Antinociceptive properties of an oral formulation of Δ9-tetrahydrocannabinol in aqueous 2-hydroxypropyl-β-cyclodextrin in female rats

Background: Previous research demonstrated that an aqueous complex of Δ9-tetrahydrocannabinol (THC) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) effectively reduced pain in male rats, even when administered orally. In this study, researchers aimed to determine if the same oral formulation would provide analgesic benefits in female rats.

Methods: The researchers tested the THC/HPβCD complex in two doses (0.3 and 3 mg/kg) using the tail flick test, measuring its effects after both short-term (acute) and long-term (chronic) administration in female rats. They also assessed locomotor activity and anxiety-like behavior during the same tests. Additionally, they analyzed dopamine and glutamate levels in the periaqueductal gray (PAG) to understand the complex's impact on the brain region responsible for pain relief.

Results: After a single dose, the antinociceptive effect of the THC/HPβCD complex was observed only at the higher dose of 3 mg/kg, with peak effectiveness occurring at 30 minutes post-administration. When the treatment was given for 15 days, the analgesic effects were still present but reduced to approximately 20% of the initial potency.

The higher dose also caused slight changes in locomotor activity and a biphasic effect, meaning it slightly reduced anxiety-like behavior in some cases. Neurochemical testing revealed that the 3 mg/kg dose significantly increased dopamine and glutamate concentrations in the PAG after a single administration, but this increase diminished after 15 days of chronic treatment.

Conclusions: The findings of this study confirm that the THC/HPβCD complex possesses antinociceptive properties in female rats, even when taken orally. This effect surpasses that of other carriers previously investigated. However, the researchers noted a reduction in analgesic effectiveness with chronic administration, indicating a potential for tolerance development.

These results are significant for the development of THC-based oral formulations that could provide pain relief in humans, particularly for those who prefer non-invasive and orally-administered treatments.