Antinociceptive Effects of Free and β-Cyclodextrin-Associated α-Phellandrene in CFA-Induced Inflammatory Pain

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.