"It frees your body from that pain thought": A mixed-methods exploration of patterns, contexts, and experiences of cannabis use for pain in rural communities.

U.S. adults increasingly report using cannabis to manage chronic pain and rural areas have inadequate comprehensive pain management. Using mixed methods, we aimed to understand how and why some rural adults use cannabis for pain, including within the context of co-use with opioids. Participants (N = 14, Oklahoma) were rural-dwelling adults who used tobacco and ≥1 other substance, including cannabis and opioids, ≥3 days per week. Participants completed 14 days of ecological momentary assessment (EMA) regarding substance use and subsequent in-depth interviews discussing maps of their substance use reports. Half (7/14) described cannabis use for chronic pain, and most of these (85%) reported use on ≥75% of EMA days. The most frequently reported cannabis use motive was therapeutic/medicinal (90% of use reports). Most reports were of combusted cannabis (88% of use reports) at home (99% of use reports). Same-day use of cannabis and opioids was relatively common (45% of daily surveys), but seemingly not within close temporal proximity. Interview narratives characterized cannabis as modifying pain-adjacent factors (eg, thoughts), not eliminating pain itself. They recounted using a repertoire of substances to manage different pain dimensions (eg, intensity, quality) and balance perceived trade-offs of different substances. Participants described high medical cannabis access, low pain specialist access, and most physicians as unwilling to discuss cannabis for pain. The findings suggest that rural-dwelling patients could benefit from increased access to comprehensive pain management, having cannabis addressed within pain management provider discussions, and that risks and benefits of cannabis use for pain must be better established. PERSPECTIVE: This study used a geographically explicit EMA mixed method to gather rich, intensive pilot data on cannabis use and co-use for chronic pain in rural Oklahoma. It provides unique insights to inform future research on cannabis use among a vulnerable and understudied subgroup of adults with pain-rural residents.

Period Poverty: Surveying the Prevalence in Toledo-Area Schools.

Background: The lack of access to period products, which has been colloquially termed "period poverty," is a problem that millions of people face worldwide. Investigators have found that period poverty is a pervasive issue in the United States, despite its status as a high resource country. The purpose of this study was to determine the prevalence of period poverty in school-aged adolescents in Toledo, Ohio. Methods: This study used an observational cross-sectional design and was approved by the institutional review board. Participants completed a survey that assessed their access to period products, their level of understanding about their sexual/menstrual health, their feelings toward menstruation, and the perceived impact of periods on their lives. Results: Younger students were more likely to miss school due to lack of period products (p = 0.0084). To the question "Why don't you have pads or tampons?" 36.2% expressed financial concerns and 18.3% reported inadequate transportation. When asked whether students ever had to miss school due to their cycle, 9.4% identified a lack of products as their reason. Participants also reported high rates of absence from sports, work, spending time with family/friends, and theater/music practice due to their menstrual period. Discussion: As people across the globe experience period poverty, our study demonstrates evidence of this phenomenon among Toledo adolescents. Owing to the lack of access to menstrual hygiene products, students report repurposing miscellaneous items in place of pads or tampons, missing school or work, and associating negative connotations with their cycles.

Ocular delivery of Pigment Epithelium-Derived Factor (PEDF) as a neuroprotectant for Geographic Atrophy.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), that starts with atrophic lesions in the outer retina that expand to cover the macula and fovea, leading to severe vision loss over time. Pigment Epithelium-Derived Factor (PEDF) has a diverse-range of properties, including its ability to promote cell survival, reduce inflammation, inhibit angiogenesis, combat oxidative stress, regulate autophagy, and stimulate anti-apoptotic pathways, making it a promising therapeutic candidate for GA. However, the relatively short half-life of PEDF protein has precluded its potential as a clinical therapy for GA since it would require frequent injections. Therefore, we describe administration of a PEDF gene, comparing and contrasting delivery routes, viral and non-viral vectors, and consider the critical challenges for PEDF as a neuroprotectant for GA.

PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models.

Unabated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is linked with the pathogenesis of various inflammatory disorders. Polo-like kinase 1 (PLK1) has been widely studied for its role in mitosis. Here, using both pharmacological and genetic approaches, we demonstrate that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased proximity-dependent biotin identification (Bio-ID) screen for the PLK1 interactome in macrophages, we show an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3 and identified the interacting domains. Mechanistically, we show that PLK1 orchestrated the microtubule-organizing center (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation. Treatment with a selective PLK1 kinase inhibitor suppressed IL-1ß production in in vivo inflammatory models, including LPS-induced endotoxemia and monosodium urate-induced peritonitis in mice. Our results uncover a role of PLK1 in regulating NLRP3 inflammasome activation during interphase and identify pharmacological inhibition of PLK1 as a potential therapeutic strategy for inflammatory diseases with excessive NLRP3 inflammasome activation.

Risk Factors for Pediatric Anxiety Disorders.

This review summarizes risk factors for developing anxiety disorders in children and adolescents. A surfeit of risk factors, including temperament, family environment (eg, parenting style), environmental exposures (eg, particulate matter), and cognitive factors (eg, threat bias), increases the risk of anxiety in children. These risk factors can significantly impact the trajectory of pediatric anxiety disorders. The impact of severe acute respiratory syndrome coronavirus 2 infection on anxiety disorders in children is discussed in addition to its public health implications. Identifying risk factors for pediatric anxiety disorders creates a scaffold for the development of prevention strategies and for reducing anxiety-related disability.

Developmental Epidemiology of Pediatric Anxiety Disorders.

This review summarizes the developmental epidemiology of childhood and adolescent anxiety disorders. It discusses the coronavirus disease of 2019 (COVID-19) pandemic, sex differences, longitudinal course, and stability of anxiety disorders in addition to recurrence and remission. The trajectory of anxiety disorders-whether homotypic (ie, the same anxiety disorder persists over time) or heterotypic (ie, an anxiety disorder shifts to a different diagnosis over time) is discussed with regard to social, generalized, and separation anxiety disorders as well as specific phobia, and panic disorder. Finally, strategies for early recognition, prevention, and treatment of disorders are discussed.

Young Adult Outcomes Associated With Adolescent Suicidality: A Meta-analysis.

CONTEXT: Suicide is one of the leading causes of death among adolescents worldwide. Adolescents who present with suicidality may be at an increased risk for future mental illness and suicidality in young adulthood. OBJECTIVE: The objective of this study was to systematically assess the relationship between adolescent suicidal ideation and suicide attempts (suicidality) and young adult psychopathological outcomes. DATA SOURCES: Medline, Embase, and PsychInfo (OVID Interface) were searched for articles published before August 2021. STUDY SELECTION: Included articles were prospective cohort studies that compared young adult (19-30 years) psychopathological outcomes between suicidal and nonsuicidal adolescents. DATA EXTRACTION: We extracted data related to suicidality in adolescence, mental health outcomes in young adulthood, and covariates. Outcomes were analyzed via random-effect meta-analyses and reported using odds ratios. RESULTS: Of 9401 references screened, we included 12 articles comprising over 25 000 adolescents. Four outcomes were meta-analyzed: depression, anxiety, suicidal ideation, and suicide attempt. Adjusted meta-analyses showed that adolescent suicidal ideation was associated with young adult suicide attempt (odds ratio [OR] = 2.75, 95% confidence interval [CI]:1.70-4.44), depressive disorders (OR = 1.58, 95% CI: 1.20-2.08), and anxiety disorders (OR = 1.41, 95% CI: 1.01-1.96), whereas adolescent suicide attempts were associated with young adult suicide attempt (OR = 5.71, 95% CI: 2.40-13.61), and young adult anxiety disorders (OR = 1.54, 95% CI: 1.01-2.34). Results for young adult substance use disorders were mixed. LIMITATIONS: Significant heterogeneity between studies was observed because of differences in timing, method of assessments, and covariate adjustment. CONCLUSIONS: Adolescents experiencing suicidal ideation or with a history of suicide attempt may have increased odds of further suicidality or mental disorders in young adulthood.

Inverted repeats in the monkeypox virus genome are hot spots for mutation.

The current monkeypox virus (MPXV) strain differs from the strain arising in 2018 by 50+ single nucleotide polymorphisms (SNPs) and is mutating much faster than expected. The cytidine deaminase apolipoprotein B messenger RNA editing enzyme, catalytic subunit B (APOBEC3) was hypothesized to be driving this increased mutation. APOBEC has recently been identified to preferentially mutate cruciform DNA secondary structures formed by inverted repeats (IRs). IRs were recently identified as hot spots for mutation in severe acute respiratory syndrome coronavirus 2, and we aimed to identify whether IRs were also hot spots for mutation within MPXV genomes. We found that MPXV genomes were replete with IR sequences. Of the 50+ SNPs identified in the 2022 outbreak strain, 63.9% of these were found to have arisen within IR regions in the 2018 reference strain (MT903344.1). Notably, IR sequences found in the 2018 reference strain were significantly lost over time, with an average of 32.5% of these sequences being conserved in the 2022 MPXV genomes. This evidence was highly indicative that mutations were arising within IRs. This data provides further support to the hypothesis that APOBEC may be driving MPXV mutation and highlights the necessity for greater surveillance of IRs of MPXV genomes to detect new mutations.

Short-term mating orientation as a predictor of alcohol use and risky sexual behavior.

OBJECTIVES: Sexual Strategies Theory suggests people fall on a continuum between having short-term mating orientation (STMO) and long-term mating orientation. One way STMO individuals signal mating goals is via risky drinking. The current study therefore aims to investigate drinks per week (DPW) as a mediator between STMO and risky sexual behavior (RSB), with gender as a moderator between STMO and DPW. PARTICIPANTS: Undergraduate students (N = 300) from a Midwestern university during Fall 2019. METHOD: Participants completed questionnaires assessing STMO, DPW, and RSB frequency. RESULTS: A moderated-mediation model indicated DPW significantly mediated the relationship between STMO and RSB. Positive associations were found among all three variables. Gender was not a moderator between STMO and DPW. CONCLUSIONS: Mating orientation was a correlate of alcohol use and RSB for women and men, contributing to the literature identifying STMO as an indicator of those in need of substance use and RSB intervention.

Displacement imposition scale assesses reactions of cigarette and e-cigarette users impacted by a campus-wide smoking ban.

OBJECTIVE: The present study developed a measure assessing the emotional responses, "Displacement Imposition," of cigarette and e-cigarette users on a college campus with a smoking/vaping ban. It also examined the relationship between Displacement Imposition and readiness to quit smoking/vaping, and how this relationship differed between cigarette and e-cigarette users. PARTICIPANTS: Participants (N = 297) were from a large, Midwestern university. METHODS: Participants completed online questionnaires assessing demographics, cigarette and e-cigarette use, Displacement Imposition, and readiness to quit. RESULTS: All six Displacement Imposition items loaded onto a single factor. A significant interaction emerged between Displacement Imposition and product use in predicting readiness to quit. At high levels of Displacement Imposition, cigarette users were less ready to quit than e-cigarette users. CONCLUSIONS: Findings suggest restrictions imposed on cigarette and e-cigarette users were associated with reduced readiness to quit. Findings inform tobacco control policies as tobacco denormalization may increase the burden placed on tobacco users.

Intentions to Reduce Alcohol Use Following Brief Alcohol-Related Health Messages Among College Students.

OBJECTIVE: Health care providers using brief alcohol-related health messaging is an effective manner of reducing risky drinking; however, research is needed to guide the content of such messages. The present study compared current drinkers' and nondrinkers' perspectives on the value of four different alcohol-related messages and the hypothetical impact of the messages on intentions to reduce drinking. METHOD: Undergraduates (n = 286 current drinkers, n = 101 nondrinkers) from a large, public, Southern Plains university identified primarily as White (82.9%) and female (70%), with a mean age of 19.98 years. They viewed four video recordings containing different alcohol-related messages in random order and were asked to rate how likely they were to change their drinking behaviors after watching each video. RESULTS: All participants generally had a comparably positive appraisal of all four messages. Among current drinkers, one-way analyses of variance revealed significant differences across messages for intention to change drinking frequency, F(3, 260) = 5.69, p = .001, ηp2 = .06, and quantity, F(3, 263) = 4.95, p = .002, ηp2 = .05. Post hoc tests showed that the condition warning students of severe consequences resulted in higher intentions to reduce drinking compared with other conditions describing less severe consequences, drinking norms, or protective behavioral strategies. No significant differences emerged among nondrinkers. CONCLUSIONS: Despite mixed research regarding the effectiveness of fear-based warning messages in reducing high-risk drinking, the message containing severe alcohol-related consequences evoked the greatest hypothetical intentions to reduce quantity and frequency of drinking. Future studies should track actual drinking behaviors longitudinally following each message.

Chronic health effects associated with electronic cigarette use: A systematic review.

Introduction: Over the last decade, e-cigarette use has been on the rise but with growing health concerns. The objective of this systematic review was to update findings for chronic health outcomes associated with e-cigarette use from the 2018 National Academies of Sciences, Engineering, and Medicine (NASEM) report. Methods: Three bibliographic databases were searched to identify studies comparing the chronic health effects of e-cigarette users (ECU) to non-smokers (NS), smokers, and/or dual users indexed between 31 August 2017 and 29 January 2021. Two independent reviewers screened abstracts and full texts. Data were extracted by one reviewer and verified by a second one. Outcomes were synthesized in a narrative manner using counts and based on statistical significance and direction of the association stratified by study design and exposure type. Risk of bias and certainty of evidence was assessed. The protocol was prospectively registered on Open Science Framework https://osf.io/u9btp. Results: A total of 180 articles were eligible. This review focused on 93 studies for the 11 most frequently reported outcomes and from which 59 reported on daily e-cigarette use. The certainty of evidence for all outcomes was very low because of study design (84% cross-sectional) and exposure type (27% reported on exclusive ECU, i.e., never smoked traditional cigarettes). Overall, the summary of results for nearly all outcomes, including inflammation, immune response, periodontal and peri-implant clinical parameters, lung function, respiratory symptoms, and cardiovascular disease, suggested either non-significant or mixed results when daily ECU was compared to NS. This was also observed when comparing exclusive ECU to NS. The only notable exception was related to oral health where most (11/14) studies reported significantly higher inflammation among daily ECU vs. NS. Compared to the smokers, the exclusive-ECUs had no statistically significant differences in inflammation orperiodontal clinical parameters but had mixed findings for peri-implant clinical parameters. Conclusions: This review provides an update to the 2018 NASEM report on chronic health effects of e-cigarette use. While the number of studies has grown, the certainty of evidence remains very low largely because of cross-sectional designs and lack of reporting on exclusive e-cigarette exposure. There remains a need for higher quality intervention and prospective studies to assess causality, with a focus on exclusive e-cigarette use.

Targeting Microtubules for the Treatment of Heart Disease.

Heart disease remains the leading cause of morbidity and mortality worldwide. With the advancement of modern technology, the role(s) of microtubules in the pathogenesis of heart disease has become increasingly apparent, though currently there are limited treatments targeting microtubule-relevant mechanisms. Here, we review the functions of microtubules in the cardiovascular system and their specific adaptive and pathological phenotypes in cardiac disorders. We further explore the use of microtubule-targeting drugs and highlight promising druggable therapeutic targets for the future treatment of heart diseases.

Self-help behaviors partially mediate the relationship between personalized depression risk disclosure and psychological distress: A mediation analysis using data from a randomized controlled trial.

Major depressive disorder (MDD) is one of the most prevalent forms of mental illness. Multivariate risk predictive (MVRP) algorithms provide a new means of identifying high-risk individuals for mental health disorders. Self-help behaviors may provide accessible methods to mitigate depression risk. The objective of this study is to investigate the mediating effects of self-help behavior on the relationship between depression risk disclosure and psychological distress. A sample (n = 556) of high-risk Canadians for a major depressive episode (MDE) were randomized into risk-disclosure or control groups and followed-up at 6 and 12 months. Mediation analysis using repeated measure mixed effects models was used to investigate the mediating effects of self-help behaviors on the relationship between depression risk disclosure and psychological distress over time. Self-help behavior was found to partially mediate the relationship between risk disclosure and psychological distress at month 12. Both unadjusted and adjusted associations were found to be negative and significant (ßunadj = -0.16 [-0.30, -0.03]) (ßadj = -0.15[-0.29, -0.02]). Self-help plays a partial mediating role in the relationship between depression risk disclosure and psychological distress over time. More research is required in this field to increase knowledge about the role of self-help in mental health treatment.

Analysis of putative quadruplex-forming sequences in fungal genomes: novel antifungal targets?

Fungal infections cause >1 million deaths annually and the emergence of antifungal resistance has prompted the exploration for novel antifungal targets. Quadruplexes are four-stranded nucleic acid secondary structures, which can regulate processes such as transcription, translation, replication and recombination. They are also found in genes linked to virulence in microbes, and ligands that bind to quadruplexes can eliminate drug-resistant pathogens. Using a computational approach, we quantified putative quadruplex-forming sequences (PQS) in 1359 genomes across the fungal kingdom and explored their presence in genes related to virulence, drug resistance and biological processes associated with pathogenicity in Aspergillus fumigatus. Here we present the largest analysis of PQS in fungi and identify significant heterogeneity of these sequences throughout phyla, genera and species. PQS were genetically conserved in Aspergillus spp. and frequently pathogenic species appeared to contain fewer PQS than their lesser/non-pathogenic counterparts. GO-term analysis identified that PQS-containing genes were involved in processes linked with virulence such as zinc ion binding, the biosynthesis of secondary metabolites and regulation of transcription in A. fumigatus. Although the genome frequency of PQS was lower in A. fumigatus, PQS could be found enriched in genes involved in virulence, and genes upregulated during germination and hypoxia. Moreover, PQS were found in genes involved in drug resistance. Quadruplexes could have important roles within fungal biology and virulence, but their roles require further elucidation.

Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles.

Harmful algal blooms (HAB) have become a major health concern worldwide, not just to humans that consume and recreate on contaminated waters, but also to the fauna that inhabit the environments surrounding affected areas. HABs contain heterotrophic bacteria, cyanobacterial lipopolysaccharide, and cyanobacterial toxins such as microcystins, that can cause severe toxicity in many aquatic species as well as bioaccumulation within various organs. Thus, the possibility of trophic transference of this toxin through the food chain has potentially important health implications for other organisms in the related food web. While some species have developed adaptions to attenuate the toxic effects of HAB toxins, there are still numerous species that remain vulnerable, including Lithobates catesbeiana (American bullfrog) tadpoles. In the current study we demonstrate that acute, short-term exposure of tadpoles to HAB toxins containing 1 µg/L (1 nmol/L) of total microcystins for only 7 days results in significant liver and intestinal toxicity within tadpoles. Exposed tadpoles had increased intestinal diameter, decreased intestinal fold heights, and a constant number of intestinal folds, indicating pathological intestinal distension, similar to what is seen in various disease processes, such as toxic megacolon. HAB-toxin-exposed tadpoles also demonstrated hepatocyte hypertrophy with increased hepatocyte binucleation consistent with carcinogenic and oxidative processes within the liver. Both livers and intestines of HAB-toxin-exposed tadpoles demonstrated significant increases in protein carbonylation consistent with oxidative stress and damage. These findings demonstrate that short-term exposure to HAB toxins, including microcystins, can have significant adverse effects in amphibian populations. This acute, short-term toxicity highlights the need to evaluate the influence HAB toxins may have on other vulnerable species within the food web and how those may ultimately also impact human health.

The relationship between depression risk perception and self-help behaviours in high risk Canadians: a cross-sectional study.

BACKGROUND: Self-help may reduce the risk of depression, and risk perception of depression may influence initiating self-help. It is unknown how risk perception is associated with self-help behaviours. The objectives of this study are to (1) describe the self-help strategies used by high-risk Canadians in relation to the accuracy of perceived depression risk, by sex, and (2) identify demographic and clinical factors associated with self-help behaviours. METHODS: Baseline data from a randomized controlled trial including 358 men and 356 women at high-risk of developing depression were used. Following methods used in cancer research, risk perception accuracy was determined by comparing the participant's self-perceived and objective risk of developing depression and classifying as accurate, over-estimation and under-estimation based on a ± 10% threshold. The participant's objective depression risk was assessed using sex-specific multivariable risk predictive algorithms. Frequency of using 14 self-help strategies was assessed. One-way ANOVA testing was used to detect if differences in risk perception accuracy groups existed, stratified by sex. Linear regression was used to investigate the clinical and demographic factors associated with self-help behaviours, also stratified. RESULTS: Compared to accurate-estimators, male over-estimators were less likely to "leave the house daily," and "participate in activities they enjoy." Male under-estimators were also less likely to "participate in activities they enjoy." Both male 'inaccurate' perception groups were more likely to 'create lists of strategies which have worked for feelings of depression in the past and use them'. There were no significant differences between self-help behaviours and risk perception accuracy in women. Regression modeling showed negative relationships between self-rated health and self-help scores, irrespective of sex. In women, self-help score was positively associated with age and educational attainment, and negatively associated with perceived risk. In men, a positive relationship with unemployment was also seen. CONCLUSIONS: Sex differences exist in the factors associated with self-help. Risk perception accuracy, work status, and self-rated health is associated with self-help behaviours in high-risk men. In women, factors related to self-help included age, education, self-rated health status, and perceived risk. More research is needed to replicate findings. TRIAL REGISTRATION: Prospectively registered at ClinicalTrials.gov (NCT02943876) as of 10/21/16.

CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis.

Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn's disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1ß, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis.

Duplex DNA from Sites of Helicase-Polymerase Uncoupling Links Non-B DNA Structure Formation to Replicative Stress.

BACKGROUND: Replication impediments can produce helicase-polymerase uncoupling allowing lagging strand synthesis to continue for as much as 6 kb from the site of the impediment. MATERIALS AND METHODS: We developed a cloning procedure designed to recover fragments from lagging strand near the helicase halt site. RESULTS: A total of 62% of clones from a p53-deficient tumor cell line (PC3) and 33% of the clones from a primary cell line (HPS-19I) were within 5 kb of a G-quadruplex forming sequence. Analyses of a RACK7 gene sequence, that was cloned multiple times from the PC3 line, revealed multiple deletions in region about 1 kb from the cloned region that was present in a non-B conformation. Sequences from the region formed G-quadruplex and i-motif structures under physiological conditions. CONCLUSION: Defects in components of non-B structure suppression systems (e.g. p53 helicase targeting) promote replication-linked damage selectively targeted to sequences prone to G-quadruplex and i-motif formation.

Behavioral pharmacology of the mixed-action delta-selective opioid receptor agonist BBI-11008: studies on acute, inflammatory and neuropathic pain, respiration, and drug self-administration.

RATIONALE AND OBJECTIVES: The present study characterized the behavioral pharmacology of a novel, mixed-action delta-selective (78:1) opioid receptor agonist, BBI-11008. This glycopeptide drug candidate was tested in assays assessing antinociception (acute, inflammatory, and neuropathic pain-like conditions) and side-effect endpoints (respiratory depression and drug self-administration). RESULTS: BBI-11008 had a 78-fold greater affinity for the delta opioid receptor than the mu receptor, and there was no binding to the kappa opioid receptor. BBI-11008 (3.2-100; 10-32 mg kg-1, i.v.) and morphine (1-10; 1-3.2 mg kg-1, i.v.) produced antinociceptive and anti-allodynic effects in assays of acute thermal nociception and complete Freund's adjuvant (CFA)-induced inflammatory pain, with BBI-11008 being less potent than morphine in both assays. BBI-11008 (1-18 mg kg-1, i.v.) had similar efficacy to gabapentin (10-56 mg kg-1, i.v.) in a spinal nerve ligation (SNL) model of neuropathic pain. In the respiration assay, with increasing %CO2 exposure, BBI-11008 produced an initial increase (32 mg kg-1, s.c.) and then decrease (56 mg kg-1, s.c.) in minute volume (MV) whereas morphine (3.2-32 mg kg-1, s.c.) produced dose-dependent decreases in MV. In the drug self-administration procedure, BBI-11008 did not maintain self-administration at any dose tested. CONCLUSIONS: These results suggest that the glycopeptide drug candidate possesses broad-spectrum antinociceptive and anti-allodynic activity across a range of pain-like conditions. Relative to morphine or fentanyl, the profile for BBI-11008 in the respiration and drug self-administration assays suggests that BBI-11008 may have less pronounced deleterious side effects. Continued assessment of this compound is warranted.