Glial TNFα in the spinal cord regulates neuropathic pain induced by HIV gp120 application in rats

<p>Abstract</p> <p>Background</p> <p>HIV-associated sensory neuropathy (HIV-SN) is one of the most common forms of peripheral neuropathy, affecting about 30% of people with acquired immune deficiency syndrome (AIDS). The symptoms of HIV-SN are dominated by neuropathic pain. Glia activation in the spinal cord has become an attractive target for attenuating chronic pain. This study will investigate the role of spinal TNFα released from glia in HIV-related neuropathic pain.</p> <p>Results</p> <p>Peripheral gp120 application into the rat sciatic nerve induced mechanical allodynia for more than 7 weeks, and upregulated the expression of spinal TNFα in the mRNA and the protein levels at 2 weeks after gp120 application. Spinal TNFα was colocalized with GFAP (a marker of astrocytes) and Iba1 (a marker of microglia) in immunostaining, suggesting that glia produce TNFα in the spinal cord in this model. Peripheral gp120 application also increased TNFα in the L4/5 DRG. Furthermore, intrathecal administration of TNFα siRNA or soluble TNF receptor reduced gp120 application-induced mechanical allodynia.</p> <p>Conclusions</p> <p>Our results indicate that TNFα in the spinal cord and the DRG are involved in neuropathic pain, following the peripheral HIV gp120 application, and that blockade of the glial product TNFα reverses neuropathic pain induced by HIV gp120 application.</p

Characteristics of convective storm activity during the warm season over Anhui Province based on radar mosaic climatology and the possible causes

In order to understand the radar climatology characteristics of convective activity over Anhui Province, the climatological distribution and influencing factors of convective activity during the warm season (May-September) were investigated using Doppler radar mosaic data from five Next Generation Weather Radars and ERA5 reanalysis data between 2015 and 2020. Results indicate that: (1) There are obvious inter-monthly variations and spatial differences of convective activity during the warm season. The convective activity peaks during the Meiyu period, with the highest frequency in June and July, followed by May and August, and the lowest in September. The region with the highest convective in July and July is mainly distributed in the southwest-northeast direction. (2) It is found that the diurnal variation of convective number is bimodally distributed in summer (June-August), with the main peak in the afternoon and a subpeak in the early morning. In June, the peak convective activity mainly occurs in the early morning, which is related to the strengthening of low-level southwest airflow from night to early morning, and thus enhancing the moisture flux convergence in Anhui. In July, the peak convective activity appears in the afternoon, with a subpeak in the early morning. Note that the main peak is stronger and the duration is longer, which is related to the enhancement of convective available potential energy in Anhui in July. The second peak in early morning is also caused by the strengthening of the low-level southwest airflow, which is similar to that in June, but the intensity is weaker. Convective activity in August exhibits a single peak in the afternoon with the most significant diurnal variation, which shows a typical afternoon thermal convection type

Current gene therapy using viral vectors for chronic pain

The complexity of chronic pain and the challenges of pharmacotherapy highlight the importance of development of new approaches to pain management. Gene therapy approaches may be complementary to pharmacotherapy for several advantages. Gene therapy strategies may target specific chronic pain mechanisms in a tissue-specific manner. The present collection of articles features distinct gene therapy approaches targeting specific mechanisms identified as important in the specific pain conditions. Dr. Fairbanks group describes commonly used gene therapeutics (herpes simplex viral vector (HSV) and adeno-associated viral vector (AAV)), and addresses biodistribution and potential neurotoxicity in pre-clinical models of vector delivery. Dr. Tao group addresses that downregulation of a voltage-gated potassium channel (Kv1.2) contributes to the maintenance of neuropathic pain. Alleviation of chronic pain through restoring Kv1.2 expression in sensory neurons is presented in this review. Drs Goins and Kinchington group describes a strategy to use the replication defective HSV vector to deliver two different gene products (enkephalin and TNF soluble receptor) for the treatment of post-herpetic neuralgia. Dr. Hao group addresses the observation that the pro-inflammatory cytokines are an important shared mechanism underlying both neuropathic pain and the development of opioid analgesic tolerance and withdrawal. The use of gene therapy strategies to enhance expression of the anti-pro-inflammatory cytokines is summarized. Development of multiple gene therapy strategies may have the benefit of targeting specific pathologies associated with distinct chronic pain conditions (by Guest Editors, Drs. C. Fairbanks and S. Hao)

Copulas for statistical signal processing (Part I) : extensions and generalization

Existing works on multivariate distributions mainly focus on limited distribution functions and require that the associated marginal distributions belong to the same family. Although this simplifies problems, it may fail to deal with practical cases when the marginal distributions are arbitrary. To this end, copula function is employed since it provides a flexible way in decoupling the marginal distributions and dependence structure for random variables. Among different copula functions, most researches focus on Gaussian, Student's t and Archimedean copulas for simplicity. In this paper, to extend bivariate copula families, we have constructed new bivariate copulas for exponential, Weibull and Rician distributions. We have proved that the three copula functions of exponential, Rayleigh and Weibull distributions are equivalent, constrained by only one parameter, thus greatly facilitating practical applications of them. We have also proved that the copula function of log-normal distribution is equivalent to the Gaussian copula. Moreover, we have derived the Rician copula with two parameters. In addition, the modified Bessel function or incomplete Gamma function with double integrals in the copula functions are simplified by single integral or infinite series for computational efficiency. Associated copula density functions for exponential, Rayleigh, Weibull, log-normal, Nakagami-m and Rician distributions are also derive

The Role of TNFα in the Periaqueductal Gray During Naloxone-Precipitated Morphine Withdrawal in Rats

Tolerance and dependence are common complications of long-term treatment of pain with opioids, which substantially limit the long-term use of these drugs. The mechanisms underlying these phenomena are poorly understood. Studies have implicated the midbrain periaqueductal gray (PAG) in the pathogenesis of morphine withdrawal, and recent evidence suggests that proinflammatory cytokines in the PAG may play an important role in morphine withdrawal. Here we report that chronic morphine withdrawal-induced upregulation of glial fibrillary acidic protein (GFAP), tumor necrosis factor alpha (TNF α ) and phosphorylation of ERK1/2 (pERK1/2) in the caudal ventrolateral PAG (vlPAG). Microinjection of recombinant TNF α into the vlPAG followed by intraperitoneal naloxone resulted in morphine withdrawal-like behavioral signs, and upregulation of pERK1/2, expression of Fos, and phosphorylation of cAMP response element binding (pCREB) protein. We used a herpes simplex virus (HSV)-based vector expressing p55 soluble TNF receptor (sTNFR) microinjected into the PAG to examine the role of the proinflammatory cytokine TNF α in the PAG in the naloxone-precipitated withdrawal response. Microinjection of HSV vector expressing sTNFR into the PAG before the start of morphine treatment significantly reduced the naloxone-precipitated withdrawal behavioral response and downregulated the expression of GFAP and TNF α in astrocytes of the PAG. TNFR type I colocalized with neuronal pERK1/2. Microinjection of HSV vector expressing sTNFR into the PAG also significantly reduced the phosphorylation of both ERK1/2 and CREB, and reduced Fos immunoreactivity in neurons of the PAG following naloxone-precipitated withdrawal. These results support the concept that proinflammatory cytokines expressed in astrocytes in the PAG may play an important role in the pathogenesis of morphine withdrawal response

TNFα and IL-1β are mediated by both TLR4 and Nod1 pathways in the cultured HAPI cells stimulated by LPS

► LPS induces proinflammatory cytokine release in HAPI cells. ► JNK pathway is dependent on TLR4 signaling to release cytokines. ► NF-κB pathway is dependent on Nod1 signaling to release cytokines. A growing body of evidence recently suggests that glial cell activation plays an important role in several neurodegenerative diseases and neuropathic pain. Microglia in the central nervous system express toll-like receptor 4 (TLR4) that is traditionally accepted as the primary receptor of lipopolysaccharide (LPS). LPS activates TLR4 signaling pathways to induce the production of proinflammatory molecules. In the present studies, we verified the LPS signaling pathways using cultured highly aggressively proliferating immortalized (HAPI) microglial cells. We found that HAPI cells treated with LPS upregulated the expression of TLR4, phospho-JNK (pJNK) and phospho-NF-κB (pNF-κB), TNFα and IL-1β. Silencing TLR4 with siRNA reduced the expression of pJNK, TNFα and IL-1β, but not pNF-κB in the cells. Inhibition of JNK with SP600125 (a JNK inhibitor) decreased the expression of TNFα and IL-1β. Unexpectedly, we found that inhibition of Nod1 with ML130 significantly reduced the expression of pNF-κB. Inhibition of NF-κB also reduced the expression of TNFα and IL-1β. Nod1 ligand, DAP induced the upregulation of pNF-κB which was blocked by Nod1 inhibitor. These data indicate that LPS-induced pJNK is TLR4-dependent, and that pNF-κB is Nod1-dependent in HAPI cells treated with LPS. Either TLR4–JNK or Nod1–NF-κB pathways is involved in the expression of TNFα and IL-1β

Crosstalk Between JNK and NF-κB in the KDO2-Mediated Production of TNFα in HAPI Cells

Both nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases mediate production of proinflammatory cytokines in many types of cells. c-Jun N-terminal kinases (JNK) is a key regulator of many cellular events including cell inflammation and/or programmed cell death (apoptosis). In addition to mediating immune and inflammatory responses, NF-κB transcription factors control cell survival. It is reported that activation of NF-κB antagonizes apoptosis or programmed cell death by numerous triggers. It has been reported that NF-κB activation results in rapid inactivation of JNK in tumor necrosis factor alpha (TNFα)-treated murine embryonic fibroblasts. It is not clear about the relationship of JNK and NF-κB in the microglial cells induced by TLR4 activity. In the present study, we investigated the relationship of JNK and NF-κB in the highly aggressively proliferating immortalized microglial cell line treated with KDO2 (a TLR4 agonist). KDO2 treatment significantly induced the phosphorylation of JNK and NF-κB, and released TNFα. Knockdown of TLR4 with TLR4 siRNA significantly reduced phosphorylation of JNK (pJNK), phosphorylation of NF-κB, and release of TNFα. Inhibition of JNK reduced the release of TNFα, but not phosphorylation of NF-κB. Unexpectedly, inhibition of NF-κB enhanced pJNK and the release of TNFα. These results showed that TNFα induced by KDO2 was JNK-dependent, and that NF-κB negatively modulated both pJNK and TNFα in the cultured microglial cell line. The current study may provide a new insight in the modulation of TNFα in the microglial cell line