E-cigarette or vaping product use-associated lung injury without pulmonary symptoms: A case report and literature review.

Opioids remain essential analgesics for managing acute pain following injury or surgery. While generally effective, ~2% of opioid-naïve individuals transition to extended opioid use—a minority that nonetheless accounts for ~75% of opioid use disorder cases in the United States. Opioids signal to multiple brain cell types, yet it’s unclear if their multifaceted short-term effects can be separated from the cumulative neural-circuit changes that drive abuse progression. Diverse synthetic opioid-receptor agonists have been developed, yet none dissociate analgesia from reward learning—a process implicated in early stages of abuse progression. Aiming to achieve this dissociation, adjuncts that disrupt opioid-mediated dopamine signaling are being devleoped, capitalizing on dopamine’s central role in reward learning. However, dopamine is also essential for the modulation of central-pain perception by opioids, underscoring the need for alternative approaches. Against this backdrop, a recent double-blind placebo-controlled human trial tested the pro-cholinergic drug galantamine, motivated by a neocortical cognitive hypothesis, and reported significantly reduced illicit opioid use. Genetic variants of acetylcholinesterase that accelerate acetylcholine breakdown have also been associated with human vulnerability to heroin addiction, further supporting the idea that sustained cholinergic tone may be protective. Moreover, pro-cholinergic drugs attenuate opioid-reward learning in rodent models, suggesting that cholinergic tone may influence opioid-reward processing across species. Nevertheless, the relevant circuits remain unresolved. Cortical cholinergic architectures are poorly conserved across mammals and galantamine did not improve cognitive outcomes in the human trial, challenging a purely neocortical explanation. The nucleus accumbens (NAc) is a subcortical circuit implicated in central pain perception and reward learning, with substantially higher cross-species conservation—making it an attractive candidate for a conserved cholinergic influence on opioid-reward learning. The NAc is a major target of opioid-evoked dopamine release, triggered primarily by μ-opioid receptor (μOR)–mediated disinhibition in the distant ventral tegmental area. By contrast, local cholinergic interneurons (CINs) are the NAc’s primary source of acetylcholine. Local opioid manipulations in the NAc can modulate opioid reinforcement but prior work has neither tested whether NAc opioid receptors are required for the acquisition of associative opioid-reward learning nor identified the cell types involved. Specifically, efforts to establish a causal role for CINs have been inconclusive. Targeted ablation of CINs leads to dopamine hypersensitivity and broad circuit adaptations, whereas CIN-specific opioid-receptor knockouts had little impact on morphine’s acute or cumulative effects. Both approaches are susceptible to developmental and network-level compensation, leaving unresolved whether opioid signaling on CINs contributes to the acquisition of opioid-reward learning. Addressing this question requires tools that can acutely block native opioid receptors on CINs with cellular specificity.