Transcriptomic Profiling in Mice With CB1 receptor Deletion in Primary Sensory Neurons Suggests New Analgesic Targets for Neuropathic Pain

Abstract

Type 1 and type 2 cannabinoid receptors (CB1 and CB2, respectively) mediate cannabinoid-induced analgesia. Loss of endogenous CB1 is associated with hyperalgesia. However, the downstream targets affected by ablation of CB1 in primary sensory neurons remain unknown. In the present study, we hypothesized that conditional knockout of CB1 in primary sensory neurons (CB1cKO) alters downstream gene expression in the dorsal root ganglion (DRG) and that targeting these pathways alleviates neuropathic pain. We found that CB1cKO in primary sensory neurons induced by tamoxifen in adult Advillin-Cre:CB1-floxed mice showed persistent hyperalgesia. Transcriptome/RNA sequencing analysis of the DRG indicated that differentially expressed genes were enriched in energy regulation and complement and coagulation cascades at the early phase of CB1cKO, whereas pain regulation and nerve conduction pathways were affected at the late phase of CB1cKO. Chronic constriction injury in mice induced neuropathic pain and changed transcriptome expression in the DRG of CB1cKO mice, and differentially expressed genes were mainly associated with inflammatory and immune-related pathways. Nerve injury caused a much larger increase in CB2 expression in the DRG in CB1cKO than in wildtype mice. Interfering with downstream target genes of CB1, such as antagonizing CB2, inhibited activation of astrocytes, reduced neuroinflammation, and alleviated neuropathic pain. Our results demonstrate that CB1 in primary sensory neurons functions as an endogenous analgesic mediator. CB2 expression is regulated by CB1 and may be targeted for the treatment of neuropathic pain.

Nerve injury inhibitsOprd1andCnr1transcription through REST in primary sensory neurons

“…Cnr1 expression levels in DRG neurons are important for regulating pain hypersensitivity; Cnr1 cKO in DRG neurons causes pain hypersensitivity in mice (Liu et al 2021). Similarly, we observed that nerve injury diminishes Cnr1 expression in the DRG via G9a (Luo et al 2020), a cofactor of REST.…”

Electroacupuncture Reduces Visceral Pain Via Cannabinoid CB2 Receptors in a Mouse Model of Inflammatory Bowel Disease

“…The CB2 receptor inhibitor AM630 (Sigma-Aldrich, St. Louis, United States) was dissolved in a vehicle consisting of 1:2:7 ratio of dimethylsulfoxide (DMSO), Tween 80 and normal saline as previously described (Liu et al, 2021). Mice were intraperitoneally administrated with 100 μl of AM630 at 5 mg/kg body weight (Lopes et al, 2020) or vehicle 30 min before EA treatment, every day for 7 days.…”