Unravelling a potential therapeutic effect of polymeric lipid-core nanoencapsulated cannabidiol on anxiety-and panic-like behaviours elicited by Bothrops jararaca lancehead pit vipers

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Rodrigues, Bruno Mangili de Paula ; Hernandes, Paloma Molina ; Balvedi, Rafael Canalle ; Alves, Higor Ferreira Martins ; da Silva, Karoline Paiva ; Bicudo, Rogrio de Campos ; Eberhardt, Marcelo Jung ; Poletto, Fernanda ; Paese, Karina ; Guterres, Silvia Staniscaski ; Khan, Asmat Ullah ; Pohlmann, Adriana Raffin ; Ferrarini, Stela Regina ; Cysne, Norberto

• Document type: Journal article
• Source: International Journal of Pharmaceutics; v. 679, p. 19-pg., 2025-06-30.

Abstract

The burgeoning interest in cannabinoid-based therapies for mental disorders motivates research into their efficacy. This study investigates the acute effects of nanoencapsulated Cannabidiol (CBD) on panic attack-like defensive responses elicited in mice by the venomous snake Bothrops jararaca in polygonal arenas validated as a panic attack experimental model. The aim of this work was to investigate if polymeric lipid corenanoencapsulated CBD at low doses was able to cause antiaversive effects in comparison to non-encapsulated CBD at a higher dose. Mice were habituated in the enriched polygonal arena during three days and treated with either CBD in a dose already demonstrated to cause antiaversive effects (3 mg/kg), used as a positive control, or nanostructured CBD at much lower doses before snake confrontation. Both non-encapsulated and nanoencapsulated CBD significantly attenuated antipredatory responses in mice. Interestingly. Polymeric lipid core-nanoencapsulated CBD, particularly at lower doses, attenuated panic-like responses, including defensive attention, flat back approach, and escape behaviours to safe places after reaching limbic system structures. Additionally, rhodamine-labeled polymeric lipid core-nanoencapsulated CBD, administered either intraperitoneally or intranasally, effectively crossed the blood-brain barrier, with fluorescence observed in multiple limbic and paralimbic brain structures implicated in the elaboration of defensive/antipredatory behavioural responses. These findings indicate that nanoencapsulation improves the bioavailability of CBD and its targeting of the central nervous system, thereby supporting its potential for low-dose therapeutic applications in the treatment of anxiety and panic disorders. (AU)

• FAPESP's process: 12/03798-0 - Involvement of opioid and endocanabinoid receptors of the substantia nigra on the activity of Nigro-Tectal GABAergic pathways during defensive behaviour elicited by rodents confronted with venomous snakes
• Grantee: Norberto Cysne Coimbra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/11855-8 - Study of corpus striatum and ventral mesencephalon endocanabinoid influence on neostriato-nigro-tectal GABAergic pathways during panic reactions of rodents threatened by venomous snakes
• Grantee: Norberto Cysne Coimbra
• Support Opportunities: Regular Research Grants
• FAPESP's process: 24/01368-6 - Exploring the role of the orexinergic system and its interaction with cannabinoid receptors in the Dorsal Periaqueductal Gray Matter: implications for modulating panic-associated defensive responses.
• Grantee: Paloma Molina Hernandes
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/15050-7 - Study of the role played by endocannabinoid and endovaniloid signalling in the pallidum on the activity of the neostriatum-pallido-nigral disinhibitory and nigro-tectal inhibitory pathways during the organization of innate fear of animals confronted to snakes
• Grantee: Norberto Cysne Coimbra
• Support Opportunities: Regular Research Grants