Substance use disorders (SUDs) are debilitating neuropsychiatric conditions that exact enormous costs in terms of loss of life and individual suffering. While much progress has been made defining the neurocircuitry and intracellular signaling cascades that contribute to SUDs, these studies have yielded limited effective treatment options. This has prompted greater exploration of non-traditional targets in addiction. Emerging data suggest inputs from peripheral systems, such as the immune system and the gut microbiome, impact multiple neuropsychiatric diseases, including SUDs. Until recently the gut microbiome, peripheral immune system, and the CNS have been studied independently; however, current work shows the gut microbiome and immune system critically interact to modulate brain function. Additionally, the gut microbiome and immune system intimately regulate one another via extensive bidirectional communication. Accumulating evidence suggests an important role for gut-immune-brain communication in the pathogenesis of substance use disorders. Thus, a better understanding of gut-immune-brain signaling could yield important insight to addiction pathology and potential treatment options.Across centuries and civilizations opioids have been used to relieve pain. In our modern societies, opioid-based analgesics remain one of the most efficient treatments for acute pain. However, the long-term use of opioids can lead to the development of analgesic tolerance, opioid-induced hyperalgesia, opioid use disorders, and overdose, which can ultimately produce respiratory depressant effects with fatal consequences. In addition to the nociceptive sensory component of pain, negative affective states arising from persistent pain represent a risk factor for developing an opioid use disorder. Several studies have indicated that the increase in prescribed opioid analgesics since the 1990s represents the root of our current opioid epidemic. In this review, we will present our current knowledge on the endogenous opioid system within the pain neuroaxis and the plastic changes occurring in this system that may underlie the occurrence of pain-induced negative affect leading to misuse and abuse of opioid medications. Xevinapant Dissecting the allostatic neuronal changes occurring during pain is the most promising avenue to uncover novel targets for the development of safer pain medications. We will discuss this along with current and potential approaches to treat pain-induced negative affective states that lead to drug misuse. Moreover, this chapter will provide a discussion on potential avenues to reduce the abuse potential of new analgesic drugs and highlight a basis for future research and drug development based on recent advances in this field.Mood disorders, including major depressive disorder (MDD), are the most prevalent psychiatric illnesses, and pose an incredible burden to society, both in terms of disability and in terms of costs associated with medical care and lost work time. MDD has extremely high rates of comorbidity with substance use disorders (SUD) as many of the same neurobiological circuits and molecular mechanisms regulate the reward pathways disrupted in both conditions. MDD may induce SUDs, SUD may contribute to MDD development, or underlying vulnerabilities and common life experience may confer risk to developing both conditions. In this chapter we explore theories of MDD and SUD comorbidity, the neurobiological underpinnings of depression, overlapping cellular and molecular pathways for both conditions, and current treatment approaches for these comorbid conditions.Traumatic brain injury (TBI), most often classified as concussion, is caused by biomechanical forces to the brain resulting in short- or long-term impairment in brain function. TBI resulting from military combat, sports, violence, falls, and vehicular accidents is a major cause of long-term physical, cognitive, and psychiatric dysfunction. Psychiatric disorders associated with TBI include depression, anxiety, and substance use disorder, all having significant implications for post-TBI recovery and rehabilitation. This chapter reviews the current preclinical and clinical literature describing the bidirectional relationship between TBI and misuse of three commonly abused drugs alcohol, opioids, and cannabis. We highlight the influence of each of these drugs on the incidence of TBI, as well as trends in their use after TBI. Furthermore, we discuss factors that may underlie post-injury substance use. Understanding the complex relationship between TBI and substance misuse will enhance the clinical treatment of individuals suffering from these two highly comorbid conditions.Cannabis use is increasing among some demographics in the United States and is tightly linked to anxiety, trauma, and stress reactivity at the epidemiological and biological level. Stress-coping motives are highly cited reasons for cannabis use. However, with increased cannabis use comes the increased susceptibility for cannabis use disorder (CUD). Indeed, CUD is highly comorbid with posttraumatic stress disorder (PTSD). Importantly, endogenous cannabinoid signaling systems play a key role in the regulation of stress reactivity and anxiety regulation, and preclinical data suggest deficiencies in this signaling system could contribute to the development of stress-related psychopathology. Furthermore, endocannabinoid deficiency states, either pre-existing or induced by trauma exposure, could provide explanatory insights into the high rates of comorbid cannabis use in patients with PTSD. Here we review clinical and preclinical literature related to the cannabis use-PTSD comorbidity, the role of endocannabinoids in the regulation of stress reactivity, and potential therapeutic implications of recent work in this area.Alcohol is an effective and widely utilized analgesic. However, the chronic use of alcohol can actually facilitate nociceptive sensitivity over time, a condition known as hyperalgesia. Excessive and uncontrollable alcohol drinking is also a hallmark feature of alcohol use disorder (AUD). Both AUD and chronic pain are typically accompanied by negative affective states that may underlie reinforcement mechanisms contributing to AUD maintenance or progression. Frequent utilization of alcohol to relieve pain in individuals suffering from AUD or other chronic pain conditions may thus represent a powerful negative reinforcement construct. This chapter will describe ties between alcohol-mediated pain relief and potential exacerbation of AUD. We describe neurobiological systems engaged in alcohol analgesia as well as systems recruited in the development and maintenance of AUD and hyperalgesia. Although few effective therapies exist for either chronic pain or AUD, the common interaction of these conditions will likely lead the way for promising new discoveries of more effective and even simultaneous treatment of AUD and co-morbid hyperalgesia.