The paraDrosophila melanogaster as Model for Chronic Nociception: Insights Into Cannabidiol Analgesic Effects.

Abstract

BACKGROUND: Chronic pain, which is often unrelated to ongoing injury, is poorly understood and difficult to treat. Genetic studies have identified voltage-gated sodium (Na) channels, particularly gain-of-function mutations such as L858F and R1150W in human Na1.7, as involved in the development of chronic pain. METHODS: A chronic pain model was proposed in Drosophila using the paramutant. Behavioural chemical nociceptive assay was conducted, and sensitivity was pharmacologically tested with carbamazepine and cannabidiol to assess the model's validity for analgesic screening. RESULTS: Sequence alignment and 3D structural modelling revealed strong homology between human Na1.7 and the para gene, though no structural alterations were observed between the parabss1 allele and the wild-type allele. Functionally, paralarvae exhibited enhanced sensitivity to chemical, nociceptive stimuli compared to wlarvae. Furthermore, carbamazepine increased response latency in w; however, parashowed a time and dose-dependent response to this treatment. Oral administration of cannabidiol significantly increased latency to chemical stimuli in both genotypes, supporting cannabidiol's modulatory role in nociceptive circuits. These findings validate the paramutant as a tractable in vivo platform for chronic nociception studies and pharmacological screening. CONCLUSIONS: The paramutant demonstrates heightened chemical nociception, resistance to carbamazepine and sensitivity to cannabidiol, thereby validating it as a pertinent Drosophila model for chronic pain. This model facilitates the screening of candidate analgesics targeting sodium channel dysfunctions in an in vivo setting, thereby demonstrating translational potential. SIGNIFICANCE STATEMENT: This study proposes the Drosophila melanogaster paramutant as a valid and manageable in vivo model for chronic nociception. By exhibiting selective hypersensitivity, resistance to conventional treatment and sensitivity to cannabidiol, this model provides a cost-effective and ethically favourable platform for the preclinical screening of novel analgesics that target sodium channel dysfunctions. This study opens a new avenue for translational pain research and aligns with the ongoing demand for alternative animal models in pain therapeutic development.