Xiaoyan Lin, Ph.D. of the Hohmann Lab at Indiana University Bloomington will present a lecture entitled: Roles of RNA psydouridylation in Drosophilanociception.
Abstract: Cannabinoid CB2 receptors represent a promising therapeutic target because their activation suppresses neuropathic pain without unwanted psychotropic effects associated with activation of cannabinoid CB1 receptors in the central nervous system (CNS). However, the cell types that contain CB2 receptors and mediate the antinociceptive effects of CB2 agonists remain poorly understood, at least in part, due to questionable specificity of existing CB2 antibodies. In the present study, we used a transgenic mouse (CB2f/f) line in which enhanced green fluorescent protein (GFP) is under control of the CB2 promoter (Lopez et al. (2018) J. Neuroinflammation 15: 158) to aid in detection of CB2 receptors in different cell types. In this mouse line, the CB2 gene is flanked by loxP sites allowing for conditional deletion of CB2 receptors from cells expressing Cre recombinase. We also examined the impact of conditionally deleting CB2 from peripheral sensory neurons by generating advillinCre/+;CB2f/f mice on paclitaxel-induced neuropathic pain as well as CB2 agonist efficacy. GFP-labeled CB2f/f mice developed and maintained neuropathic pain that was induced by treatment with the chemotherapeutic agent paclitaxel. In CB2f/f reporter mice, multiple CB2 agonists (i.e. AM1710, LY2828360) suppressed paclitaxel-induced mechanical and cold allodynia with sustained efficacy. CB2f/f mice showed native CB2 expression, marked by GFP positive cells, in spleen as well as in keratinocytes in the epidermis. GFP was differentially expressed on epidermal keratinocytes in stratified patterns that shifted and increased in intensity, especially after repeated paclitaxel injections. Novel expression of CB2 on dendritic and Langerhans cells that invaded the epidermis were also observed. By contrast, CB2 expression in CNS was below the threshold for detection. Anti-allodynic effects of the CB2 agonist AM1710, were also blocked by SR144528, a CB2 antagonist that exhibits limited CNS penetration. The anti-allodynic efficacy of CB2 agonists was absent in advillinCre/+;CB2f/f mice. These observations also suggest that CB2 receptors in primary sensory neurons were necessary for the antinociceptive effects of CB2 agonists. Our studies suggest potential targets for cannabinoid CB2 agonists in suppressing chemotherapy-induced neuropathic pain.
Supported by DA047858, DA041229 and DA009158 (to AGH and KM). LC was supported by T32 DA024628.