Modeling Rett Syndrome Using TALEN-Edited MECP2 Mutant Cynomolgus Monkeys.

Gene-editing technologies have made it feasible to create nonhuman primate models for human genetic disorders. Here, we report detailed genotypes and phenotypes of TALEN-edited MECP2 mutant cynomolgus monkeys serving as a model for a neurodevelopmental disorder, Rett syndrome (RTT), which is caused by loss-of-function mutations in the human MECP2 gene. Male mutant monkeys were embryonic lethal, reiterating that RTT is a disease of females. Through a battery of behavioral analyses, including primate-unique eye-tracking tests, in combination with brain imaging via MRI, we found a series of physiological, behavioral, and structural abnormalities resembling clinical manifestations of RTT. Moreover, blood transcriptome profiling revealed that mutant monkeys resembled RTT patients in immune gene dysregulation. Taken together, the stark similarity in phenotype and/or endophenotype between monkeys and patients suggested that gene-edited RTT founder monkeys would be of value for disease mechanistic studies as well as development of potential therapeutic interventions for RTT.

Frontopolar tDCS Induces Frequency-Dependent Changes of Spontaneous Low-Frequency Fluctuations: A Resting-State fMRI Study.

Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique that can modulate cortical excitability and behavioral performance. However, its effects on spontaneous low-frequency fluctuations of brain activity are still poorly understood. Here, we systematically investigated the frontopolar tDCS effects on resting-state brain activity and connectivity. Twelve healthy participants were recruited and received anode, cathode, and sham stimulation in a randomized order. Resting-state functional magnetic resonance imaging was performed before and after stimulation. Functional connectivity was calculated to examine tDCS effects within and beyond the frontopolar network. To assess the frequency-dependent changes of brain activity, fractional amplitude of low-frequency fluctuations (fALFF) was computed in the slow-4 (0.027-0.073 Hz) and slow-5 (0.01-0.027 Hz) bands. The results showed anodal tDCS-induced widespread connectivity reduction within and beyond the frontopolar network. Regardless of tDCS polarity, stimulation effect on fALFF was significantly larger in slow-5 band compared with the slow-4. Notably, anodal tDCS-induced connectivity changes were associated with pre-tDCS fALFF in slow-4 band, showing positive correlations in the frontal regions and negative correlations in the temporal regions. Our findings imply that tDCS-induced brain alterations may be frequency-dependent, and pre-tDCS regional brain activity could be used to predict post-tDCS connectivity changes.

TMEM100 Regulates Neuropathic Pain by Reducing the Expression of Inflammatory Factors.

There is no effective treatment for peripheral nerve injury-induced chronic neuropathic pain (NP), which profoundly impacts the quality of life of those affected. Transmembraneprotein100 (TMEM100) is considered to be a pain regulatory protein and is expressed in the dorsal root ganglion (DRG) of rats. However, the mechanism of pain regulation and the expression of TMEM100 following various peripheral nerve injuries are unclear. In this study, we constructed two pain models of peripheral nerve injury: tibial nerve injury (TNI) and chronic constriction injury (CCI). This study found that the Paw Withdrawal Mechanical Threshold (PWMT) and Paw Withdraw Thermal Latency (PWTL) of the rats in the two pain models decreased significantly, and the expression of TMEM100 in the DRG of two groups also decreased significantly. Furthermore, the decrease in the CCI group was more obvious than in the TNI group. There was no significant statistical significance (P > 0.05). We constructed an adeno-associated virus 6 (AAV6) vector expressing recombinant fluorescent TMEM100 protein and injected it into the sciatic nerve (SN) of two pain models: CCI and TNI. PWMT and PWTL were significantly increased in the two groups, along with the expression of TMEM100 in the spinal cord and DRG. It also significantly inhibited the activation of microglia, astrocytes, and several inflammatory mediators (TNF- α, IL-1 ß, and IL-6). In summary, the results of this study suggested that TMEM100 might be a promising molecular strategy for the treatment of NP, and its anti-inflammatory effects might play an important role in pain relief.

Age-related changes in local and global visual perception.

Over the past 40 years, research has addressed the impact of the aging process on various aspects of visual function. Most studies have focused on age-related visual impairment in low-level local features of visual objects, such as orientation, contrast sensitivity and spatial frequency. However, whether there are lifespan changes in global visual perception is still unclear. To suitably frame this question, we defined global visual patterns by a topological approach, and local visual patterns were manipulated with different levels of geometrical invariants in descending order of structural stability from projective, affine, and then Euclidean features. Using the Configural Superiority Effect, we investigated the influence of aging on local and global visual perception through a comparison of young and old adults in Experiment 1; moreover, we provided continuous-aging data from 21 to 78 years of age to investigate age-related changes in visual perception in Experiment 2. We found a large perceptual decline across increasing age groups in local geometrical perception: for example, Euclidean (orientation), affine (parallelism), and projective (collinearity) discrimination. Moreover, the study provides a counterintuitive finding that global topological perception resists the aging process and remains constant throughout adult lifespan. These findings highlight the possibility that for humans, global topology may be a stable and fundamental component by which visual systems represent and characterize objects.

Parcellation of Macaque Cortex with Anatomical Connectivity Profiles.

The macaque model has been widely used to investigate the brain mechanisms of specific cognitive functions and psychiatric disorders. However, a detailed functional architecture map of the macaque cortex in vivo is still lacking. Here, we aimed to construct a new macaque cortex atlas based on its anatomical connectivity profiles using in vivo diffusion MRI. First, we defined the macaque cortical seed areas using the NeuroMaps atlas. Then, we applied the anatomical connectivity patterns-based parcellation approach to parcellate the macaque cortex into 80 subareas in each hemisphere, which were approximately symmetric between the two hemispheres. In each hemisphere, we identified 14 subareas in the frontal cortex, 9 subareas in the somatosensory cortex, 13 subareas in the parietal cortex, 16 subareas in the temporal cortex, 16 subareas in the occipital cortex, and 12 subareas in the limbic system. Finally, the graph-based network analyses of the anatomical network based on newly constructed macaque cortex atlas identified seven hub areas including bilateral ventral premotor cortex, bilateral superior parietal lobule, right medial precentral gyrus, and right precuneus. This newly constructed macaque cortex atlas may facilitate studies of the structure and functions of the macaque brain in the future.

[Superior colliculus-pulvinar-amygdala subcortical visual pathway and its biological significance].

Superior colliculus-pulvinar-amygdala pathway is one of the subcortical visual pathways in mammalian brain. Some recent studies suggest that this pathway is involved in processing emotion-related visual information. This review discusses the possibility that this pathway is more related to visual alert rather than simply the early visual information processing. The biological significance of this pathway is also discussed. Instead of detecting "where" or "what" the visual target is, the task of this early visual stage is to send out a warning signal, i.e., "something appears", so that the brain can be set up in a state of alert, which is important for the survival of animals. Thus, in the early visual information process, detection of new object "emerging" or "disappearing" takes priority over the acquisition of its feature information of "texture" and "shape", etc. The subcortical pathway may provide the neural basis of early visual warning in topological perception, a biological significance critical for animal survival.

Morphine-induced conditioned place preference in rhesus monkeys: Resistance to inactivation of insula and extinction.

Drug addicts experience strong craving episodes in response to drug-associated cues. Attenuating these responses using pharmacological or behavioral approaches could aid recovery from addiction. Cue-induced drug seeking can be modeled using the conditioned place preference procedure (CPP). Our previous work showed that conditioned place preference (CPP) can be induced by administration of increasing doses of morphine in rhesus monkeys. Here, we investigated whether expression of morphine-induced CPP can be attenuated by inhibiting activity of insular cortex or by repeated unreinforced exposures to the CPP test. The insula has been demonstrated to be involved in addiction to several drugs of abuse. To test its role in morphine CPP, bilateral cannulae were implanted into the insula in seven adult monkeys. The CPP was established using a biased apparatus by intramuscular injections of morphine at increasing doses (1.5, 3.0 and 4.5mg/kg) for each monkey. After the monkeys established morphine CPP, their insulae were reversibly inactivated by bilateral microinjection with 5% lidocaine (40µl) prior to the post-conditioning test (expression) of CPP using a within-subject design. The microinjections of lidocaine failed to affect CPP expression when compared to saline injections. We subsequently investigated morphine-associated memory during six episodes of CPP tests performed in these monkeys over the following 75.0±0.2months. While the preference score showed a declining trend with repeated testing, morphine-induced CPP was maintained even on the last test performed at 75months post-conditioning. This observation indicated strong resistance of morphine-induced memories to extinction in rhesus monkeys. Although these data do not confirm involvement of insula in morphine-induced CPP, our observation that drug-associated memories can be maintained over six drug-free years following initial experience with morphine has important implications for treatment of drug addiction using extinction therapy.

Rhesus monkey brain development during late infancy and the effect of phencyclidine: a longitudinal MRI and DTI study.

Early brain development is a complex and rapid process, the disturbance of which may cause the onset of brain disorders. Based on longitudinal imaging data acquired from 6 to 16 months postnatal, we describe a systematic trajectory of monkey brain development during late infancy, and demonstrate the influence of phencyclidine (PCP) on this trajectory. Although the general developmental trajectory of the monkey brain was close to that of the human brain, the development in monkeys was faster and regionally specific. Gray matter volume began to decrease during late infancy in monkeys, much earlier than in humans in whom it occurs in adolescence. Additionally, the decrease of gray matter volume in higher-order association regions (the frontal, parietal and temporal lobes) occurred later than in regions for primary functions (the occipital lobe and cerebellum). White matter volume displayed an increasing trend in most brain regions, but not in the occipital lobe, which had a stable volume. In addition, based on diffusion tensor imaging, we found an increase in fractional anisotropy and a decrease in diffusivity, which may be associated with myelination and axonal changes in white matter tracts. Meanwhile, we tested the influence of 14-day PCP treatment on the developmental trajectories. Such treatment tended to accelerated brain maturation during late infancy, although not statistically significant. These findings provide comparative information for the understanding of primate brain maturation and neurodevelopmental disorders.

Responsiveness and functional connectivity of the scene-sensitive retrosplenial complex in 7-11-year-old children.

Brain imaging studies have identified two cortical areas, the parahippocampal place area (PPA) and the retrosplenial complex (RSC), that respond preferentially to the viewing of scenes. Contrary to the PPA, little is known about the functional maturation and cognitive control of the RSC. Here we used functional magnetic resonance imaging and tasks that required attention to scene (or face) images and suppression of face (or scene) images, respectively, to investigate task-dependent modulation of activity in the RSC and whole-brain functional connectivity (FC) of this area in 7-11-year-old children and young adults. We compared responsiveness of the RSC with that of the PPA. The RSC was selectively activated by scene images in both groups, albeit less than the PPA. Children modulated activity between the tasks similarly in the RSC and PPA, and to the same extent as adults in PPA, whereas adults modulated activity in the RSC less than in PPA. In children, the whole brain FC of the RSC was stronger in the Sf than Fs task between the left RSC and right fusiform gyrus. The between groups comparison suggested stronger FC in children than adults in the Sf task between the right RSC and the left inferior parietal lobule and intraparietal sulcus. Together the results suggest that the function of the RSC and the related networks undergo dynamic changes over the development from 7-11-year-old children to adulthood.

Functional degradation of the primary visual cortex during early senescence in rhesus monkeys.

Visual function in humans degrades during the early stage of senescence beginning from middle 50s to 60s. To identify its underlying neural mechanisms, we investigated the aging effects on the primary visual cortex (V1) cells in early senescent (ES) monkeys (Macaca mulatta). Under anesthesia, receptive field properties of V1 cells were examined by extracellular single-unit recordings in the young adult (YA; 5-6 years old), ES (19-24 years old), and late senescent (LS; 28-32 years old) monkeys. We found clear indications of functional degradation in early senescence, including impaired stimulus selectivities, increased level of spontaneous activity and declined signal-to-noise ratio, and dynamic range of V1 cell responses. Importantly, the functional degradation in early senescence exhibited unique features that were different from the results for the LS animals, such as remarkable individual variability in orientation selectivity and unchanged peak response elicited by visual stimulation. Our results demonstrate that the function of V1 degrades during the early stage of aging in nonhuman primate, suggesting potential neural correlates for functional deficits observed in early senescence in human subjects. Moreover, these results provide new insight into the dynamics of the aging-related functional deterioration, revealing a more complex and heterogeneous picture of this process.

Maternal separation produces lasting changes in cortisol and behavior in rhesus monkeys.

Maternal separation (MS), which can lead to hypothalamic pituitary adrenal axis dysfunction and behavioral abnormalities in rhesus monkeys, is frequently used to model early adversity. Whether this deleterious effect on monkeys is reversible by later experience is unknown. In this study, we assessed the basal hair cortisol in rhesus monkeys after 1.5 and 3 y of normal social life following an early separation. These results showed that peer-reared monkeys had significantly lower basal hair cortisol levels than the mother-reared monkeys at both years examined. The plasma cortisol was assessed in the monkeys after 1.5 y of normal social life, and the results indicated that the peak in the peer-reared cortisol response to acute stressors was substantially delayed. In addition, after 3 y of normal social life, abnormal behavioral patterns were identified in the peer-reared monkeys. They showed decreases in locomotion and initiated sitting together, as well as increases in stereotypical behaviors compared with the mother-reared monkeys. These results demonstrate that the deleterious effects of MS on rhesus monkeys cannot be compensated by a later normal social life, suggesting that the effects of MS are long-lasting and that the maternal-separated rhesus monkeys are a good animal model to study early adversity and to investigate the development of psychiatric disorders induced by exposure to early adversity.

A Novel TSC2 c.2489T>C Missense Variant Associated With Tuberous Sclerosis Complex: Case Report.

Objectives: Tuberous sclerosis complex (TSC) is a genetic disorder caused by a TSC1 or TSC2 gene variation characterized by widespread hamartomas in organs such as the skin, brain, heart, lungs, liver, and kidneys. Methods: We report a case of a patient with TSC who presented with broad clinical manifestations, including epilepsy. Results: An 18-year-old man was diagnosed with recurrent drug-resistant epilepsy. Neuroimaging revealed bilateral cortical and subcortical tubers with multiple calcified subependymal nodules. His skin involvement and psychomotor retardation raised the suspicion of TSC. Genetic testing confirmed the diagnosis, and a combined treatment including mTOR inhibitors was initiated. Discussion: TSC, although considered rare, needs to be considered when evaluating patients with broad clinical manifestations. Our report has significant implications for understanding the impact of genotype on the prognosis of TSC and the selection of treatment strategies for TSC-related refractory epilepsy.

Identification of biomarkers and immune infiltration characterization of lipid metabolism-associated genes in osteoarthritis based on machine learning algorithms.

Osteoarthritis (OA) is a prevalent degenerative condition commonly observed in the elderly, leading to consequential disability. Despite notable advancements made in clinical strategies for OA, its pathogenesis remains uncertain. The intricate association between OA and metabolic processes has yet to receive comprehensive exploration. In our investigation, we leveraged public databases and applied machine learning algorithms, including WGCNA, LASSO, RF, immune infiltration analysis, and pathway enrichment analysis, to scrutinize the role of lipid metabolism-associated genes (LAGs) in the OA. Our findings identified three distinct biomarkers, and evaluated their expression to assess their diagnostic value in the OA patients. The exploration of immune infiltration in these patients revealed an intricate relationship between immune cells and the identified biomarkers. In addition, in vitro experiments, including qRT-PCR, Western blot, chondrocyte lipid droplets detection and mitochondrial fatty acid oxidation measurement, further verified abnormal expressions of selected LAGs in OA cartilage and confirmed the correlation between lipid metabolism and OA.

Regulation of brain activity in the fusiform face and parahippocampal place areas in 7-11-year-old children.

Developmental studies have demonstrated that cognitive processes such as attention, suppression of interference and memory develop throughout childhood and adolescence. However, little is currently known about the development of top-down control mechanisms and their influence on cognitive performance. In the present study, we used functional magnetic resonance imaging to investigate modulation of activity in the ventral visual cortex in healthy 7-11-year-old children and young adults. The participants performed tasks that required attention to either face (Fs task) or scene (Sf task) images while trying to ignore distracting scene or face images, respectively. A face-selective area in the fusiform gyrus (fusiform face area, FFA) and an area responding preferentially to scene images in the parahippocampal gyrus (parahippocampal place area, PPA) were defined using functional localizers. Children responded slower and less accurately in the tasks than adults. In children, the right FFA was less selective to face images and regulation of activity between the Fs and Sf tasks was weaker compared to adults. In the PPA, selectivity to scenes and regulation of activity, there according to the task demands were comparable between children and adults. During the tasks, children activated prefrontal cortical areas including the middle (MFG) and superior (SFG) frontal gyrus more than adults. Functional connectivity between the right FFA and left MFG was stronger in adults than children in the Fs task. Children, on the other hand, had stronger functional connectivity than adults in the Sf task between the right FFA and right PPA and between right MFG and medial SFG. There were no group differences in the functional connectivity between the PPA and the prefrontal cortex (PFC). Together the results suggest that, in 7-11-year-old children, the FFA is still immature, whereas the selectivity to scenes and regulation of activity in the PPA is comparable to adults. The results also indicated functional immaturity of the PFC in children compared to adults and weaker connectivity between the PFC and the rFFA, explaining the weaker regulation of activity in the rFFA between the Fs and Sf tasks.

Effects of exposure to a 50 Hz sinusoidal magnetic field during the early adolescent period on spatial memory in mice.

Adolescence is a critical developmental stage during which substantial remodeling occurs in brain areas involved in emotional and learning processes. Although a robust literature on the biological effects of extremely low frequency magnetic fields (ELF-MFs) has been documented, data on the effects of ELF-MF exposure during this period on cognitive functions remain scarce. In this study, early adolescent male mice were exposed from postnatal day (P) 23-35 to a 50 Hz MF at 2 mT for 60 min/day. On P36-45, the potential effects of the MF exposure on spatial memory performance were examined using the Y-maze and Morris water maze tasks. The results showed that the MF exposure did not affect Y-maze performance but improved spatial learning acquisition and memory retention in the water maze task under the present experimental conditions.

Kisspeptin-10 modulates the proliferation and differentiation of the rhesus monkey derived stem cell line: R366.4.

The rhesus monkey embryonic stem cell line R366.4 has been identified to differentiate into a number of cell types. However, it has not been well characterized for its response to drugs affecting reproductive endocrinology. Kisspeptins (KPs) are ligands for the GPR-54, which is known to modulate reproductive function. The current study was designed to determine the effect of the KP-10 peptide on R366.4 cells and to investigate the role of KP-GPR54 in the cell proliferation process. Four different doses (0.1, 1, 10, and 100 nM) of KP-10 and control were selected to evaluate cell growth parameters and cellular morphological changes over a 72 hr period. The cells were treated with kisspeptin-10 during the early rosette stage. Proliferation rates, analyzed by flow cytometry and cell count methods, were found to be decreased after treatment. Moreover, the number of rosettes was found to decrease following KP-10 treatments. Morphological changes consisting of neuronal projections were also witnessed. This suggested that KP-10 had an antiproliferative effect on R366.4 cells leading to a differentiation state and morphological changes consistent with neuronal stem cell development. The R366.4 stem cell line differentiates based on kisspeptin signaling and may be used to investigate reproductive cell endocrinology in vitro.

Identification and validation of metabolism-related genes signature and immune infiltration landscape of rheumatoid arthritis based on machine learning.

Rheumatoid arthritis (RA) causes irreversible joint damage, but the pathogenesis is unknown. Therefore, it is crucial to identify diagnostic biomarkers of RA metabolism-related genes (MRGs). This study obtained transcriptome data from healthy individuals (HC) and RA patients from the GEO database. Weighted gene correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and random forest (RF) algorithms were adopted to identify the diagnostic feature biomarker for RA. In addition, biomarkers were verified by qRT-PCR and Western blot analysis. We established a mouse model of collagen-induced arthritis (CIA), which was confirmed by HE staining and bone structure micro-CT analysis, and then further verified the biomarkers by immunofluorescence. In vitro NMR analysis was used to analyze and identify possible metabolites. The correlation of diagnostic feature biomarkers and immune cells was performed using the Spearman-rank correlation algorithm. In this study, a total of 434 DE-MRGs were identified. GO and KEGG enrichment analysis indicated that the DE-MRGs were significantly enriched in small molecules, catabolic process, purine metabolism, carbon metabolism, and inositol phosphate metabolism. AKR1C3, MCEE, POLE4, and PFKM were identified through WGCNA, LASSO, and RF algorithms. The nomogram result should have a significant diagnostic capacity of four biomarkers in RA. Immune infiltration landscape analysis revealed a significant difference in immune cells between HC and RA groups. Our findings suggest that AKR1C3, MCEE, POLE4, and PFKM were identified as potential diagnostic feature biomarkers associated with RA's immune cell infiltrations, providing a new perspective for future research and clinical management of RA.

Zeolitic Imidazolate Framework (ZIF-8) Decorated Iron Oxide Nanoparticles Loaded Doxorubicin Hydrochloride for Osteosarcoma Treatment - in vitro and in vivo Preclinical Studies.

Background: As a broad-spectrum antitumorigenic agent, doxorubicin (DOX) is commonly used as a chemotherapeutic drug for treating osteosarcoma (OS). Still, it is associated with significant cell toxicity and ineffective drug delivery, whereas the zeolite imidazolate framework is extensively applied in the biomedical field as a carrier owing to its favorable biocompatibility, high porosity, and pH-responsiveness. Therefore, we need to develop a drug delivery platform that can effectively increase the antitumorigenic effect of the loaded drug and concurrently minimize drug toxicity. Methods: In this study, a Fe3O4@ZIF-8 nanocomposite carrier was prepared with ZIF-8 as the shell and encapsulated with Fe3O4 by loading DOX to form DOX- Fe3O4@ZIF-8 (DFZ) drug-loaded magnetic nanoparticles. Then, we characterized and analyzed the morphology, particle size, and characteristics of Fe3O4@ZIF-8 and DFZ by TEM, SEM, and Malvern. Moreover, we examined the inhibitory effects of DFZ in vitro and in vivo. Meanwhile, we established a tumor-bearing mouse model, evaluating its tumor-targeting by external magnetic field guidance. Results: DFZ nanoparticles possessed have a size of ~110 nm, with an encapsulation rate of 21% and pH responsiveness. DFZ exerted a superior cytostatic effect and apoptosis rate on K7M2 cells in vitro compared to DOX(p<0.01). In animal experiments, DFZ offers up to 67% tumor inhibition and has shown a superior ability to induce apoptosis than DOX alone in TUNEL results(p<0.01). Tumor-targeting experiments have validated that DFZ can be effectively accumulated in the tumor tissue and enhance anticancer performance. Conclusion: In summary, the DFZ nano-delivery system exhibited a more substantial anti-tumorigenic effect as well as superior active tumor targeting of DOX- Fe3O4@ZIF-8 compared to that of DOX alone in terms of biocompatibility, drug loading capacity, pH-responsiveness, tumor-targeting, and anti-tumorigenic effect, indicating its chemotherapeutic application potential.

The Role of IL-6 and TMEM100 in Lumbar Discogenic Pain and the Mechanism of the Glycine-Serine-Threonine Metabolic Axis: A Metabolomic and Molecular Biology Study.

Background: It is well established that discogenic low back pain (DLBP) is often caused by the inflammatory response during intervertebral disc degeneration (IDD). However, it remains unclear how inflammatory mediators such as Interleukin-6 (IL-6) are involved in discogenic pain caused by degeneration and intervertebral disc (IVD) metabolism. The purpose of this study is to study the relationship between IL-6 and Transmembrane protein 100 (TMEM100), and to analyze the different metabolites and metabolic pathways in various rat intervertebral discs by metabonomics. Methods: We established a rat model of IDD-DLBP by disc punctures and PBS infusion to examine the rat pain behaviors. Intervertebral disc tissues were harvested for molecular biology experiments to explore the relationship between IL-6 and TMEM100. High-resolution mass spectrometry (HRMS) was performed for untargeted metabolomics, and nuclear magnetic resonance spectroscopy metabolomics (MRS) for differential metabolites and metabolic pathways. Results: The results showed a significant decrease in vonFrey test, hot plate test and acetone test (P < 0.05). The expression of IL-6 and TMEM100 in DLBP model was significantly higher than that in sham control group and IDD discs without PBS infusion group (P < 0.05). There were 15 major contributing metabolites identified in the DLBP intervertebral discs through metabolomic studies, involving 6 major metabolic pathways. The main differential metabolites included nitric oxide (NO), ammonia, and lactic acid as the metabolic endpoints; and the differential metabolic pathways included the glycine-serine-threonine (Gly-Ser-Thr), which is gradually weakened with the progression of inflammation. Conclusion: The change of TMEM100 expression mediated by il-6 is related to the Gly-Ser-Thr metabolic axis and plays an important role in the relief of discogenic pain.

Effect of morphine on conditioned place preference in rhesus monkeys.

In rodents, a conditioned place preference (CPP) can be induced by morphine. In the current study, we designed a biased place conditioning paradigm to test the rewarding effects of morphine in freely moving rhesus monkeys. Five monkeys were first placed in three serial rooms with the doors open between them for three days. After this habituation period, during which baseline preference for each of the two end rooms was measured, CPP conditioning occurred when the monkeys were injected intramuscularly with morphine at an increasing dose (1.5, 3, 4.5 mg/kg) before they entered the non-preferred room and on alternate days, with saline before they entered the preferred room. Morphine and saline treatment lasted for six days, respectively. CPP was tested 24 hours after the end of CPP training. The result showed that in all five monkeys, CPP was induced by the morphine treatment. The preference lasted for at least 15.3 ± 1.7 months.