Nociceptor-restricted cannabinoid receptor 1 contributes to chronic but not acute analgesia

Understanding the complex network that regulates pain is fundamental to develop strategies to combat its growing prevalence and increase useful therapeutics. Although extensive literature identifies the importance of cannabinoid receptors and endocannabinoids in controlling pain, their efficacy and loci of action remain debated. To directly test the actions of peripherally restricted cannabinoids and elucidate the minimal circuitry capable of producing cannabinoid-mediated analgesia, we utilized a novel genetic approach that allows for cell-specific reactivation of cannabinoid receptor 1 (CB1R) selectively in peripheral sensory neurons using newly developed CB1R floxed-stop-floxed mice (CB1R ^LOXTB ) crossed with Nav1.8-cre mice (Na _v 1.8 ^+/- :CB1R ^LOXTB ). Ex vivo and in vivo experiments confirmed successful knockout and reactivation of CB1R. Wildtype littermate controls, but neither Na _v 1.8 ^+/- :CB1R ^LOXTB nor CB1R ^LOXTB animals, exhibited robust analgesia after systemic WIN55,212-2 (WIN) treatment in the tail flick assay. Furthermore, the presence of CB1R on Na _v 1.8 neurons was not associated with either a difference in the development of inflammatory pain or the response to WIN. However, after neuropathic injury, CB1R ^LOXTB animals displayed an earlier onset of both mechanical and thermal hypersensitivity than their Na _v 1.8 ^+/- :CB1R ^LOXTB or wildtype counterparts, suggesting a dual role for CB1R in inflammatory and neuropathic pain. These studies represent an important approach to further improve our mechanistic understanding of cannabinoid modulation of pain in the nervous system and begins to settle long-standing controversies in cannabinoid literature.