Understanding the intricacies of how the body regulates pain is fundamental to develop rational strategies to combat the growing prevalence of chronic pain states, opioid dependency, and the resulting increased financial burden to the medical care system. Pain is the most prominent reason why Americans seek medical attention and extensive literature has identified the importance of the endocannabinoid pathway in controlling pain. Endocannabinoid signaling machinery operates in a synapse-specific manner, and its modulation offers new therapeutic opportunities for the selective control of excessive neuronal activity in several pain conditions (acute, inflammatory, chronic, and neuropathic). Cannabinoids have a long history of medicinal use and their analgesic properties are well documented; however, there are major impediments to understanding cannabinoid pain modulation. One major issue is the presence of psychotropic side effects associated with Δ9tetrahydrocannabinoil (THC) or synthetic derivatives, which puts an emphatic brake on their use. This dose-limiting effect lends to the idea that the appropriate degree of analgesia cannot be reached before the presence of severe side effects. Animal studies have shown that the psychotropic effects are mediated via brain cannabinoid type 1 (CB1) receptors, while analgesic activity in chronic pain states may be mediated via CB1R action in the spinal cord, brainstem, peripheral sensory neurons, or immune cells. The development of appropriate therapies is incumbent on our understanding of the role of peripheral versus central endocannabinoid-driven analgesia. Recent physiological, pharmacological, and anatomical studies provide evidence that one of the main roles of the endocannabinoid system is the regulation of gamma-aminobutyric acid (GABA) and/or glutamate release. This article will review this evidence in the context of its implications for pain. We first provide a brief overview of CB1R's role in the regulation of nociception, followed by a review of the evidence that the peripheral endocannabinoid system modulates nociception. We then look in detail at regulation of central-mediated analgesia, followed up with evidence that cannabinoid-mediated modulation of pain involves modulation of GABAergic and glutamatergic neurotransmission in key brain regions. Finally, we discuss cannabinoid action on non-neuronal cells in the context of inflammation and direct modulation of neurons. This work stands to reveal long-standing controversies in the cannabinoid analgesia area *

Purpose of review Cannabis use disorders (CUDs) are prevalent worldwide. Current epidemiological studies underscore differences in behaviors that contribute to cannabis use across cultures that can be leveraged towards prevention and treatment of CUDs. This review proposes a framework for understanding the effects of cross-cultural differences on psychological, neural, and genomic processes underlying CUDs that has the potential to inform global policies and impact global public health. Recent findings We found that cultural factors may influence (1) the willingness to acknowledge CUD-related symptoms among populations of different countries, and (2) neural responses related to the sense of self, perception, emotion, and attention. These findings leverage the potential effects of culture on neural mechanisms underlying CUDs. Summary As the number of individuals seeking treatment for CUDs increases globally, it is imperative to incorporate cultural considerations to better understand and serve differing populations and develop more targeted treatment strategies and interventions.

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