SnapShot: Neurobiology of opioid use disorder.

The use of opioid drugs and related overdose deaths, which rose to epidemic proportions over the past decade, have been exacerbated by the COVID pandemic, a time of great uncertainty and isolation. Much is known about opioid pharmacology and related neural circuits that, combined with novel emerging neurobiological insights, can help guide new treatment strategies. To view this SnapShot, open or download the PDF.

Adolescent exposure to Δ9-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons.

Neuronal circuits within the prefrontal cortex (PFC) mediate higher cognitive functions and emotional regulation that are disrupted in psychiatric disorders. The PFC undergoes significant maturation during adolescence, a period when cannabis use in humans has been linked to subsequent vulnerability to psychiatric disorders such as addiction and schizophrenia. Here, we investigated in a rat model the effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), a psychoactive component of cannabis, on the morphological architecture and transcriptional profile of layer III pyramidal neurons-using cell type- and layer-specific high-resolution microscopy, laser capture microdissection and next-generation RNA-sequencing. The results confirmed known normal expansions in basal dendritic arborization and dendritic spine pruning during the transition from late adolescence to early adulthood that were accompanied by differential expression of gene networks associated with neurodevelopment in control animals. In contrast, THC exposure disrupted the normal developmental process by inducing premature pruning of dendritic spines and allostatic atrophy of dendritic arborization in early adulthood. Surprisingly, there was minimal overlap of the developmental transcriptomes between THC- and vehicle-exposed rats. THC altered functional gene networks related to cell morphogenesis, dendritic development, and cytoskeleton organization. Marked developmental network disturbances were evident for epigenetic regulators with enhanced co-expression of chromatin- and dendrite-related genes in THC-treated animals. Dysregulated PFC co-expression networks common to both the THC-treated animals and patients with schizophrenia were enriched for cytoskeletal and neurite development. Overall, adolescent THC exposure altered the morphological and transcriptional trajectory of PFC pyramidal neurons, which could enhance vulnerability to psychiatric disorders.

Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder.

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.

Patient reported outcome measures of pain intensity: Do they tell us what we need to know?

OBJECTIVE: To determine the relationship between chronic pain patients' responses to self-report measures of pain intensity, and self-reported strategies when completing such measures. PARTICIPANTS: Ambulatory outpatients suffering from one of the following chronic pain conditions: painful HIV neuropathy, painful diabetic neuropathy, chronic Low-Back Pain. METHOD: As part of a previously reported study using qualitative methods, participants completed standard pain intensity questionnaires as well as a measure of pain related disturbances in activities of daily living. In the previous study, participants' responses during a focus group were then used to identify their strategies and beliefs about their approach to completing the questionnaires. Among the beliefs were: (1) difficulties averaging pain over different time periods (i.e., "what was your average pain during the last 24h" versus "what was your average pain during the last 2 weeks"); (2) difficulty in comparing pain from different etiologies; (3) difficulties in reporting sensations of pain in a manner unaffected by issues and situations secondary to the pain experience, such as difficulties in activities of daily living. In the present paper we use ANOVA (analysis of variance) and partial correlation to determine whether the qualitatively derived perceptions are reflected in the quantitative pain intensity scores. RESULTS: Participants' belief that it was difficult to "average" pain intensity over different time periods was supported. The data do not support their belief that pain intensity scores are affected by other factors: their specific pain diagnosis, and the extent to which pain interfered with their activities of daily living. CONCLUSIONS: (1) Patients tend to report different levels of pain intensity when asked to report their pain over different periods; (2) insofar as it can be said to exist, the relationship between measures of intensity and interference with activities of daily living is minimal; (3) participants tend to report similar levels of pain intensity, irrespective of etiology. IMPLICATIONS: (1) Chronic pain patients' elicited beliefs and strategies concerning how they complete pain intensity questionnaires are sometimes, but not invariably, reflected in their responses to these measures. Thus, purely qualitative methodologies alone cannot provide completely reliable information and point to the need to use a "mixed methods" approach combining both qualitative and quantitative data; (2) the lack of association between pain intensity measures and interference with activities of daily living, as well as relative insensitivity to different etiologies underlines the problem in relying on pain intensity measures as the primary means of evaluating the success of a treatment, either for pain management or in clinical research.