GDF15 is a major determinant of ketogenic diet-induced weight loss.

A ketogenic diet (KD) has been promoted as an obesity management diet, yet its underlying mechanism remains elusive. Here we show that KD reduces energy intake and body weight in humans, pigs, and mice, accompanied by elevated circulating growth differentiation factor 15 (GDF15). In GDF15- or its receptor GFRAL-deficient mice, these effects of KD disappeared, demonstrating an essential role of GDF15-GFRAL signaling in KD-mediated weight loss. Gdf15 mRNA level increases in hepatocytes upon KD feeding, and knockdown of Gdf15 by AAV8 abrogated the obesity management effect of KD in mice, corroborating a hepatic origin of GDF15 production. We show that KD activates hepatic PPARγ, which directly binds to the regulatory region of Gdf15, increasing its transcription and production. Hepatic Pparγ-knockout mice show low levels of plasma GDF15 and significantly diminished obesity management effects of KD, which could be restored by either hepatic Gdf15 overexpression or recombinant GDF15 administration. Collectively, our study reveals a previously unexplored GDF15-dependent mechanism underlying KD-mediated obesity management.

Hippocampus: Molecular, Cellular, and Circuit Features in Anxiety.

Anxiety disorders are currently a major psychiatric and social problem, the mechanisms of which have been only partially elucidated. The hippocampus serves as a major target of stress mediators and is closely related to anxiety modulation. Yet so far, its complex anatomy has been a challenge for research on the mechanisms of anxiety regulation. Recent advances in imaging, virus tracking, and optogenetics/chemogenetics have permitted elucidation of the activity, connectivity, and function of specific cell types within the hippocampus and its connected brain regions, providing mechanistic insights into the elaborate organization of the hippocampal circuitry underlying anxiety. Studies of hippocampal neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, dopaminergic, and serotonergic systems, have contributed to the interpretation of the underlying neural mechanisms of anxiety. Neuropeptides and neuroinflammatory factors are also involved in anxiety modulation. This review comprehensively summarizes the hippocampal mechanisms associated with anxiety modulation, based on molecular, cellular, and circuit properties, to provide tailored targets for future anxiety treatment.

[Establishment of High-Resolution Emissions Inventory in Wuhai and Its Application in Exploring the Causes of Ozone Pollution].

Wuhai is a typical coking industrial base including three industrial parks within its jurisdiction. The emission amount of air pollutants is considerable here, and O3 pollution has become serious in recent years. Clarifying the air pollutant emission characteristics and exploring the formation mechanism of O3 are the basis for objectively understanding the O3 pollution and formulating scientific prevention and control measures. This study established the high-resolution emission inventory of Wuhai in 2018 (HEI-WH18) based on the "coefficient method," evaluated the applicability and accuracy of HEI-WH18 using the WRF-Chem model, and explored the causes of O3 pollution in summer using WRF-Chem diagnosis module output. The HEI-WH18 showed that the total emissions amount of SO2, NOx, CO, PM10, PM2.5, VOCs, NH3, BC, and OC were 65943, 40934, 172867, 159771, 47469, 69191, 1407, 1491, and 1648 t·a-1, respectively. HEI-WH18 could capture the variation and magnitude of O3 and its precursors better than the MEIC, which was suitable for the O3 simulation and source analysis in summer. From the perspective of spatial distribution, Haibowan was a high-value area of O3 during the daytime, and the three industrial parks were low-value areas of O3 and high-value areas of NO2 during the daytime and nighttime. The spatial distribution characteristics of CO were consistent with the spontaneous combustion of coal and coal gangue sources. According to the diagnostic analysis of two O3 pollution processes, the O3 increase in the upper boundary layer was mainly related to the advection transport and chemical process, and it was caused by vertical mixing and the advection transport process in the lower boundary layer. The contribution of the chemical process in the lower boundary layer was complicated, and its positive contribution played a role in maintaining a high O3 concentration, whereas its negative contribution combined with advection transport resulted in the final dissipation of O3 pollution.

An mNUTRIC-based nomogram for predicting the in-hospital death risk in patients with acute stroke.

OBJECTIVES: To establish a risk prediction model for in-hospital death in acute stroke patients based on nutritional risk scores. METHODS: A retrospective analysis was performed including 268 acute stroke patients. The Nutritional Risk Screening 2002 (NRS2002) and modified Nutritional Risk in the Critically Ill (mNUTRIC) score were used to evaluate the nutritional status of patients with acute stroke after admission to the neurological intensive care unit (NICU), and laboratory parameters and clinical characteristics were collected. Multivariate logistic regression analysis was performed to screen the risk factors for in-hospital death in acute stroke patients, and a nomogram for predicting death based on the nutritional risk score was established. RESULTS: The mortality of acute stroke in the NICU was 25.8%. Multivariate logistic regression analysis showed that the mNUTRIC score, female sex, lymphocyte count, pulmonary infection and mechanical ventilation were independent risk factors for in-hospital mortality in acute stroke patients (P < 0.001 or 0.05). The above indexes were used to establish a prediction model of the in-hospital death risk for acute stroke patients. The area under the ROC curve, sensitivity, and specificity of the prediction model were 0.891 (95% CI = 0.853-0.928), 82.5%, and 81.7%, respectively. The nomogram was established and then internally validated using bootstrap repeat sampling 2000 times, the C-index was 0.880, and the predicted values of the calibration curve were in agreement with the measured values. CONCLUSION: The mNUTRIC-based nomogram model can be used as a reliable tool to predict the in-hospital mortality risk of acute stroke patients.

Optineurin promotes myogenesis during muscle regeneration in mice by autophagic degradation of GSK3ß.

Skeletal muscle regeneration is essential for maintaining muscle function in injury and muscular disease. Myogenesis plays key roles in forming new myofibers during the process. Here, through bioinformatic screen for the potential regulators of myogenesis from 5 independent microarray datasets, we identify an overlapping differentially expressed gene (DEG) optineurin (OPTN). Optn knockdown (KD) delays muscle regeneration in mice and impairs C2C12 myoblast differentiation without affecting their proliferation. Conversely, Optn overexpression (OE) promotes myoblast differentiation. Mechanistically, OPTN increases nuclear levels of ß-catenin and enhances the T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription activity, suggesting activation of Wnt signaling pathway. The activation is accompanied by decreased protein levels of glycogen synthase kinase 3ß (GSK3ß), a negative regulator of the pathway. We further show that OPTN physically interacts with and targets GSK3ß for autophagic degradation. Pharmacological inhibition of GSK3ß rescues the impaired myogenesis induced by Optn KD during muscle regeneration and myoblast differentiation, corroborating that GSK3ß is the downstream effector of OPTN-mediated myogenesis. Together, our study delineates the novel role of OPTN as a potential regulator of myogenesis and may open innovative therapeutic perspectives for muscle regeneration.

Camptothecin effectively treats obesity in mice through GDF15 induction.

Elevated circulating levels of growth differentiation factor 15 (GDF15) have been shown to reduce food intake and lower body weight through activation of hindbrain receptor glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) in rodents and nonhuman primates, thus endogenous induction of this peptide holds promise for obesity treatment. Here, through in silico drug-screening methods, we found that small molecule Camptothecin (CPT), a previously identified drug with potential antitumor activity, is a GDF15 inducer. Oral CPT administration increases circulating GDF15 levels in diet-induced obese (DIO) mice and genetic ob/ob mice, with elevated Gdf15 expression predominantly in the liver through activation of integrated stress response. In line with GDF15's anorectic effect, CPT suppresses food intake, thereby reducing body weight, blood glucose, and hepatic fat content in obese mice. Conversely, CPT loses these beneficial effects when Gdf15 is inhibited by a neutralizing antibody or AAV8-mediated liver-specific knockdown. Similarly, CPT failed to reduce food intake and body weight in GDF15's specific receptor GFRAL-deficient mice despite high levels of GDF15. Together, these results indicate that CPT is a promising anti-obesity agent through activation of GDF15-GFRAL pathway.

[Improved Performance of PMF Source Apportionment for Volatile Organic Compounds Based on Classification of VOCs' Aging Degree in Air Mass].

VOCs are the key precursors of ozone and secondary organic aerosols. The results of source apportionment for VOCs are very important for the coordinated control of ozone and second organic particulate matter. However, VOCs do not fully meet the assumption of the receptor model because the VOCs released from each source are relatively unstable in the transmission process for their reactivity. As a result, we do not accurately obtain the actual source contribution when the receptor model is used for the source apportionment of VOCs. In order to solve the problem that the relative changes in the components caused by VOCs reactivity are not consistent with the PMF model hypothesis, the aging degree of VOCs was introduced to distinguish the state characteristics after their photochemical reactions in the ambient air. According to the ratio of ethylbenzene to m/p-xylene, VOCs monitored at Wuhai were divided into three aging states:high, medium, and low. The results showed that the model parameters, such as regression equation parameters (slope and intercept), standard error, determination coefficient, and pass rate of residual error, were improved obviously compared to the sample set after classification. Because the degree of aging is closely related to the transport time of air mass and the atmospheric oxidation in the atmosphere, it also reflects the different sources of air mass to some extent. In the high-aging VOCs samples, the coking source occupied a high proportion (up to 47.20%). In the low-aging VOCs samples, the combustion source and coking source accounted for a higher proportion, 28.67% and 24.39%, respectively. After the classification according to the aging degree, the results of VOCs source apportionment by PMF are more consistent with the actual contribution of emission sources.

Knockout of interleukin-17A diminishes ventricular arrhythmia susceptibility in diabetic mice via inhibiting NF-κB-mediated electrical remodeling.

Interleukin-17A (IL-17), a potent proinflammatory cytokine, has been shown to participate in cardiac electrical disorders. Diabetes mellitus is an independent risk factor for ventricular arrhythmia. In this study, we investigated the role of IL-17 in ventricular arrhythmia of diabetic mice. Diabetes was induced in both wild-type and IL-17 knockout mice by intraperitoneal injection of streptozotocin (STZ). High-frequency electrical stimuli were delivered into the right ventricle to induce ventricular arrhythmias. We showed that the occurrence rate of ventricular tachycardia was significantly increased in diabetic mice, which was attenuated by IL-17 knockout. We conducted optical mapping on perfused mouse hearts and found that cardiac conduction velocity (CV) was significantly decreased, and action potential duration (APD) was prolonged in diabetic mice, which were mitigated by IL-17 knockout. We performed whole-cell patch clamp recordings from isolated ventricular myocytes, and found that the densities of Ito, INa and ICa,L were reduced, the APDs at 50% and 90% repolarization were increased, and early afterdepolarization (EAD) was markedly increased in diabetic mice. These alterations were alleviated by the knockout of IL-17. Moreover, knockout of IL-17 alleviated the downregulation of Nav1.5 (the pore forming subunit of INa), Cav1.2 (the main component subunit of ICa,L) and KChIP2 (potassium voltage-gated channel interacting protein 2, the regulatory subunit of Ito) in the hearts of diabetic mice. The expression of NF-κB was significantly upregulated in the hearts of diabetic mice, which was suppressed by IL-17 knockout. In neonatal mouse ventricular myocytes, knockdown of NF-κB significantly increased the expression of Nav1.5, Cav1.2 and KChIP2. These results imply that IL-17 may represent a potential target for the development of agents against diabetes-related ventricular arrhythmias.

[Exploring Characteristics and Causes of Summer Ozone Pollution Based on Process Analysis in Wuhai].

In recent years, summer O3 pollution has become more severe in Wuhai, where the terrain is complex and industrial parks are densely distributed. However, the characteristics and formation mechanisms of this pollution have not yet been investigated and remain unclear. Analyzing the variation and formation mechanisms of O3 is crucial to the prevention and control of air pollution in this region. By analyzing characteristics and using a WRF-CMAQ model to simulate three O3 pollution periods in Wuhai from June to August 2018, this study explored the causes of O3 pollution based on in-depth process analysis, and the effects of regional transportation and local photochemical reaction on O3 were also discussed. The diurnal variation of ozone exhibited a single-peak distribution, and near-surface O3 was positively correlated with short-wave radiation and temperature, and negatively correlated with relative humidity. The areas of Shizuishan in Ningxia and the Ulanbuhe desert exhibited high O3 values during the day, while the three industrial parks in Wuhai exhibited low values during both the day and night. Process analysis showed that transportation, chemical processes, and their relative magnitudes had a significant impact on O3. Local photochemical reactions and transport during the pollution period in June and July led to an obvious increase in O3, while the impact of chemical processes was about twice as large as that of transport. The increase of O3 in August was mainly caused by transport. Further decomposition of the transportation effect showed that transportation in the south and northwest directions had a remarkable effects on the increase of O3. Together with the emission of O3 precursors, the main sources of transportation were the Yinchuan, Shizuishan, and Bayannaoer regions. Therefore, Wuhai and neighboring cities should strengthen regional joint prevention and control by jointly formulating and implementing control measures for air pollution to reduce the impact of regional transmission on O3.

Identification of Dacinostat as a potential anti-obesity compound through transcriptional activation of adipose thermogenesis in mice.

Obesity is a worldwide health problem. Activating fat mobilization and reducing fat synthesis is a promising strategy to mitigate obesity and its complicated metabolic diseases. However, few clinically effective and safe agents conform to the strategy. In the present study, by screening the next-generation L1000-based CMAP small molecule library, we identify histone deacetylase inhibitor Dacinostat, which has been previously tested in clinical trials for patients with advanced solid tumors, as an anti-obesity candidate. Administration of Dacinostat prevents high-fat diet-induced obesity, insulin resistance, and fatty liver in mice without causing adverse effects. Dacinostat treatment enhances adipose thermogenesis as shown by elevated body temperature, accompanied with high mRNA expression of Ucp1 and Ppargc1α. Mechanistically, we show that the thermogenic effect of Dacinostat is achieved by acetylation of histone 3 lysine 27 mediated transcriptional activation of Ucp1 and Ppargc1α in adipose tissue. In conclusion, these findings suggest that Dacinostat is a potential anti-obesity compound through transcriptional activation of adipose thermogenesis.

[Nonlinear Response Characteristics and Control Scheme for Ozone and Its Precursors Based on Orthogonal Experimental Methods].

There is a highly nonlinear relationship between ozone concentrations and its precursor emissions in different regions and at different times, which makes developing effective prevention and control measures difficult. An orthogonal experimental method was introduced to assess the influence of ozone precursors and their interactions on ozone formation, clarify the sensitivity of ozone generation, and propose an optimal control scheme. Based on the WRF-Chem air quality model and an emission inventory of air pollutants in Wuhai City in 2018, this study used an ozone pollution event in the Haibowan urban area (August 17 to 20 2018) to investigate the nonlinear response of ozone formation to its precursors. The orthogonal experiment shows that NOx, VOCs interactions with CO, CO, and interactions between pollutants and meteorological factors are the main factors affects ozone concentrations in the Haibowan urban area. Ozone generation was most sensitive to NOx concentrations during the hours 12:00-18:00 when standard values were exceeded. The ozone concentrations decreased significantly by 12.6 µg·m-3 (7.8%) as NOx, VOCs, and CO were reduced by 60%, 30%, and 30%, respectively. Through the analysis of chemical reaction mechanisms, it is concluded that VOCs and CO affect the photochemical reaction by reacting with·OH, HO2·and other free radicals, which causes the significant interaction between VOCs and CO in the generation of ozone. This method provides a new approach for researching the nonlinear response of ozone formation to its precursors and for proposing ozone pollution control schemes.

[Establishment of a High-resolution Anthropogenic Emission Inventory and Its Evaluation Using the WRF-Chem Model for Lanzhou].

City-scale high-resolution anthropogenic emission inventories are an important tool for ambient air quality forecasting and early warning, the analysis of underlying causes, and policy making. At present, city-scale anthropogenic emissions inventories for use in air quality models are scarce for West China. By studying the literature on emission inventories, this paper establishes a city-scale anthropogenic emission inventory for Lanzhou (HEI-LZ16) as the basis for an air quality model. The weather research and forecasting with chemistry (WRF-Chem) model was used to evaluate the applicability of the emission inventory at different resolutions in Lanzhou. The results showed that the emission amounts of SO2, NOx, CO, NH3, VOCs, PM10, PM2.5, BC, and OC in Lanzhou were 25642, 53998, 319003, 10475, 35289, 49250, 19822, 2476, and 1482 t·a-1 in 2016,respectively. Compared with the simulation scenario of multi-resolution emission inventory for China (MEIC), normalized mean error (NME) of O3 and PM2.5 under the HEI-LZ16 scenario decreased by 140.2% and 28.8%, respectively. The HEI-LZ16 inventory is more suitable for application in air pollution research in Lanzhou, which was verified by the WRF-Chem model and the observational data. The spatiotemporal distributions of PM2.5 and O3 were also analyzed using the HEI-LZ16 scenario. The ozone concentration of the maximum daily 8-h average (MDA8) in Lanzhou was low in urban areas and high in the suburbs during winter and spring, and high in the west of the urban valley and its downwind areas during summer and autumn. MDA8 in summer and autumn was influenced by easterly winds and photochemical reactions. In winter, ozone concentrations in urban areas are suppressed by NOx emissions but the concentration decreases. High PM2.5 concentrations are mainly concentrated within the Yellow River Valley. This study shows that there is a pollutant transmission channel along the western side of the Baiyin-Lanzhou Yellow River Valley, which has a greater impact on the ambient air quality in Lanzhou.

Clinical value of nedaplatin-based chemotherapy combined with radiotherapy for locoregional advanced nasopharyngeal carcinoma: a retrospective, propensity score-matched analysis.

Aims: This study aimed to investigate the clinical value of induction chemotherapy (IC) with docetaxel, 5-fluorouracil plus nedaplatin followed by concurrent chemoradiotherapy (CCRT) with nedaplatin for locoregional advanced nasopharyngeal carcinoma (NPC). Materials and Methods: In total, 269 patients diagnosed with locoregional advanced NPC between June 2012 and June 2017 were retrospectively included and divided into two groups: IC (docetaxel plus nedaplatin and 5-fluorouracil) followed by nedaplatin-based CCRT (TNF + N group, n = 146) and IC (docetaxel plus cisplatin and 5-fluorouracil) followed by cisplatin-based CCRT (TPF + P group, n = 123). The Kaplan-Meier method and Cox proportional hazards model were applied to analyse survival and prognosis. After propensity score-matched (PSM), 113 patients remained in each group. Toxicities were compared between the two groups using the Chi-square test or Fisher's exact test. Results: The overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) rates of the TNF + N and TPF + P groups were 90.7% vs. 92.3% (P = 0.315), 78.9% vs. 79.4% (P = 0.715), 82.4% vs. 85.1% (P = 0.441) and 96.1% vs. 93.3% (P = 0.414), respectively, with no significant difference in 3-year survival outcome between the two groups, and this outcome was confirmed after using PSM analyses. In the PSM cohort, a significant higher frequency of grade 3/4 vomiting was observed in the TPF + P group compared to the TNF + N group (22.1% vs. 0%, P = 0.000). However, 15.9% of patients in the TNF + N group had grade 3/4 thrombocytopenia in comparison with 6.2% in the TPF + P group (P = 0.020). Conclusions: The TNF regimen followed by CCRT with nedaplatin is an alternative treatment strategy to the standard TPF regimen followed by CCRT with cisplatin for patients with locoregional advanced NPC.

Mitochondrial aconitase controls adipogenesis through mediation of cellular ATP production.

Mitochondrial aconitase (Aco2) catalyzes the conversion of citrate to isocitrate in the TCA cycle, which produces NADH and FADH2, driving synthesis of ATP through OXPHOS. In this study, to explore the relationship between adipogenesis and mitochondrial energy metabolism, we hypothesize that Aco2 may play a key role in the lipid synthesis. Here, we show that overexpression of Aco2 in 3T3-L1 cells significantly increased lipogenesis and adipogenesis, accompanied by elevated mitochondrial biogenesis and ATP production. However, when ATP is depleted by rotenone, an inhibitor of the respiratory chain, the promotive role of Aco2 in adipogenesis is abolished. In contrast to Aco2 overexpression, deficiency of Aco2 markedly reduced lipogenesis and adipogenesis, along with the decreased mitochondrial biogenesis and ATP production. Supplementation of isocitrate efficiently rescued the inhibitory effect of Aco2 deficiency. Similarly, the restorative effect of isocitrate was abolished in the presence of rotenone. Together, these results show that Aco2 sustains normal adipogenesis through mediating ATP production, revealing a potential mechanistic link between TCA cycle enzyme and lipid synthesis. Our work suggest that regulation of adipose tissue mitochondria function may be a potential way for combating abnormal adipogenesis related diseases such as obesity and lipodystrophy.

A Potential Nutraceutical Candidate Lactucin Inhibits Adipogenesis through Downregulation of JAK2/STAT3 Signaling Pathway-Mediated Mitotic Clonal Expansion.

The prevalence of obesity has increased dramatically worldwide in the past ~50 years. Searching for safe and effective anti-obesity strategies are urgently needed. Lactucin, a plant-derived natural small molecule, is known for anti-malaria and anti-hyperalgesia. The study is to investigate whether lactucin plays a key role in adipogenesis. To this end, in vivo male C57BL/6 mice fed a high-fat diet (HFD) were treated with 20 mg/kg/day of lactucin or vehicle by gavage for seven weeks. Compared with vehicle-treated controls, Lactucin-treated mice showed lower body mass and mass of adipose tissue. Consistently, in vitro 3T3-L1 cells were treated with 20 µM of lactucin. Compared to controls, lactucin-treated cells showed significantly less lipid accumulation during adipocyte differentiation and lower levels of lipid synthesis markers. Mechanistically, we showed the anti-adipogenic property of lactucin was largely limited to the early stage of adipogenesis. Lactucin-treated cells fail to undergo mitotic clonal expansion (MCE). Further studies demonstrate that lactucin-induced MCE arrests might result from reduced phosphorylation of JAK2 and STAT3. We then asked whether activation of JAK2/STAT3 would restore the inhibitory effect of lactucin on adipogenesis with pharmacological STAT3 activator colivelin. Our results revealed similar levels of lipid accumulation between lactucin-treated cells and controls in the presence of colivelin, indicating that inactivation of STAT3 is the limiting factor for the anti-adipogenesis of lactucin in these cells. Together, our results provide the indication that lactucin exerts an anti-adipogenesis effect, which may open new therapeutic options for obesity.

Spinal interleukin-17 promotes thermal hyperalgesia and NMDA NR1 phosphorylation in an inflammatory pain rat model.

It is known that interleukin-17 (IL-17) is associated with autoimmune disorders and that peripheral IL-17 plays a role in arthritis and neuropathic pain. The present study investigated the possibility of spinal cell expression of IL-17 during inflammatory pain and possible IL-17 involvement in such pain. Hyperalgesia was induced by injecting complete Freund adjuvant (CFA, 0.08mL, 40µg Mycobacterium tuberculosis) into one hind paw of the rat. Paw withdrawal latency (PWL) was tested before (-48h) and 2 and 24h after CFA injection to assess hyperalgesia. IL-17 antibody (0.2-2µg/rat) was given intrathecally (i.t.) 24h before CFA to block the action of basal IL-17 and 2h before each of 2 PWL tests to block CFA-induced IL-17. I.t. recombinant IL-17 (10-400ng per rat) was administered to naive rats to determine its effects on PWL and phosphorylated NR1 (p-NR1). p-NR1 modulates N-methyl-d-aspartate receptor (NMDAR) activity to facilitate pain. Spinal cords were removed for IL-17 immunostaining, double immunostaining of IL-17/cell markers and IL-17 receptor A (IL-17RA)/NR1, for Western blot testing of IL-17, p-NR1, IL-17RA, and GFAP, for in situ IL-17RA hybridization, and for real time polymerase chain reaction of IL-17RA. The data reveal that IL-17 is up-regulated in activated and nonactivated astrocytes; that IL-17RA is localized in NR1-immunoreactive neurons and up-regulated; and that IL-17 antibody at 2µg/rat significantly increased PWL (P<.05) and decreased p-NR1 and IL-17RA compared to control in CFA- and IL-17-injected rats. The results suggest that spinal IL-17 is produced by astrocytes and enhances p-NR1 to facilitate pain.

The effects of opioid receptor antagonists on electroacupuncture-produced anti-allodynia/hyperalgesia in rats with paclitaxel-evoked peripheral neuropathy.

Research supports the effectiveness of acupuncture for conditions such as chronic low back and knee pain. In a five-patient pilot study the modality also improved the symptoms of chemotherapy-induced neuropathic pain. Using an established rat model of paclitaxel-induced peripheral neuropathy, we evaluated the effect of electroacupuncture (EA) on paclitaxel-induced hyperalgesia and allodynia that has not been studied in an animal model. We hypothesize that EA would relieve the paclitaxel-induced mechanical allodynia and hyperalgesia, which was assessed 30 min after EA using von Frey filaments. Beginning on day 13, the response frequency to von Frey filaments (4-15 g) was significantly increased in paclitaxel-injected rats compared to those injected with vehicle. EA at 10 Hz significantly (P<0.05) decreased response frequency at 4-15 g compared to sham EA; EA at 100 Hz only decreased response frequency at 15 g stimulation. Compared to sham EA plus vehicle, EA at 10 Hz plus either a µ, δ, or κ opioid receptor antagonist did not significantly decrease mechanical response frequency, indicating that all three antagonists blocked EA inhibition of allodynia and hyperalgesia. Since we previously demonstrated that µ and δ but not κ opioid receptors affect EA anti-hyperalgesia in an inflammatory pain model, these data show that EA inhibits pain through different opioid receptors under varying conditions. Our data indicate that EA at 10 Hz inhibits mechanical allodynia/hyperalgesia more potently than does EA at 100 Hz. Thus, EA significantly inhibits paclitaxel-induced allodynia/hyperalgesia through spinal opioid receptors, and EA may be a useful complementary treatment for neuropathic pain patients.

Serotonin Receptor 2A/C Is Involved in Electroacupuncture Inhibition of Pain in an Osteoarthritis Rat Model.

Osteoarthritis currently has no cure. Acupuncture can benefit patients with knee osteoarthritis by providing pain relief, improving joint function and serving as an effective complement to standard care. However, the underlying mechanisms of its effects are still not completely understood. The present study, an investigation of the effectiveness and mechanisms of electroacupuncture (EA) in attenuating osteoarthritis pain in a rat model, is focused on the involvement of 5-hydroxytryptamine 2A/C (5-HT2A/C) receptors, which play an important role in pain modulation at the spinal level. Osteoarthritis was induced under isoflurane anesthesia by a single intraarticular injection of monosodium iodoacetate (3 mg/50 µL/rat) into one hind leg of each rat. EA was given at acupoints GB 30 and ST 36 on days 1-4 after the injection. Vehicle or ketanserin, a 5-HT2A/C receptor antagonist, was given intraperitoneally (1 mg kg(-1)) or intrathecally (5 µg or 10 µg/10 µL), 30 min before each EA treatment. Assessment of weight-bearing difference between injected and uninjected hind legs was done on days 0, 1-4 and 7. Fos /serotonin and serotonin/Fluorogold double labeling were performed to determine EA activation of serotonergic neurons in the nucleus raphe magnus (NRM) that project to spinal cord. The results showed that EA significantly decreases weight-bearing difference compared to sham EA. Ketanserin pretreatment blocked the analgesic effect of EA but did not influence weight bearing in sham EA control rats. EA also activated serotonergic NRM neurons that project to the spinal cord. These data show that EA inhibits osteoarthritis-induced pain by enhancing spinal 5-HT2A/2C receptor activity.

Acupuncture alleviates the affective dimension of pain in a rat model of inflammatory hyperalgesia.

Although studies demonstrate that electroacupuncture (EA) alleviates the sensory dimension of pain, they have not addressed EA's effect on the affective dimension. An inflammatory pain rat model, produced by a complete Freund adjuvant (CFA) injection into the hind paw, was combined with a conditioned place avoidance test to determine EA's effects and its underpinning mechanism on the affective dimension of pain. CFA-injected rats showed place aversion, i.e. the affective dimension of pain, by spending less time in a pain-paired compartment after conditioning than before, while saline-injected rats did not. CFA rats given EA treatment at GB30 before a post-conditioning test showed no aversion to the pain-paired compartment, indicating that EA inhibited the affective response. Intra-rostral anterior cingulate cortex (rACC) administration of a κ-, but not µ-opioid receptor antagonist, blocked EA action. These data demonstrate that EA activates opioid receptors in the rACC to inhibit the affective dimension of pain.