Conditional deletion of CB2 cannabinoid receptors from peripheral sensory neurons eliminates CB2-mediated antinociceptive efficacy in a mouse model of carrageenan-induced inflammatory pain

Cannabinoid CB2receptors in primary sensory neurons are implicated in CB2agonist-mediated suppression of paclitaxel-induced neuropathic nociception and sexually-dimorphic sparing of morphine tolerance

“…By contrast, CB2 receptors found on CX3CR1 expressing microglia/macrophages do not appear to be involved in the anti-allodynic efficacy of these CB2 agonists. A similar effect was observed in our prior study showing that LY2828360 retains efficacy in CX3CR1 CRE/+ ; CB2 f/f but not Advillin CRE/+ ; CB2 f/f mice in a carrageenan model of inflammatory pain (Guenther et al 2023). Additionally, LY2828360 reduced neuropathic nociception produced by the antiretroviral agent 2,3dideoxycytidine (ddC) in CB2 f/f but not in Advillin CRE/+ ; CB2 f/f mice (Carey et al 2023).…”

“…By contrast, CB2 receptors in CX3CR1 expressing microglia/macrophages are unlikely to be involved in this phenomenon. Our CX3CR1 CRE/+ ; CB2 f/f mouse model is specific to microglia expressing the C-X3-C Motif Chemokine Receptor 1 gene; therefore our results do not preclude the possibility that other microglia subtypes may contribute to the anti-allodynic effect of CB2 agonists in our studies of inflammatory nociception (Guenther et al 2023) and toxic neuropathy (Carey et al 2023) or in other pain models.…”

“…LY2828360 is a potent CB2 receptor agonist with similar affinity for both human and rat CB2 receptors and low affinity for the CB1 receptor (Hollinshead et al 2013). Previous studies have shown that LY2828360 suppresses behavioral hypersensitivities in models of neuropathic (Lin et al 2018;Lin et al 2022;Carey et al 2023) and inflammatory (Guenther et al 2023) pain and can prevent the development of morphine tolerance in mouse models of neuropathic pain (Lin at al. 2018;Carey et al 2023).…”

“…Given the apparent safety of LY2828360, further investigation of the potential analgesic applications for this compound is important to fully understand its range of therapeutic benefits and to identify which pain states it can best treat. Previously, our lab has identified CB2 receptors in peripheral sensory neurons to be necessary for antiallodynic effects of LY2828360 in both carrageenan-induced inflammatory pain (Guenther et al 2023) and 2,3-dideoxycytidine (ddC) anti-retroviral neuropathic pain (Carey et al 2023) using cell type specific conditional KO mice. However, the specific cell types involved in the efficacy of 4 LY2828360 in the chemotherapy-induced neuropathic pain model or in its ability to prevent the development of tolerance to morphine's analgesic effect in this model remain unknown.…”

Imaging and Genetic Tools for the Investigation of the Endocannabinoid System in the CNS

“…Neurodegeneration, neuroinflammation, and synaptic plasticity C57BL/6J CB2R −/− Del Higher corticosterone levels after stress in the prefrontal cortex (PFC), higher hippocampal and PFC neuron excitability CB2R activation mediates PFC neuron excitability [237] Chronic CB2R activation in the hippocampus increases excitatory synaptic transmission [238] C57BL/6J CB2R Tau protein levels increase CB2R during early stages of neurodegeneration [239] CB2R depletion reduces inflammatory pain behaviours and markers of neuroinflammation [240] Nociception and neuropathic pain…”