γ-Terpinene complexed with β-cyclodextrin attenuates spinal neuroactivity in animals with cancer pain by Ca2+ channel block

Objectives Considering that gamma-terpinene (gamma-TPN) is a monoterpene found in Cannabis oil, with high lipophilicity and limited pharmacokinetics, our objective was to evaluate whether its complexation in beta-cyclodextrin (gamma-TPN/beta-CD) could improve its physicochemical properties and action on cancer pain, as well as verify the mechanisms of action involved. Methods The gamma-TPN/beta-CD was prepared and submitted to physicochemical characterization. Animals with sarcoma 180 were treated (vehicle, gamma-TPN 50 mg/kg, gamma-TPN/beta-CD 5 mg/kg or morphine) and assessed for hyperalgesia, TNF-alpha and IL-1 beta levels, iNOS and c-Fos activity. The effects of gamma-TPN on calcium channels were studied by patch-clamp and molecular docking. Results beta-CD improved the physicochemical properties and prolonged the anti-hyperalgesic effect of gamma-TPN. This compound also reduced the levels of IL-1 beta, TNF-alpha and iNOS in the tumour, and c-Fos protein in the spinal cord. In addition, it reduced Ca2+ current, presenting favourable chemical interactions with different voltage-dependent calcium channels. Conclusion These results indicate that the complexation of gamma-TPN into beta-CD increases its stability and time effect, reducing spinal neuroactivity and inflammation by blocking calcium channels.