Background: Video game loot boxes, which can typically be purchased by players or are given as reward, contain random virtual items, or loot, ranging from simple customization options for a player's avatar or character, to game-changing equipment such as weapons and armor. Loot boxes have drawn concern, as purchasing loot boxes might lead to the development of problematic gambling for adolescents. Although parental problem gambling is associated with adolescent problem gambling, no studies have evaluated the prevalence of loot box purchases in adolescents’ parents. Objective: This study investigated the association between loot box purchasing among adolescents and parents, and problem online gaming in population-based samples. Methods: In total, 1615 adolescent (aged 14 years) gamers from Japan responded to a questionnaire regarding their loot box purchasing and problem online gaming behaviors. Problem online gaming was defined as four or more of the nine addictive behaviors from the Diagnostic and Statistical Manual of Mental Disorders. The adolescents’ primary caregivers were asked about their loot box purchasing. Results: Of the 1615 participants, 57 (3.5%) reported loot box purchasing. This prevalence did not differ according to primary caregivers’ loot box purchasing, but adolescents who purchased loot boxes were significantly more likely to exhibit problem online gaming (odds ratio 3.75, 95% CI 2.17-6.48). Conclusions: Adolescent loot box purchasing is linked to problem online gaming, but not with parents’ loot box purchasing. Measures to reduce these behaviors should target reducing addictive symptoms in young video gamers.

Background: Although alterations in not only the pain sensitivity but also the analgesic effects of opioids have been reported under conditions of stress, the influence of unpredictable chronic mild stress (UCMS) on the antinociceptive effects of opioid analgesics remains to be fully investigated. The present study examined the influence of UCMS on the thermal pain sensitivity and antinociceptive effects of two opioid analgesics, morphine (an agonist of opioid receptors) and tramadol (an agonist of μ-opioid receptor and an inhibitor of both noradrenaline and serotonin transporters). We also examined the effects of pretreatment with maprotiline (a noradrenaline reuptake inhibitor) and escitalopram (a serotonin reuptake inhibitor) on the antinociceptive action of morphine in mice under an UCMS condition.Results: Unpredictable chronic mild stress did not affect the basal thermal pain sensitivity in a mouse hot-plate test. Although morphine dose-dependently induced thermal antinociceptive effects under both the UCMS and non-stress conditions, the thermal antinociceptive effect of 3 mg/kg morphine under the UCMS condition was significantly lower than under the non-stressed condition. Unlike the case with morphine, we observed no significant difference in the thermal antinociceptive effect of tramadol between the UCMS and non-stress conditions. Furthermore, the reduced thermal antinociceptive effect of 3 mg/kg morphine under the UCMS condition was significantly ameliorated by pretreatment with 10 mg/kg maprotiline but not 3 mg/kg escitalopram. Pretreatment with neither maprotiline nor escitalopram alone was associated with an antinociceptive effect under either condition.Conclusions: We demonstrated that the antinociceptive effect of morphine but not tramadol was reduced in mice that had experienced UCMS. The reduced antinociceptive effect of morphine under the UCMS condition was ameliorated by pretreatment with maprotiline but not escitalopram. These results suggest that the reduced antinociceptive effects of morphine under conditions of chronic stress may be ameliorated by activation of the noradrenergic but not the serotonergic system.

Introduction: Opioid analgesics are widely used as effective analgesics for the treatment of moderate‐to‐severe pain. However, the analgesic efficacy of opioids is well known to vary widely among individuals, and effective pain treatment is hampered by vast individual differences. Although these differences in opioid requirements have been attributed to various factors, genetic factors are becoming increasingly relevant to the development of genome science.Aim: This review covers the association between opioid analgesic requirements and particularly gene polymorphisms.Future perspectives: Personalized pain treatment has begun using prediction formulas based on associated gene polymorphisms. Improvements in personalized pain treatment are expected as scientific knowledge further expands in the future.

Addiction has become a profound societal problem worldwide, and few effective treatments are available. The nematode Caenorhabditis elegans (C. elegans) is an excellent invertebrate model to study neurobiological disease states. C. elegans reportedly developed a preference for cues that had previously been paired with addictive drugs, similar to place conditioning findings in rodents. Moreover, several recent studies discovered and reported the existence of an opioid-like system in C. elegans. Still unclear, however, is whether C. elegans exhibits addictive-like behaviors for opioids, such as morphine. In the present study, we found that C. elegans exhibited dose-dependent preference for morphine using the conditioned chemosensory-cue preference (CCP) test. This preference was blocked by co-treatment with the opioid receptor antagonist naloxone. C. elegans also exhibited aversion to naloxone-precipitated withdrawal from chronic morphine exposure. The expression of morphine-induced CCP and morphine withdrawal were abolished in worms that lacked the opioid-like receptor NPR-17. Dopamine-deficient mutant (cat-2 (e1112)) worms also did not exhibit morphine-induced CCP. These results indicate that the addictive function of the opioid system exists in C. elegans, which may serve as a useful model of opioid addiction.

Substance use disorders (SUDs) are chronic, lifelong disorders that have serious consequences. Repeated substance use alters brain function. G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed widely in the brain, including the reward system, and regulate neuronal excitability. Functional GIRK channels are identified as heterotetramers of GIRK subunits (GIRK1–4). The GIRK1, GIRK2, and GIRK3 subunits are mainly expressed in rodent brain regions, and various addictive substances act on the brain through GIRK channels. Studies with animals (knockout and missense mutation animals) and humans have demonstrated the involvement of GIRK channels in the effects of addictive substances. Additionally, GIRK channel blockers affect behavioral responses to addictive substances. Thus, GIRK channels play a key role in SUDs, and GIRK channel modulators may be candidate medications. Ifenprodil is a GIRK channel blocker that does not have serious side effects. Two clinical trials were conducted to investigate the effects of ifenprodil in patients with alcohol or methamphetamine use disorder. Although the number of participants was relatively low, evidence of its safety and efficacy was found. The present review discusses the potential of GIRK channel modulators as possible medications for addiction. Therapeutic agents that target GIRK channels may be promising for the treatment of SUDs.

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, has attracted attention for its acute and sustained antidepressant effects in patients with depression. Hydroxynorketamine (HNK), a metabolite of ketamine, exerts antidepressant effects without exerting ketamine's side effects and has attracted much attention in recent years. However, the detailed pharmacological mechanism of action of HNK remains unclear. We previously showed that the GluN2D NMDA receptor subunit is important for sustained antidepressant-like effects of (R)-ketamine. Therefore, we investigated whether the GluN2D subunit is involved in antidepressant-like effects of (2R,6R)-HNK and (2S,6S)-HNK. Treatment with (2R,6R)-HNK but not (2S,6S)-HNK exerted acute and sustained antidepressant-like effects in the tail-suspension test in wildtype mice. Interestingly, sustained antidepressant-like effects of (2R,6R)-HNK were abolished in GluN2D-knockout mice, whereas acute antidepressant-like effects were maintained in GluN2D-knockout mice. When expression levels of GluN2A and GluN2B subunits were evaluated, a decrease in GluN2B protein expression in the nucleus accumbens was found in stressed wildtype mice but not in stressed GluN2D-knockout mice. These results suggest that the GluN2D subunit and possibly the GluN2B subunit are involved in the sustained antidepressant-like effect of (2R,6R)-HNK.