Background/Objectives: Primary dysmenorrhea is a prevalent condition that causes severe uterine cramps in women worldwide. The objective of this work was to synthesize and characterize a novel immediate-release system using vitexin and ZIF-8, and to evaluate its pharmacological action in a model of primary dysmenorrhea. Methods: A 2² full factorial design guided the synthesis of the system. Physicochemical characterization was performed by FT-IR, TG, DSC, SEM, XRD, and in vitro release tests. Pharmacological activity was assessed in an oxytocin-induced dysmenorrhea model in mice. In addition, in silico molecular docking and molecular dynamics simulations were conducted to explore the potential mechanism of action of vitexin. Results: Optimal yield and loading capacity were achieved at the high levels of the factorial design. Characterization analyses confirmed the successful formation of the vitexin@ZIF-8 (VIT@ZIF-8) system. The release study demonstrated a markedly enhanced dissolution rate of vitexin. Both isolated vitexin and VIT@ZIF-8 reduced abdominal writhing when administered orally at 3 and 30 mg/kg, while intraperitoneal activity was observed only at 30 mg/kg. Computational analyses revealed favorable interactions of vitexin with aldose reductase (AKR1C3), suggesting this enzyme as a potential molecular target in dysmenorrhea. Conclusions: The VIT@ZIF-8 system represents a promising strategy to improve the dissolution profile of vitexin, although pharmacological activity in this model was not superior to the isolated compound. The combined in vivo and in silico evidence supports vitexin as a potential antidysmenorrheic agent, possibly through modulation of AKR1C3. These findings open avenues for future studies addressing the molecular pathways of vitexin and for the development of novel therapeutic approaches for primary dysmenorrhea.

Background/Objectives: α-Phellandrene (α-PHEL) is a monoterpene found in essential oils and is known for its antinociceptive and anti-inflammatory properties. This study investigated the antinociceptive effects of free α-PHEL and β-cyclodextrin-associated α-PHEL (α-PHEL/β-CD) in a Complete Freund’s adjuvant (CFA)-induced model of chronic inflammatory pain. Methods: Mechanical allodynia and hyperalgesia were evaluated in female Wistar rats using the von Frey and Randall–Selitto tests, respectively. Locomotor activity and motor performance were evaluated in male Swiss mice. Animals received α-PHEL (6.25–100 mg/kg) and α-PHEL/β-CD (3.12–12.5 mg/kg), as well as vehicle (2% Tween 80/0.9% saline) and dexamethasone (0.5 mg/kg, p.o.), with evaluations conducted in the von Frey test at intervals of 1 to 24 h. The antihyperalgesic effect was evaluated using α-PHEL, α-PHEL/β-CD, vehicle, and diclofenac (5 mg/kg, p.o.), with assessments in the Randall–Selitto test from 1 to 6 h. Over 10 days, the animals were treated and evaluated daily to determine the effect during repeated treatment. The involvement of the opioid pathway was assessed using naloxone, whereas the serotonergic pathway was investigated using PCPA and ketanserin in the von Frey test. Motor coordination was tested in the rotarod, and exploratory behavior was assessed in the open field. Results: α-PHEL reduced CFA-induced hyperalgesia and allodynia in both acute and chronic phases. The α-PHEL/β-CD preparation produced significant antinociceptive effects at all tested doses during repeated administration. Naloxone and 5-HT₂A receptor blockade reduced the antinociceptive effect of α-PHEL, while α-PHEL and the α-PHEL/β-CD preparation did not alter locomotor activity or motor coordination. Conclusions: The α-PHEL/β-CD preparation exhibits antinociceptive activity in inflammatory pain without affecting locomotor activity or motor coordination. The findings with free α-PHEL suggest the possible contribution of opioid and serotonergic pathways to its antinociceptive effect.