

Mechanisms of Actions Involved in The Antinociceptive Effect of Estragole and its β-Cyclodextrin Inclusion Complex in Animal Models

Roger Henrique Sousa da Costa et al. Plants (Basel). 2022.

. 2022 Oct 26;11(21):2854.

doi: 10.3390/plants11212854.

Authors

Affiliations

¹ Laboratory of Pharmacology and Molecular Chemistry (LFQM), Department of Biological Chemistry, Regional University of Cariri-URCA, Pimenta 63.100-000, Ceará, Brazil.
² Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 61421, Saudi Arabia.
³ Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia.
⁴ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia.
⁵ Graduate Program in Biotechnology-Northeast Biotechnology Network (RENORBIO), State University of Ceará (UECE), Fortaleza 60741-000, Ceará, Brazil.
⁶ Nursing Academic Collegiate, Federal University of Vale do São Francisco (UNIVASF), Petrolina 56330-400, Pernambuco, Brazil.
⁷ CECAPE College, Juazeiro do Norte-CE 63.024-015, Ceará, Brazil.
⁸ Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri-URCA, Pimenta 63.100-000, Ceará, Brazil.
⁹ CBIOS (Research Center for Biosciences and Health Technologies), Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal.
¹⁰ Department of Animal Pathology and Production, Bromatology and Food Technology, Faculty of Veterinary, Universidad de Las Palmas de Gran Canaria, Trasmontaña s/n, 35413 Arucas, Spain.
¹¹ Departamento de Morfologia, Facultad de Veterinaria, Universidad de Las Palmas de Gran Canaria, 35413 Las Palmas de Gran Canaria, Spain.

PMID: 36365307
PMCID: PMC9654024
DOI: 10.3390/plants11212854

Abstract

(1) Background: estragole is a monoterpene found in the essential oils of several aromatic plants, which can be used for several pharmacological activities. The aim of this study was to evaluate the antinociceptive effect of estragole (Es) and its β-cyclodextrins inclusion complex (Es/β-CD). (2) Methods: the effects of Es and Es/β-CD on the central nervous system (CNS) were evaluated through open field and rota-rod assays, and the antinociceptive effect in formalin models, abdominal writhing induced by acetic acid, hot plate, tail flick test and plantar mechanical hyperalgesia. (3) Results: Es and Es/β-CD showed no alterations on the CNS evaluated parameters and the results suggested there was an antinociceptive action in the formalin, abdominal writhing, hot plate, tail flick tests and plantar mechanical hyperalgesia, proposing the involvement of the nitric oxide, glutamatergic signaling pathways, cyclic guanosine monophosphate and vanilloid pathways. (4) Conclusion: the results suggest that Es and Es/β-CD have a promising antinociceptive potential as a possible alternative for the pharmacological treatment of pain, also showing that the encapsulation of Es in β-cyclodextrins probably improves its pharmacological properties, since the complexation process involves much lower amounts of the compound, contributing to better bioavailability and a lower probability of adverse effect development.

Keywords: cyclodextrins; estragole; monoterpene; nociception.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Spectrum in the infrared region: (A) estragole; (B) β-cyclodextrin; (C) Es/β-CD.

**Figure 2**
(A) Antinociceptive effect of estragole (Es) (60, 30 and 15 mg/kg) in the abdominal writhing test induced by acetic acid. (B) Antinociceptive effect of complex of estragole in β-CD (60, 30 and 15 mg/kg) in the abdominal writhing test induced by acetic acid, for (n = 6/group). The values show the arithmetic mean ± S.E.M (Standard Error of the Mean). One-way ANOVA followed by Tukey’s test (**** p < 0.0001, when compared to the negative control group).

**Figure 3**
Evaluation of antinociceptive effect of estragole and Es/β-CD (60, 30 and 15 mg/kg) in the Formalin test. Effect in the neurogenic phase of Es (A) and Es/β-CD (B) and inflammatory phase to of Es (C) and Es/β-CD (D). Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/groups). One-way ANOVA followed by Tukey’s test (**** p < 0.0001, when compared to the negative control group).

**Figure 4**
Antinociceptive effect of estragole (A) and Es/β-CD (B) (60, 30 and 15 mg/kg) in the hot plate test. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/groups). Two-way ANOVA followed by Tukey’s test (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001, when compared to the negative control group).

**Figure 5**
Antinociceptive effect of estragole (A) and Es/β-CD (B) (60, 30 and 15 mg/kg) in the tail flick test. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/groups). Two-way ANOVA followed by Tukey’s test. (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001, when compared to the negative control group).

**Figure 6**
Antinociceptive effect of estragole (A) and Es/β-CD (B) (60, 30 and 15 mg/kg)in the von Frey test,. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/groups). Two-way ANOVA followed by Tukey’s test (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001, when compared to the negative control group).

**Figure 7**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the opioid signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (**** p < 0.0001, when compared to the negative control group). (#### p < 0.0001, when comparing the antagonist + agonist vs. agonist.

**Figure 8**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the cholinergic system signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (significance of p < 0.0001—*** when compared to the negative control group). ####p < 0.0001, when comparing the antagonist + agonist vs. agonist).

**Figure 9**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the nitric oxide signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test, when compared to the negative control group). (#### p < 0.0001, when comparing antagonist + agonist vs. agonist; estragole alone vs. atropine + estragole; Es/β-CD alone vs. atropine + Es/β-CD; ns – no significant.

**Figure 10**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the α-2 adrenergic system signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (**** p < 0.0001, when compared to the negative control group). (#### p < 0.0001, when comparing antagonist + agonist vs. agonist).

**Figure 11**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the dopaminergic signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (**** p < 0.0001, when compared to the negative control group).

**Figure 12**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the adenosinergic signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (*** p < 0.001; ** p < 0.01, when compared to the negative control group).

**Figure 13**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the glutamatergic signaling pathway. Values show as the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (ns – no significant; ** p < 0.01; *** p < 0.001, when compared to the negative control group).

**Figure 14**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the cyclic guanosine monophosphate (cGMP) signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (* p < 0.05; **** p < 0.0001, when compared to the negative control group).

**Figure 15**
Antinociceptive response of estragole and Es/β-CD (15 mg/kg) in the vanilloid signaling pathway. Values show the mean ± S.E.M (Standard Error of the Mean) for (6 = n/group). One-way (ANOVA) followed by Tukey’s test (**** p < 0.0001; when compared to the negative control group).

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Mechanisms of Actions Involved in The Antinociceptive Effect of Estragole and its β-Cyclodextrin Inclusion Complex in Animal Models

Affiliations

Mechanisms of Actions Involved in The Antinociceptive Effect of Estragole and its β-Cyclodextrin Inclusion Complex in Animal Models

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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References

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