The efforts of dedicated researchers and clinicians has resulted in significant progress in understanding the pathophysiology of neuropathic pain. However, currently available pharmacotherapies have limited efficacy and exhibit undesirable adverse effects. Opioid and cannabinoid agonists are potent class of analgesics but their CNS side effects including sedation, dizziness, cognitive impairments and addiction limit their clinical usefulness for chronic pain. We hypothesized that targeting the peripheral nervous system (PNS) may provide safer therapies for NP. We earlier reported that peripherally restricted cannabinoid (CB) and mu-opioid (MOR) receptor agonists attenuated neuropathic pain in rodents. In this session we will present results from recent molecular, behavioral and pharmacological studies aimed: 1) to determine the anatomical characterization of CB1 and MORs in human and mouse primary sensory neurons and 2) to investigate the physical and pharmacological interactions between these two receptor systems. We found that CB1R and MOR are colocalized in primary sensory neurons of human and mouse DRG tissues and physically interact with each other. Systemic co-administration of peripherally restricted CB and MOR agonists synergistically inhibited mechanical hypersensitivity in nerve-injured mice. Combination of CB and MOR agonists also attenuated spontaneous ongoing pain without eliciting drug preference in naïve mice or central side effects. We conclude that selective co-activation of peripheral CB and MOR receptors may provide an efficacious and safer treatment for neuropathic pain.