Dynamic alterations in gene co-expression networks and gene-transcript associations characterize co-morbidities in cocaine use disorder.

Background: Individuals with cocaine use disorder (CUD) who attempt abstinence experience craving and relapse, which poses challenges in treatment. Longitudinal studies linking behavioral manifestations in CUD to the blood transcriptome in living individuals are limited. Therefore, we investigated the connection between drug use behaviors during abstinence with blood transcriptomics. Methods: We conducted a comprehensive longitudinal study involving 12 subjects (9 males, 3 females) with CUD and RNA sequencing on blood collected at a drug-free baseline, and 3, 6 & 9 months thereafter. We categorized subjects into 2 responder groups (high-low) based on scores of drug use variables, and 3 responder groups (low-intermediate-high) on days of abstinence. We investigated differential expression and gene-transcript associations across responder groups at each time point. Lastly, we examined genes that are both co-expressed and showed dynamic expression with time. Results: Genes with significant transcript associations between high and. intermediate days of abstinence at 9 months were notably enriched for cannabis use disorder, drinks weekly, and coronary artery disease risk genes. Time-specific gene co-expression analysis prioritized transcripts related to immune processes, cell cycle, RNA-protein synthesis, and second messenger signaling for days of abstinence. Conclusion: We demonstrate that abstinence reflects robust changes in drug use behaviors and the blood transcriptome in CUD. We also highlight the importance of longitudinal studies to capture complex biological processes during abstinence in CUD.

Neuroimmune Mechanisms of Opioid Use Disorder and Recovery: Translatability to Human Studies, and Future Research Directions.

Opioid use disorder (OUD) is a major current cause of morbidity and mortality. Long-term exposure to short-acting opioids (MOP-r agonists such as heroin or fentanyl) results in complex pathophysiological changes to neuroimmune and neuroinflammatory functions, affected in part by peripheral mechanisms (e.g., cytokines in blood), and by neuroendocrine systems such as the hypothalamic-pituitary-adrenal (HPA) stress axis. There are important findings from preclinical models, but their role in the trajectory and outcomes of OUD in humans is not well understood. The goal of this narrative review is to examine available data on immune and inflammatory functions in persons with OUD, and to identify major areas for future research. Peripheral blood biomarker studies revealed a pro-inflammatory state in persons with OUD in withdrawal or early abstinence, consistent with available postmortem brain studies (which show glial activation) and diffusion tensor imaging studies (indicating white matter disruptions), with gradual abstinence-associated recovery. The mechanistic roles of these neuroimmune and neuroinflammatory changes in the trajectory of OUD (including recovery and medication management) cannot be examined practically with postmortem data. Collection of longitudinal data in larger-scale human cohorts would allow examination of these mechanisms associated with OUD stage and progression. Given the heterogeneity in presentation of OUD, a precision medicine approach integrating multi-omic peripheral biomarkers and comprehensive phenotyping, including neuroimaging, can be beneficial in risk stratification, and individually optimized selection of interventions for individuals who will benefit, and assessments under refractory therapy.

Management of Postoperative Pain in Patients Following Spine Surgery: A Narrative Review.

Perioperative pain management is a unique challenge in patients undergoing spine surgery due to the increased incidence of both pre-existing chronic pain conditions and chronic postsurgical pain. Peri-operative planning and counseling in spine surgery should involve an interdisciplinary approach that includes consideration of patient-level risk factors, as well as pharmacologic and non-pharmacologic pain management techniques. Consideration of psychological factors and patient focused education as an adjunct to these measures is paramount in developing a personalized perioperative pain management plan. Understanding the currently available body of knowledge surrounding perioperative opioid management, management of opioid use disorder, regional/neuraxial anesthetic techniques, ketamine/lidocaine infusions, non-opioid oral analgesics, and behavioral interventions can be useful in developing a comprehensive, multi-modal treatment plan among patients undergoing spine surgery. Although many of these techniques have proved efficacious in the immediate postoperative period, long-term follow-up is needed to define the impact of such approaches on persistent pain and opioid use. Future techniques involving the use of precision medicine may help identify phenotypic and physiologic characteristics that can identify patients that are most at risk of developing persistent postoperative pain after spine surgery.

Lack of Premeditation Predicts Aberrant Behaviors Related to Prescription Opioids in Patients with Chronic Pain: A Cross-Sectional Study.

OBJECTIVE: In light of the opioid epidemic, there is a need to identify factors that predict aberrant opioid behaviors including misuse and abuse. Impulsivity has been extensively studied in addiction literature, but not in the context of opioid misuse. Hence, this study aimed to identify which of the impulsivity facets (negative urgency, positive urgency, sensation seeking, lack of perseverance, and lack of premeditation) would predict current aberrant opioid-related behaviors in patients with chronic pain. METHODS: Data were collected through an online survey from patients with chronic pain who visited a tertiary pain clinic. Patients were predominately female (74%), middle aged (M = 55 years), and White/Caucasian (84%). Upon consent, they completed a series of surveys including UPPS-P Impulsive Behavior Scale, the Current Opioid misuse Measure, Pain Catastrophizing Scale, PROMIS-anxiety, depression, and physical function, and a 0-10 numerical pain rating scale. Ordinal regression analyses were conducted to test study hypotheses. RESULTS: Contrary to expectations, only lack of premeditation predicted higher odds of aberrant opioid-related behaviors in the past 30 days, after controlling for known covariates, and explained 26% of variance. Interestingly, lack of premeditation together with pain catastrophizing as a covariate explained 56% of the variance in aberrant opioid-related behaviors. DISCUSSION: The current study is the first to identify a potential role of lack of premeditation as an impulsivity facet predicting aberrant opioid-related behaviors among patients with chronic pain.

Acute Pain Predictors of Remote Postoperative Pain Resolution After Hand Surgery.

INTRODUCTION: Chronic postsurgical pain (CPSP) is a global issue with high prevalence. This study compared acute pain descriptors among patients undergoing carpal tunnel release (CTR) or trigger finger release (TFR). We hypothesized worst pain intensity on postoperative day (POD) 10 would be best to predict the time to pain resolution. METHODS: In this secondary analysis of a negative, randomized, double-blind placebo-controlled trial, adult veterans undergoing CTR or TFR were enrolled January 2012-January 2014, with data analysis February 2020-October 2020. Participants were randomized to receive minocycline 200 mg or placebo 2 h prior to the operation, then minocycline 100 mg or placebo twice daily for 5 days. The Brief Pain Inventory, assessed daily, captured three pain scores: average and worst pain over the past 24 h, and current pain intensity. Fifteen acute pain descriptors based on the pain scores (clusters, mean, median, pain scores on POD 10, and linear slopes) were compared as predictors of time to pain resolution. RESULTS: Of 131 randomized participants, 114 (83 CTR, 31 TFR) were included. Average pain over the last 24 h reported on POD 10 best predicted time to pain cessation. Every one-point increase in the average pain score was associated with a 36.0% reduced rate of pain cessation (HR, 0.64, 95% CI 0.55-0.74, p < 0.001). Average pain on POD 10 was significantly associated with the development of CPSP at 90 days (OR 1.74, 95% CI 1.30-2.33, p value < 0.001). The optimal cutoff score for the high-risk group was determined as average pain on POD 10 ≥ 3. CONCLUSIONS: This study validates prior work and demonstrates the importance of assessing pain severity on POD 10 to identify patients at high risk for CPSP who are most likely to benefit from early pain intervention. Future research in diverse surgical cohorts is needed to further validate pain assessment on POD 10 as a significant predictor of CPSP.

Functional bias of morphine and oliceridine under conditions of minor injury.

Recent reports suggest pain from surgical injury may influence the risks associated with exposure to opioids. In mice, hind-paw incision attenuates morphine-primed reinstatement due to kappa opioid receptor activation by dynorphin. In this focused group of studies, we examined the hypotheses that kappa-opioid receptor activation in the nucleus accumbens mediates attenuated drug- primed reinstatement after incisional surgery, and the G-protein biased mu-opioid agonist, oliceridine, leads to less priming of the dynorphin effect in comparison to morphine. To address these hypotheses, adult C57BL/6 male mice underwent intracranial cannulation for administration of the selective kappa-opioid antagonist norBNI directly into the nucleus accumbens. After recovery, they were conditioned with morphine or oliceridine after hind-paw incisional injury, then underwent extinction followed by opioid-primed reinstatement. Intra-accumbal administration of norBNI was carried out prior to testing. The nucleus accumbens and medial prefrontal cortex were extracted and analyzed for expression of prodynorphin. We observed that animals conditioned with morphine in the setting of incisional injury demonstrated blunted responses to opioid-primed reinstatement, and that the blunted responses were reversed with intra-accumbal norBNI administration. Persistently elevated levels of prodynorphin expression in the medial prefrontal cortex and nucleus accumbens were observed in the incised morphine-treated animals. However, both behavioral and molecular changes were absent in animals with incisional injury conditioned with oliceridine. These findings suggest a role for prodynorphin expression in the nucleus accumbens with exposure to morphine after surgery that may protect individuals from relapse not shared with biased mu- opioid receptor agonists.

Incisional Injury Modulates Morphine Reward and Morphine-Primed Reinstatement: A Role of Kappa Opioid Receptor Activation.

BACKGROUND: Persistent use of prescription opioids beyond the period of surgical recovery is a large part of a public health problem linked to the current opioid crisis in the United States. However, few studies have been conducted to examine whether morphine reward is influenced by acute pain and injury. METHODS: In a mouse model of incisional injury and minor trauma, animals underwent conditioning, extinction, and drug-primed reinstatement with morphine to examine the rewarding properties of morphine in the presence of acute incisional injury and drug-induced relapse, respectively. In addition, we sought to determine whether these behaviors were influenced by kappa opioid receptor signaling and measured expression of prodynorphin messenger RNA in the nucleus accumbens and medial prefrontal cortex after conditioning and before reinstatement with morphine and incisional injury. RESULTS: In the presence of incisional injury, we observed enhancement of morphine reward with morphine-conditioned place preference but attenuated morphine-primed reinstatement to reward. This adaptation was not present in animals conditioned 12 days after incisional injury when nociceptive sensitization had resolved; however, they showed enhancement of morphine-primed reinstatement. Prodynorphin expression was greatly enhanced in the nucleus accumbens and medial prefrontal cortex of mice with incisional injury and morphine conditioning and remained elevated up to drug-primed reinstatement. These changes were not observed in mice conditioned 12 days after incisional injury. Further, kappa opioid receptor blockade with norbinaltorphimine before reinstatement reversed the attenuation induced by injury. CONCLUSIONS: These findings suggest enhancement of morphine reward as a result of incisional injury but paradoxically a protective adaptation with incisional injury from drug-induced relapse resulting from kappa opioid receptor activation in the reward circuitry. Remote injury conferred no such protection and appeared to enhance reinstatement.

Pharmacological Characters of Oliceridine, a µ-Opioid Receptor G-Protein-Biased Ligand in Mice.

BACKGROUND: A major advancement in the field of analgesic pharmacology has been the development of G-protein-biased opioid agonists that display less respiratory depression than conventional drugs. It is uncertain, however, whether these new drugs cause less tolerance, hyperalgesia, and other maladaptations when administered repeatedly. METHODS: The archetypical µ-opioid receptor agonist morphine and, separately, the G-protein-biased µ-opioid receptor agonist oliceridine were administered to mice. These drugs were used in models of acute analgesia, analgesic tolerance, opioid-induced hyperalgesia, reward, and physical dependence. In addition, morphine and oliceridine were administered for 7 days after tibia fracture and pinning; mechanical allodynia and gait were followed for 3 weeks. Finally, the expression of toll-like receptor-4 and nacht domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NALP3) and interleukin-1ß mRNA were quantified in spinal tissue to measure surgical and drug effects on glia-related gene expression. RESULTS: We observed using the tail flick assay that oliceridine was a 4-fold more potent analgesic than morphine, but that oliceridine treatment caused less tolerance and opioid-induced hyperalgesia than morphine after 4 days of ascending-dose administration. Using similar analgesic doses, morphine caused reward behavior in the conditioned place preference assay while oliceridine did not. Physical dependence was, however, similar for the 2 drugs. Likewise, morphine appeared to more significantly impair the recovery of nociceptive sensitization and gait after tibial fracture and pinning than oliceridine. Furthermore, spinal cord toll-like receptor-4 levels 3 weeks after fracture were higher in fracture mice given morphine than those given oliceridine. CONCLUSIONS: Aside from reduced respiratory depression, G-protein-biased agonists such as oliceridine may reduce opioid maladaptations and enhance the quality of surgical recovery.

Separation and enhanced detection of anesthetic compounds using solid phase micro-extraction (SPME)-Raman spectroscopy.

Polydimethylsiloxane (PDMS)-based solid-phase micro-extraction (SPME) was used along with Raman spectroscopy (RS) to separate and enhance the detection of five anesthetic compounds (halothane, propofol, isoflurane, enflurane, and etomidate) from aqueous and serum phases. Raman signals in the spectral ranges 250-450 cm(-1) and 950-1050 cm(-1) allowed the unique characterization of all five compounds when extracted into the PDMS phase. The SPME-RS detection of clinically relevant concentrations of aqueous propofol (6.5 µM) and halothane (200 µM) is shown. We quantify the partition coefficient for aqueous halothane in PDMS as log K = 1.9 ± 0.2. Solid-phase micro-extraction of the anesthetics makes their detection possible without the strong autofluorescent interference of serum proteins. Because of low solubility and/or weak Raman scattering, we found it challenging to detect enflurane, isoflurane, and etomidate directly from the aqueous phase, but could we do so with SPME enhancement. These studies show the potential of SPME-RS as a method for the direct detection of anesthetics in blood.

NK-3 receptor antagonism prevents behavioral sensitization to cocaine: a role of glycogen synthase kinase-3 in the nucleus accumbens.

Repeated administration of cocaine induces heightened behavioral hyperactivity termed sensitization. Although NK-3 receptors have been shown to modulate acute cocaine-induced behaviors, their role in behavioral sensitization is unknown. The present study investigated whether NK-3 receptor blockade altered behavioral sensitization to cocaine. Additionally, glycogen synthase kinase-3 (GSK3) has been shown to be involved in dopamine receptor signaling and in development of sensitization; therefore regulation of GSK3 activity in the nucleus accumbens was also investigated. Administration of the NK-3 receptor antagonist SB 222200 (5 mg/kg, s.c.) prior to repeated cocaine (20 mg/kg, i.p.) prevented the development of sensitized responses after a cocaine challenge. Pre-treatment with SB 222200 before a cocaine challenge also blocked expression of sensitization. Decrease in GSK3 activity demonstrated by increased phosphorylation of GSK3α and GSK3ß was detected 20 mins after an acute cocaine injection. In contrast, a cocaine challenge failed to alter phosphorylation of GSK3α and GSK3ß in sensitized mice. SB 222200 prior to repeated cocaine resulted in increased phosphorylation of GSK3α and GSK3ß akin to changes following acute cocaine. Collectively, these findings demonstrate the involvement of NK-3 receptors in development and expression of behavioral sensitization and in regulation of GSK3 activity in the nucleus accumbens after repeated cocaine.

Blockade of neurokinin-3 receptors modulates dopamine-mediated behavioral hyperactivity.

Acute activation or blockade of neurokinin-3 (NK-3) receptors has been shown to alter dopamine-mediated function and behaviors, however long-term effects of NK-3 receptor blockade remain largely unknown. The present study investigated whether acute and repeated administration of the NK-3 receptor antagonist SB 222200 altered hyperactivity induced by cocaine, and examined its effects on dopamine D1 receptor density in the striatum. Adult male CD-1 mice received either vehicle or SB 222200 (2.5 or 5 mg/kg, s.c.) 30 min before a cocaine injection (20 mg/kg, i.p.) and behavioral responses were recorded. Mice that were administered SB 222200 had an attenuated stereotypic response to cocaine compared to vehicle treated mice. Mice were also injected once daily with either vehicle or SB 222200 (5 mg/kg, s.c.) for 5 days, and after a 7-day drug-free period they were challenged with either saline, cocaine or the dopamine D1 receptor agonist SKF 82958 (0.125 or 0.25 mg/kg, i.p.). Mice injected with SB 222200 had significantly enhanced hyperactivity when challenged with cocaine or a low dose of SKF 82958 (0.125 mg/kg, i.p.) compared to control mice. Brains of mice administered vehicle or SB 222200 for 5 days were harvested after a 7-day drug-free period for dopamine D1 receptor quantification by radioligand binding. [(3)H] SCH 23390 homogenate binding studies showed a 19.7% increase in dopamine D1 receptor density in the striatum of SB 222200 treated mice. These data suggest that repeated blockade of NK-3 receptors enhances subsequent dopamine-mediated behaviors possibly resulting from dopamine D1 receptor up-regulation in the striatum.

Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat.

Chronic administration of cocaine has been shown to attenuate the functional capacity of delta opioid receptors to inhibit adenylyl cyclase activity. Abuse and withdrawal from cocaine in humans is associated with increases in anxiety and depression. Since recent research supports the role of delta opioid receptors in anxiety- and depression-like behaviors in rodents, we hypothesized that functional desensitization of delta opioid receptors contributes to anxiety- and depression-like behavioral phenotypes following short-term withdrawal from chronic administration of cocaine. To test this hypothesis, delta opioid receptor signaling and behaviors were evaluated 24h after 14days of binge-pattern cocaine administration (15mg/kg three times daily at 1h intervals) in male Sprague-Dawley rats. Results showed that the inhibition of adenylyl cyclase by delta opioid receptor agonists was attenuated in the frontal cortex, nucleus accumbens and caudate putamen 24h after cessation of cocaine administration. One day withdrawal from chronic administration of cocaine resulted in increased anxiety- and depression-like behaviors as measured by the elevated plus maze and the forced swim test respectively, and no change in locomotor activity. The anxiety- and depression-like behaviors were dose-dependently reduced by acute administration of the selective delta opioid receptor agonist, SNC80. These results demonstrate that early withdrawal from cocaine resulted in increased anxiety and depression, which accompanies the desensitization of delta opioid receptor function. Furthermore, cocaine-induced anxiety- and depression-like behaviors were reversible by the delta opioid receptor agonist SNC80.