Cerebrospinal Fluid Proteome Map Reveals Molecular Signatures of Reversible Cerebral Vasoconstriction Syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex neurovascular disorder characterized by repetitive thunderclap headaches and reversible cerebral vasoconstriction. The pathophysiological mechanism of this mysterious syndrome remains underexplored and there is no clinically available molecular biomarker. To provide insight into the pathogenesis of RCVS, this study reported the first landscape of dysregulated proteome of cerebrospinal fluid (CSF) in patients with RCVS (n = 21) compared to the age- and sex-matched controls (n  = 20) using data-independent acquisition mass spectrometry. Protein-protein interaction and functional enrichment analysis were employed to construct functional protein networks using the RCVS proteome. An RCVS-CSF proteome library resource of 1054 proteins was established, which illuminated large groups of upregulated proteins enriched in the brain and blood-brain barrier (BBB). Personalized RCVS-CSF proteomic profiles from 17 RCVS patients and 20 controls reveal proteomic changes involving the complement system, adhesion molecules, and extracellular matrix, which may contribute to the disruption of BBB and dysregulation of neurovascular units. Moreover, an additional validation cohort validated a panel of biomarker candidates and a two-protein signature predicted by machine learning model to discriminate RCVS patients from controls with an area under the curve of 0.997. This study reveals the first RCVS proteome and a potential pathogenetic mechanism of BBB and neurovascular unit dysfunction. It also nominates potential biomarker candidates that are mechanistically plausible for RCVS, which may offer potential diagnostic and therapeutic opportunities beyond the clinical manifestations.

Effects of Dextromethorphan on Nicotine-Induced Reward, Behavioral Sensitization, Withdrawal Signs, and Drug Seeking-Related Behavior in Rats.

INTRODUCTION: Tobacco products are addictive, with nicotine serving as the major addictive ingredient. Chronic tobacco use or chronic administration of nicotine alone results in both physiological and psychological dependence. Our previous studies indicated that dextromethorphan (DM) could effectively attenuate the dependence of morphine and methamphetamine. Thus, we further investigated the possible effects of DM on nicotine dependence. AIMS AND METHODS: Conditioned place preference (CPP) test was used to examine nicotine-induced rewarding effects as well as the drug-seeking-related behavior in rats. Nicotine dependence was induced by continuous subcutaneous infusion of nicotine via an osmotic minipump for 7 days and abstinence was initiated by removal of the pump. Withdrawal signs were observed and quantified. Locomotor activity was measured to determine the behavioral sensitization induced by nicotine. To investigate the activity of mesolimbic dopaminergic neuronal activity in correlation with the effects of nicotine, the animals were sacrificed and the nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC) were dissected and used to determine the contents of dopamine (DA) and its metabolites using high-performance liquid chromatography (HPLC). RESULTS: Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. CONCLUSIONS: The results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence. IMPLICATIONS: Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. These results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.

Case report: the management for a gestational hypertensive woman with influenza A virus pneumonia and peripartum cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is defined as an idiopathic cardiomyopathy occurring in the last month of pregnancy or the first 6 months postpartum without an identifiable cause. PPCM is suspected to be triggered by the generation of a cardiotoxic fragment of prolactin and the secretion of a potent antiangiogenic protein from the placental, but no single factor has been identified or defined as the underlying cause of the disease. Influenza virus can cause PPCM through immune-mediated response induced by proinflammatory cytokines from host immunity and endothelial cell dysfunction. We report a case in a parturient woman undergoing a cesarean delivery, who had influenza A pneumonia and PPCM. CASE PRESENTATION: A parturient woman at 40 weeks and 1 day of gestation who had experienced gestational hypertension accompanied by pulmonary edema developed hypotension after undergoing an emergency cesarean delivery. An elevation of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was noted, and echocardiography revealed a left ventricular ejection fraction of 20%. She underwent a nasopharyngeal swab test, in which influenza A antigen was positive. She was diagnosed as having PPCM and received anti-viral treatment. After antiviral treatment, hemodynamic dysfunction stabilized. We present and discuss the details of this event. CONCLUSION: PPCM is a heart disease that is often overlooked by medical personnel. Rapid swab tests, serum creatine kinase measurement, and echocardiography are imperative diagnostic approaches for the timely recognition of virus-associated cardiomyopathy in peripartum women with influenza-like disease and worsening dyspnea, especially during the epidemic season. Prompt antiviral treatment should be considered, particularly after PPCM is diagnosed.

Implementing a flipped classroom model in an evidence-based medicine curriculum for pre-clinical medical students: evaluating learning effectiveness through prospective propensity score-matched cohorts.

BACKGROUND: In a flipped classroom (FC) model, blended learning is used to increase student engagement and learning by having students finish their readings at home and work on problem-solving with tutors during class time. Evidence-based medicine (EBM) integrates clinical experience and patient values with the best evidence-based research to inform clinical decisions. To implement a FC and EBM, students require sufficient information acquisition and problem-solving skills. Therefore, a FC is regarded as an excellent teaching model for tutoring EBM skills. However, the effectiveness of a FC for teaching EBM competency has not been rigorously investigated in pre-clinical educational programs. In this study, we used an innovative FC model in a pre-clinical EBM teaching program. METHODS: FC's teaching was compared with a traditional teaching model by using an assessment framework of prospective propensity score matching, which reduced the potential difference in basic characteristics between the two groups of students on 1:1 ratio. For the outcome assessments of EBM competency, we used an analysis of covariance and multivariate linear regression analysis to investigate comparative effectiveness between the two teaching models. A total of 90 students were prospectively enrolled and assigned to the experimental or control group using 1:1 propensity matching. RESULTS: Compared with traditional teaching methods, the FC model was associated with better learning outcomes for the EBM competency categories of Ask, Acquire, Appraise, and Apply for both written and oral tests at the end of the course (all p-values< 0.001). In particular, the "appraise" skill for the written test (6.87 ± 2.20) vs. (1.47 ± 1.74), p < 0.001), and the "apply" skill for the oral test (7.34 ± 0.80 vs. 3.97 ± 1.24, p < 0.001) had the biggest difference between the two groups. CONCLUSIONS: After adjusting for a number of potential confunding factors, our study findings support the effectiveness of applying an FC teaching model to cultivate medical students' EBM literacy.

Sex Difference of Angiotensin IV-, LVV-Hemorphin 7-, and Oxytocin-Induced Antiallodynia at the Spinal Level in Mice With Neuropathic Pain.

BACKGROUND: We demonstrated previously that angiotensin IV (Ang IV) and LVV-hemorphin 7 (LVV-H7) act through the blockade of insulin-regulated aminopeptidase to decrease oxytocin degradation, thereby causing antihyperalgesia at the spinal level in rats. We determined that intrathecal oxytocin can induce significant antihyperalgesia in male rats with inflammation but not in female rats. Thus, we speculate that Ang IV, LVV-H7, and oxytocin can induce antiallodynia, which could be of great therapeutic potential. Because the antihyperalgesia by using these peptides was with sex difference, their possible antiallodynia was examined in male and female mice for comparison. We investigated whether Ang IV, LVV-H7, and oxytocin produce antiallodynia at the spinal level in mice and whether this antiallodynia differs between the sexes. METHODS: Partial sciatic nerve ligation surgery was performed on adult male and female C57BL/6 mice from the same litter (25-30 g). The effects of intrathecal injections of Ang IV (25.8 nmol), LVV-H7 (27.2 nmol), and oxytocin (0.125 or 1.25 nmol) were assessed through the von Frey test 3 days after partial sciatic nerve ligation. RESULTS: Intrathecal injection of Ang IV, LVV-H7, and oxytocin all produced a potent antiallodynia in male mice. However, these antiallodynia effects were either extremely weak or absent in female mice at the same dose. CONCLUSIONS: Intrathecal Ang IV, LVV-H7, and oxytocin can all cause significant antiallodynia in male mice. The Ang IV-, LVV-H7-, and oxytocin-induced antiallodynia effects differed between the sexes at the spinal level in mice.

Effect of early removal of urinary catheter on recovery after vaginal surgery: A systematic review and meta-analysis.

Prolonged retention of urinary catheters (UC) after vaginal surgery is a common practice aimed at preventing postoperative urinary retention and enhancing the success rate of surgery. However, this approach also increases the chance of urinary tract infection (UTI), prolongs hospital stay (LOS), and delays recovery. Balancing these considerations, we investigated the effect of the timing of UC removal. We conducted a comprehensive literature search using four databases to identify all randomized controlled trials (RCTs) involving patients who underwent transvaginal surgery and had UC removal within 7 days postsurgery. This systematic review was conducted by two reviewers independently following the PRISMA guideline. This study investigated the timing of catheter removal in relation to the incidence of urinary retention, UTI, and LOS. A total of 8 RCT studies, involving 952 patients were included in the meta-analysis. Six studies revealed no significant difference in the urinary retention rate between early catheter removal group (24 h) and delayed removal group (>48 h, P = 0.21), but exhibited a significantly reduced UTI rate (P < 0.001) in 4 studies. In 2 studies, no significant difference in urinary retention rate between the earlier removal (3 h) and removal at 24 h (P = 0.09), and also UTI rate (P = 0.57). Overall, 5 studies revealed that early catheter removal significantly shortened the LOS by an average of 1-3 days (P ≤ 0.001). Early removal of UC can considerably reduce the rate of UTI and shorten the LOS. Moreover, it has potential benefits in terms of improving the quality of patient care and reducing medical costs.

Yangonin, one of the kavalactones isolated from Piper methysticum G. Forst, acts through cannabinoid 1 (CB1) receptors to induce an intrathecal anti-hyperalgesia.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper methysticum G. Forst (Piperaceae) is traditionally consumed in Polynesian culture. The roots are used to produce an entheogenic drink and traditional medicine with sedative and anxiolytic properties. There is also evidence that it functions as a pain reliever. Kavalactones, its main active ingredients, exhibit psychoactive effects on the central nervous system. However, the active ingredients and pharmacological mechanisms underlying the analgesic effect of kavalactones are unclear. AIM OF THE STUDY: This study investigated the effects of kavain and yangonin on nociception, inflammatory hyperalgesia, and neuropathic mechanical allodynia at the spinal level. MATERIALS AND METHODS: Male Sprague-Dawley rats were administered kavain and yangonin (27.14 and 19.36 nmol/rat) via intrathecal injection. Tail-flick tests were performed to evaluate the anti-nociceptive properties. The efficacy of kavain and yangonin on inflammatory hyperalgesia was examined using a plantar test in rats with carrageenan-induced paw inflammation. The von Frey test was used to assess mechanical allodynia induced by partial sciatic nerve ligation. RESULTS: Intrathecal injection of yangonin demonstrated a relatively potent anti-nociceptive effect and attenuated carrageenan-induced hyperalgesia. These effects were completely reversed by the co-administration of PF 514273, a cannabinoid 1 (CB1) receptor antagonist. However, yangonin did not affect mechanical allodynia at the spinal level. Kavain, another abundant kavalactone, did not affect nociception, hyperalgesia, or mechanical allodynia at the spinal level. CONCLUSIONS: Overall, our study demonstrated that yangonin exerts anti-nociception and anti-inflammatory hyperalgesia effects via CB1 receptors at the spinal level. We identified a single kavalactone, yangonin, extracted from kava as a promising treatment for pain.

Intrathecal injections of angiotensin IV and oxytocin conjugates induce antihyperalgesia and antiallodynia in both sexes of rats.

Our previous studies have established that intrathecal oxytocin (OT) and angiotensin IV (Ang IV) injections induce antihyperalgesia and antiallodynia in rodents. Ang IV, a renin-angiotensin system hexapeptide, acts as an endogenous inhibitor that inhibits the oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP). The pain inhibitory effects by Ang IV were found to be through its inhibition on IRAP to potentiate the effect of OT. However, these effects were found to be with a significant sex difference, which could be partially due to the higher expression of IRAP at the spinal cords of female. Therefore, we synthesized Ang IV and OT conjugates connected with a peptide bond and tested for their effects on hyperalgesia and allodynia. Carrageenan-induced hyperalgesia and partial sciatic nerve ligation (PSNL) were performed using rat models. Conjugates Ang IV-OT (Ang IV at the N-terminal) and OT-Ang IV (OT at the N-terminal) were synthesized and intrathecally injected into male and female rats. Our results showed that Ang IV-OT exhibited prominent antihyperalgesia in male rats, particularly during hyperalgesia recovery, whereas OT-Ang IV was more effective during development stage. Ang IV-OT showed clear antihyperalgesia in female rats, but OT-Ang IV had no significant effect. Notably, both conjugates alleviated neuropathic allodynia in male rats; however, OT-Ang IV had no effect in female rats, whereas Ang IV-OT induced significant antiallodynia. In conclusion, Ang IV-OT has greater therapeutic potential for treating hyperalgesia and allodynia than OT-Ang IV. Its effects were not affected by sex, unlike those of OT and OT-Ang IV, extending its possible clinical applications.

Decreasing the incidence of central line-associated bloodstream infection in a medical intensive care unit: a best practice implementation project.

INTRODUCTION AND OBJECTIVES: Bloodstream infections are common in critically ill patients using central venous access devices (CVAD) in intensive care units (ICU). This project aimed to decrease the incidence of central line-associated bloodstream infections (CLABSI) by using evidence-based strategies. METHODS: The project applied the JBI audit and feedback methods. Thirty-two nurses and five resident physicians from the medical ICU of a medical center participated in the project. Preintervention compliance was measured for the 11 key evidence-based criteria (six audit criteria of central venous catheter insertion and five audit criteria of dressing and catheter securement). Strategies were implemented to overcome the barriers identified in the baseline assessment. Impact evaluation and sustainability were conducted to change the CLABSI rate and the competence of healthcare professionals in providing CVAD care. The JBI Practical Application of Clinical Evidence System and Getting Research into Practice audit tools were used for the data collection, analysis, and implementation planning. RESULTS: Barriers included insufficient knowledge among nurses and physicians, poor compliance with the standard CVAD insertion procedure by physicians, inadequate cooperation among the CVAD care team members, and lack of CVAD-related equipment. The strategies included education and training in CVAD care, the establishment of a team resource management program, and the provision of appropriate equipment. Following project implementation, the CLABSI rate decreased from 8.38 to 3.9 BSIs/1000 CVAD-days. CONCLUSIONS: The project successfully decreased the CLABSI rate and increased the competence of healthcare professionals. Implementation of best practices in clinical care should focus on leadership, team resource management, education, monitoring, and innovation.

Estrogen can abolish oxytocin-induced spinal anti-hyperalgesia.

Our previous study verified a sex difference of anti-hyperalgesia in rats and anti-allodynia in mice induced by intrathecal oxytocin (OT). In the model of intraplantar carrageenan-induced inflammatory hyperalgesia, intrathecal OT injection induced a substantial anti-hyperalgesia in male rats even at a low dose (0.125 nmol). In contrast, female rats only responded to an extremely high dose (1.25 nmol). This sex difference concurs with a lower expression of OT receptors and higher expression of insulin-regulated aminopeptidase (IRAP; OT degrading enzyme) in the spinal cords of female rats. In this study, we further determined the role of female hormones in this sex difference by using ovariectomized rats. Our results show that a low dose of intrathecal OT caused a significant anti-hyperalgesia effect in ovariectomized female rats, similar to that seen in male rats. Ovariectomy did not cause any change of paw edema except at the late stage of convalescence when compared with the sham-operated group. Ovariectomy-induced faster recovery from edema but did not affect the severity of hyperalgesia. Moreover, there was a similar amount of IRAP expression in ovariectomized and sham rats. When estradiol (E2) was given together with OT, OT-induced anti-hyperalgesia was abolished at the developmental stage of hyperalgesia in ovariectomized rats. These results show an inhibitory role of female hormones generated from ovaries (mainly estrogen) in the sex difference of anti-hyperalgesia induced by OT. This study suggests the feasibility of a novel OT-based remedy to treat hyperalgesia in men and in menopausal women no receiving hormonal supplements.

Effects of Exercise Programs in older adults with Muscle Wasting: A Systematic Review and Meta-analysis: Effects of Exercise Programs in Muscle Wasting.

OBJECTIVES: To conduct a comprehensive evidence synthesis to verify the available literature on the effects of exercise intervention on muscle mass, muscle strength, and physical function in older adults with muscle wasting. METHODS: Systematic literature searches of the PubMed/Medline, CINAHL, EMBASE, Cochrane Library, and Airiti Library databases were performed for exercise-related randomized controlled trials among adults aged 60 years and above with muscle wasting disease, published from 2010 to April 30, 2021. The search included the keywords and synonyms: "older," "sarcopenia," "cachexia," "muscle wasting," "exercise'. RESULTS: The systematic review included 34 studies: 25 on patients with sarcopenia and 9 on patients with cachexia. Sarcopenia and cachexia were analyzed as separate subgroups. The effects of exercise in the sarcopenia group showed significant improvement in the following parameters: body composition (appendicular skeletal muscle [ASM] [standardized mean difference, SMD 0.38, P = 0.05] and ASM/height2 [SMD 0.14, P = 0.02]), muscle strength (grip strength [SMD 1.73, P < 0.0001]), and physical performance (gait speed [SMD 0.14, P < 0.00001] and the timed up and go test [SMD -1.20, P < 0.00001]). Similarly, in the cachexia group, exercise intervention showed improvement in the body composition (ASM [SMD 3.38, P = 0.001]) and physical performance (400 m walk [SMD -36.00, P = 0.02]). CONCLUSIONS: Exercise intervention has significant benefits in older adults with muscle wasting diseases. More well-designed large-sample-sized studies with long-term follow-ups are warranted to verify the benefits of exercise intervention in this population.

Effectiveness of Music-Based Intervention in Improving Uncomfortable Symptoms in ICU Patients: An Umbrella Review.

BACKGROUND: Intensive care unit (ICU) patients experience multiple uncomfortable symptoms, which may be alleviated using music-based intervention, a nondrug treatment. This umbrella review aims to combine the data of systematic reviews and/or meta-analyses to evaluate the effectiveness of music-based intervention in improving uncomfortable symptoms in ICU patients. METHODS: A comprehensive literature search was performed on the PubMed, Embase, Cochrane Library, Airiti Library, CINAHL, ProQuest, and Web of Science databases, and Epistemonikos. The search had no language restrictions, and articles on the improvement of symptoms using music-based intervention in adult ICU patients were included. This review protocol was registered on PROSPERO (CRD42021240327). RESULTS: This umbrella review retrieved 5 systematic reviews and 41 original studies, including 39 randomized controlled trials, and 2 nonrandomized controlled trials. Diverse music was the most common music type used for music-based intervention, the intervention music was typically decided by the study participants (61%), and most subjects underwent one intervention session (78%). Furthermore, most music intervention sessions lasted for 30 min (44%). The positive results included decreased anxiety, decreased pain, decreased agitation, decreased anesthesia dose and sedative use, decreased chances of delirium, decreased feelings of uncomfort, and improved sleep quality. CONCLUSIONS: A systematic review on the effectiveness of music-based intervention in improving uncomfortable symptoms in ICU patients revealed that 20-30 min intervention sessions showed the best improvement in the uncomfortable symptoms in patients. This study provides a basis for using music-based intervention to relieve the uncomfortable symptoms in critically ill ICU patients, and a reference for empirical clinical practice.

Salivary cortisol is associated with cognitive changes in patients with fibromyalgia.

Fibromyalgia (FM) is a stress-related chronic pain disorder with common cognitive complaints. This study characterized cognitive dysfunction in patients with FM and explored whether these changes are linked to altered cortisol levels. Consecutive 44 patients with FM and 48 healthy controls were enrolled for the assessments of subjective and objective cognitive functions and diurnal levels of salivary cortisol (sampled at awakening, 30 min after awakening, 3 pm, and bedtime). All measurements were compared between the groups and evaluated for clinical correlation. The FM group had more subjective cognitive complaints and performed poorer in objective cognitive testing in memory (delayed recall in Chinese Version Verbal Learning Test and Taylor Complex Figure Test), language (Boston Naming Test), and executive domains (Wisconsin Card Sorting Test) after adjustments for education. The diurnal cortisol levels of patients with FM tended to be lower, especially at 30 min after awakening and bedtime. Moreover, moderate positive correlations existed between the Chinese Version Verbal Learning Test, Boston Naming Test and the morning cortisol levels within the FM group. We suggested the altered cognitive function in FM may be linked to stress maladaptation. Future studies are warranted to elucidate whether stress management improves cognitive performance in patients with FM.

LVV-hemorphin-7 (LVV-H7) plays a role in antinociception in a rat model of alcohol-induced pain disorders.

Alcohol can increase the sensitivity to painful stimulation or convert insensibility to pain at different stages. We hypothesized that chronic alcohol consumption changes the level of LVV-hemorphin-7 (abbreviated as LVV-H7, an opioid-like peptide generated from hemoglobin ß-chain), thereby affecting pain sensation. We established a chronic alcohol-exposed rat model to investigate the effects of LVV-H7. Adult male Sprague-Dawley rats were subjected to daily intraperitoneal injection of 10 % ethanol (w/v) at 0.5 g/kg for 15 days and subsequent alcohol withdrawal for 5 days. Using different pharmacological strategies to affect the LVV-H7 level, we investigated the correlation between LVV-H7 and pain-related behavior. Tail-flick and hot plate tests were employed to investigate alcohol-induced pain-related behavioral changes. The serum level of LVV-H7 was determined by ELISA. Our results showed that alcohol first induced an analgesia followed by a hyperalgesia during alcohol withdrawal, which could be driven by the quantitative change of LVV-H7. A positive correlation between the level of LVV-H7 and Δtail-flick latency (measured latency minus basal latency) confirmed this finding. Moreover, we revealed that the LVV-H7 levels were determined by the activity of cathepsin D and red blood cell/hemoglobin counts, which could be affected by alcohol. These results suggest that the deterioration of anti-nociception induced by alcohol is correlated to the decreased level of LVV-H7, and this could be due to alcohol-induced anemia. This study may help to develop LVV-H7 structure-based novel analgesics for treating alcohol-induced pain disorders and thus ameliorate the complications in alcoholics.

Patients with alcohol use disorder increase pain and analgesics use: A nationwide population-based cohort study.

BACKGROUND: Alcohol has dual effects on many systems, including the pain system. We will test whether and how chronic alcohol consumption enhances pain sensation to develop pain disorder. METHODS: We conducted a retrospective matched cohort study using data from the National Health Insurance Research Database (NHIRD) in Taiwan, in patients with and without alcohol use disorder (AUD). This study enrolled 19,174 individuals with AUD as study cohort and 19,174 propensity score-matched individuals without AUD as comparison cohort. The outcome was the incidence of pain disorders and the need for analgesics. The hazard ratios of pain disorders and the need for analgesics were evaluated using Cox proportional hazard regression analysis after adjusting for age, sex, index year, comorbidities, urbanization, areas of residence, and insurance premium. RESULTS: The 14 years of follow-up showed that AUD patients had a higher adjusted hazard ratio (aHR) for developing pain disorders than in non-AUD controls [aHR= 1.290, 95% confidence interval (CI): 1.045-1.591]. Besides, AUD patients had a higher risk of analgesic use (aHR = 1.081, 95% CI: 1.064-1.312), including opioids and non-opioid analgesics. Most importantly, AUD patients required more days of analgesic use, increased dose of analgesics, and higher costs of analgesics. Moreover, AUD patients had more anemia (aHR=2.772, 95% CI: 2.581-2.872), which could be a mediating factor. CONCLUSIONS: AUD patients had higher risks of developing pain disorders and subsequently increased analgesic demand. These results suggest that AUD worsened pain, and pain syndrome is correlated with the duration of chronic alcohol exposure.

Gene knockdown of the N-methyl-D-aspartate receptor NR1 subunit with subcutaneous small interfering RNA reduces inflammation-induced nociception in rats.

BACKGROUND: Spinal N-methyl-D-aspartate receptors have been demonstrated to play an important role in the facilitation and maintenance of nociception. To avoid adverse effects of blocking N-methyl-D-aspartate receptors in the central nervous system, blocking N-methyl-D-aspartate receptor in peripheral nervous system is an ideal alternative. Transfection of small interfering RNAs (siRNAs) into cells has been revealed to provide potent silencing of specific genes. In this study, the authors examined the effect of subcutaneous injection of siRNA targeting the NR1 subunit of the N-methyl-D-aspartate receptor on silencing NR1 gene expression and subsequently abolishing inflammatory nociception in rats. METHODS: Male Sprague-Dawley rats received intradermal injection of NR1 siRNA and underwent injection of formalin or complete Freund's adjuvant. The flinch response and mechanical hypersensitivity by von Frey filaments were assessed. Then the messenger RNA and protein of NR1 in skin and dorsal root ganglion were analyzed. RESULTS: The results revealed that subcutaneous injection of 1 nmol NR1 siRNA effectively diminished the nociception induced by formalin and complete Freund's adjuvant stimuli and attenuated the level of NR1 messenger RNA and protein in skin and ipsilateral dorsal root ganglion. The antinociception effect and the inhibition of NR1 expression persisted for about 7 days after administration of NR1 siRNA. CONCLUSIONS: The data of this study suggest that NR1 siRNA has potential therapeutic value in the treatment of inflammatory pain induced or maintained by peripheral nociceptor activity and support the potential application of this method to the study of nociceptive processes and target the validation of pain-associated genes.

Chronic administration of nandrolone increases susceptibility to morphine dependence without correlation with LVV-hemorphin 7 in rats.

LVV-hemorphin 7 (LVVYPWTQRF; LVV-H7), an N-terminal fragment of the ß-chain of hemoglobin cleaved by cathepsin D/pepsin, is an atypical endogenous opioid peptide that is found in high concentration in blood. LVV-H7 acts as a µ-opioid agonist and an inhibitor of insulin-regulated aminopeptidase. Subchronic administration of anabolic androgenic steroids (AAS) has been clinically proven to induce the synthesis of erythrocytes and increase hemoglobin concentrations. Patients with a history of AAS abuse are more susceptible to opioid abuse. We hypothesized that this association could be at least partially attributed to the sensitization of the mesocorticolimbic dopaminergic pathway by LVV-H7. Using the conditioned place preference test and neurochemical analysis, we investigated the possible mechanism underlying the effect of chronic nandrolone administration on morphine-induced reward and its correlation with LVV-H7 in rats. Either LVV-H7 may not sensitize the rewarding neural circuits or its inhibition on locomotor activity could mask reward-related behaviors. Chronic nandrolone pretreatment indeed caused a significant reward by low dose morphine, which did not cause any reward in control rats. However, coadministration of anti-LVV-H7 antiserum with nandrolone did not block this effect. This may rule out the possibility of the involvement of LVV-H7 in the action of nandrolone to intensify morphine-induced reward. Moreover, the serum level of LVV-H7 was mildly increased in response to chronic nandrolone administration in our animal model. According to the current clinical observations, we may conclude that the chronic administration of nandrolone can increase susceptibility to morphine dependence, but that this effect is not related to elevated LVV-H7.

Sex Difference in Oxytocin-Induced Anti-Hyperalgesia at the Spinal Level in Rats with Intraplantar Carrageenan-Induced Inflammation.

Previously, we demonstrated intrathecal administration of oxytocin strongly induced anti-hyperalgesia in male rats. By using an oxytocin-receptor antagonist (atosiban), the descending oxytocinergic pathway was found to regulate inflammatory hyperalgesia in our previous study using male rats. The activity of this neural pathway is elevated during hyperalgesia, but whether this effect differs in a sex-dependent manner remains unknown. We conducted plantar tests on adult male and female virgin rats in which paw inflammation was induced using carrageenan. Exogenous (i.t.) application of oxytocin exerted no anti-hyperalgesic effect in female rats, except at an extremely high dose. Female rats exhibited similar extent of hyperalgesia to male rats did when the animals received the same dose of carrageenan. When atosiban was administered alone, the severity of hyperalgesia was not increased in female rats. Moreover, insulin-regulated aminopeptidase (IRAP) was expressed at higher levels in the spinal cords of female rats compared with those of male rats. Oxytocin-induced anti-hyperalgesia exhibits a sex-dependent difference in rats. This difference can partially result from the higher expression of IRAP in the spinal cords of female rats, because IRAP functions as an enzyme that degrades oxytocin. Our study confirms the existence of a sex difference in oxytocin-induced anti-hyperalgesia at the spinal level in rats.

Dextromethorphan differentially affects opioid antinociception in rats.

Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved. The antinociceptive effects of the mu-opioid receptor agonists morphine (5 mg kg(-1), s.c.), meperidine (25 mg kg(-1), s.c.) and codeine (25 mg kg(-1), s.c.), and the kappa-opioid agonists nalbuphine (8 mg kg(-1), s.c.) and U-50,488H (20 mg kg(-1), s.c.) were studied using the tail-flick test in male Sprague-Dawley rats. Coadministration of DM (20 mg kg(-1), i.p.) with these opioids was also performed and investigated. The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC.It was found that DM potentiated the antinociceptive effects of some mu-opioid agonists but not codeine or kappa-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine). The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids.

Effects of morphine and endomorphins on the polysynaptic reflex in the isolated rat spinal cord.

At the spinal level, mu-opioids exert their actions on nociceptive primary afferent neurons both pre- and postsynaptically. In the present study, we used an in vitro isolated neonatal rat (11-15 days old) spinal cord preparation to examine the effects of morphine and the endogenous mu-opioid ligands endomorphin-1 (EM-1) and endomorphin-2 (EM-2) on the polysynaptic reflex (PSR) of dorsal root-ventral root (DR-VR) reflex. The actions of mu-opioids on spinal nociception were investigated by quantification of the firing frequency and the mean amplitude of the PSR evoked by stimuli with 20 x threshold intensity. EM-1 decreased the mean amplitude of PSR, whereas EM-2 and morphine decreased the firing frequency. The pattern of the effects elicited by morphine was the same as that for EM-2, except at high concentration. Naloxonazine, a selective mu(1) opioid receptor antagonist, had no significant effect on PSR by itself, but blocked the inhibition of PSR firing frequency or amplitude induced by EM-1, -2 and morphine. This may suggest that EM-1, EM-2 and morphine modulate spinal nociception differently and act mainly at the mu(1)-opioid receptors. Although they all act via mu(1)-opioid receptors, their different effects on the PSR may suggest the existence of different subtypes of the mu(1)-opioid receptor. The present data is also consistent with a further hypothesis, namely, that morphine and EM-2 activate a subtype of mu(1)-opioid receptor presynaptically, while EM-1 acts mainly through another subtype postsynaptically. However, since other reports indicate that EM-2, but not EM-1, could stimulate the release of enkephalins or dynorphin, presynaptic delta and kappa receptors may be also involved indirectly in the different regulation by mu-opioids at the spinal level.