T-type calcium channels, but not Cav3.2, in the peripheral sensory afferents are involved in acute itch in mice.

T-type calcium channels are prominently expressed in primary nociceptive fibers and well characterized in pain processes. Although itch and pain share many similarities including primary sensory fibers, the function of T-type calcium channels on acute itch has not been explored. We investigated whether T-type calcium channels expressed within primary sensory fibers of mouse skin, especially Cav3.2 subtype, involve in chloroquine-, endothelin-1- and histamine-evoked acute itch using pharmacological, neuronal imaging and behavioral analyses. We found that pre-locally blocking three subtypes of T-type calcium channels in the peripheral afferents of skins, yielded an inhibition in acute itch or pain behaviors, while selectively blocking the Cav3.2 channel in the skin peripheral afferents only inhibited acute pain but not acute itch. These results suggest that T-type Cav3.1 or Cav3.3, but not Cav3.2 channel, have an important role in acute itch processing, and their distinctive roles in modulating acute itch are worthy of further investigation.

Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma.

Prevalence of neuropathic pain is high after major surgery. However, effective treatment for preventing neuropathic pain is lacking. Here we report that perisurgical treatment of neuroprotectin D1/protectin D1 (NPD1/PD1), derived from docosahexaenoic acid, prevents nerve injury-induced mechanical allodynia and ongoing pain in mice. Intrathecal post-treatment of NPD1/PD1 also effectively reduces established neuropathic pain and produces no apparent signs of analgesic tolerance. Mechanistically, NPD1/PD1 treatment blocks nerve injury-induced long-term potentiation, glial reaction, and inflammatory responses, and reverses synaptic plasticity in the spinal cord. Thus, NPD1/PD1 and related mimetics might serve as a new class of analgesics for preventing and treating neuropathic pain.

Optogenetic Activation of Peripheral Somatosensory Neurons in Transgenic Mice as a Neuropathic Pain Model for Assessing the Therapeutic Efficacy of Analgesics.

Optogenetics is a novel biotechnology widely used to precisely manipulate a specific peripheral sensory neuron or neural circuit. However, the use of optogenetics to assess the therapeutic efficacy of analgesics is elusive. In this study, we generated a transgenic mouse stain in which all primary somatosensory neurons can be optogenetically activated to mimic neuronal hyperactivation in the neuropathic pain state for the assessment of analgesic effects of drugs. A transgenic mouse was generated using the advillin-Cre line mated with the Ai32 strain, in which channelrhodopsin-2 fused to enhanced yellow fluorescence protein (ChR2-EYFP) was conditionally expressed in all types of primary somatosensory neurons (advillincre/ChR2+/+). Immunofluorescence and transdermal photostimulation on the hindpaws were used to verify the transgenic mice. Optical stimulation to evoke pain-like paw withdrawal latency was used to assess the analgesic effects of a series of drugs. Injury- and pain-related molecular biomarkers were investigated with immunohistofluorescence. We found that the expression of ChR2-EYFP was observed in many primary afferents of paw skin and sciatic nerves and in primary sensory neurons and laminae I and II of the spinal dorsal horns in advillincre/ChR2+/+ mice. Transdermal blue light stimulation of the transgenic mouse hindpaw evoked nocifensive paw withdrawal behavior. Treatment with gabapentin, some channel blockers, and local anesthetics, but not opioids or COX-1/2 inhibitors, prolonged the paw withdrawal latency in the transgenic mice. The analgesic effect of gabapentin was also verified by the decreased expression of injury- and pain-related molecular biomarkers. These optogenetic mice provide a promising model for assessing the therapeutic efficacy of analgesics in neuropathic pain.

Activin C expressed in nociceptive afferent neurons is required for suppressing inflammatory pain.

Emerging evidence suggests that the suppressive modulators released from nociceptive afferent neurons contribute to pain regulation. However, the suppressive modulators expressed in small-diameter neurons of the dorsal root ganglion remain to be further identified. The present study shows that the activin C expressed in small dorsal root ganglion neurons is required for suppressing inflammation-induced nociceptive responses. The expression of activin C in small dorsal root ganglion neurons of rats was markedly downregulated during the early days of peripheral inflammation induced by intraplantar injection of the complete Freund's adjuvant. Intrathecal treatment with the small interfering RNA targeting activin ßC or the antibodies against activin C could enhance the formalin-induced nociceptive responses, and impair the recovery from the complete Freund's adjuvant-induced thermal hyperalgesia. Intrathecally applied activin C could reduce nociceptive responses induced by formalin or complete Freund's adjuvant. Moreover, activin C was found to inhibit the inflammation-induced phosphorylation of extracellular signal-regulated kinase in the dorsal root ganglia and the dorsal spinal cord. Thus, activin C functions as an endogenous suppressor of inflammatory nociceptive transmission and may have a therapeutic potential for treatment of inflammatory pain.

Transcriptional profiles of TGF-ß superfamily members in the lumbar DRGs and the effects of activins A and C on inflammatory pain in rats.

Signaling by the transforming growth factor (TGF)-ß superfamily is necessary for proper neural development and is involved in pain processing under both physiological and pathological conditions. Sensory neurons that reside in the dorsal root ganglia (DRGs) initially begin to perceive noxious signaling from their innervating peripheral target tissues and further convey pain signaling to the central nervous system. However, the transcriptional profile of the TGF-ß superfamily members in DRGs during chronic inflammatory pain remains elusive. We developed a custom microarray to screen for transcriptional changes in members of the TGF-ß superfamily in lumbar DRGs of rats with chronic inflammatory pain and found that the transcription of the TGF-ß superfamily members tends to be downregulated. Among them, signaling of the activin/inhibin and bone morphogenetic protein/growth and differentiation factor (BMP/GDF) families dramatically decreased. In addition, peripherally pre-local administration of activins A and C worsened formalin-induced acute inflammatory pain, whereas activin C, but not activin A, improved formalin-induced persistent inflammatory pain by inhibiting the activation of astrocytes. This is the first report of the TGF-ß superfamily transcriptional profiles in lumbar DRGs under chronic inflammatory pain conditions, in which transcriptional changes in cytokines or pathway components were found to contribute to, or be involved in, inflammatory pain processing. Our data will provide more targets for pain research.

Transcriptional Profiling of TGF-ß Superfamily Members in Lumbar DRGs of Rats Following Sciatic Nerve Axotomy and Activin C Inhibits Neuropathic Pain.

BACKGROUND: Neuroinflammation and cytokines play critical roles in neuropathic pain and axon degeneration/regeneration. Cytokines of transforming growth factor-ß superfamily have implications in pain and injured nerve repair processing. However, the transcriptional profiles of the transforming growth factor-ß superfamily members in dorsal root ganglia under neuropathic pain and axon degeneration/regeneration conditions remain elusive. OBJECTIVE: We aimed to plot the transcriptional profiles of transforming growth factor-ß superfamily components in lumbar dorsal root ganglia of sciatic nerve-axotomized rats and to further verify the profiles by testing the analgesic effect of activin C, a representative cytokine, on neuropathic pain. METHODS: Adult male rats were axotomized in sciatic nerves, and lumbar dorsal root ganglia were isolated for total RNA extraction or section. A custom microarray was developed and employed to plot the gene expression profiles of transforming growth factor-ß superfamily components. Realtime RT-PCR was used to confirm changes in the expression of activin/inhibin family genes, and then in situ hybridization was performed to determine the cellular locations of inhibin α, activin ßC, BMP-5 and GDF-9 mRNAs. The rat spared nerve injury model was performed, and a pain test was employed to determine the effect of activin C on neuropathic pain. RESULTS: The expression of transforming growth factor-ß superfamily cytokines and their signaling, including some receptors and signaling adaptors, were robustly upregulated. Activin ßC subunit mRNAs were expressed in the small-diameter dorsal root ganglion neurons and upregulated after axotomy. Single intrathecal injection of activin C inhibited neuropathic pain in spared nerve injury model. CONCLUSION: This is the first report to investigate the transcriptional profiles of members of transforming growth factor-ß superfamily in axotomized dorsal root ganglia. The distinct cytokine profiles observed here might provide clues toward further study of the role of transforming growth factor-ß superfamily in the pathogenesis of neuropathic pain and axon degeneration/regeneration after peripheral nerve injury.

Inhibition of inflammatory pain by activating B-type natriuretic peptide signal pathway in nociceptive sensory neurons.

B-type natriuretic peptide (BNP) has been known to be secreted from cardiac myocytes and activate its receptor, natriuretic peptide receptor-A (NPR-A), to reduce ventricular fibrosis. However, the function of BNP/NPR-A pathway in the somatic sensory system has been unknown. In the present study, we report a novel function of BNP in pain modulation. Using microarray and immunoblot analyses, we found that BNP and NPR-A were expressed in the dorsal root ganglion (DRG) of rats and upregulated after intraplantar injection of complete Freund's adjuvant (CFA). Immunohistochemistry showed that BNP was expressed in calcitonin gene-related peptide (CGRP)-containing small neurons and IB4 (isolectin B4)-positive neurons, whereas NPR-A was present in CGRP-containing neurons. Application of BNP reduced the firing frequency of small DRG neurons in the presence of glutamate through opening large-conductance Ca2+-activated K+ channels (BKCa channels). Furthermore, intrathecal injection of BNP yielded inhibitory effects on formalin-induced flinching behavior and CFA-induced thermal hyperalgesia in rats. Blockade of BNP signaling by BNP antibodies or cGMP-dependent protein kinase (PKG) inhibitor KT5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester] impaired the recovery from CFA-induced thermal hyperalgesia. Thus, BNP negatively regulates nociceptive transmission through presynaptic receptor NPR-A, and activation of the BNP/NPR-A/PKG/BKCa channel pathway in nociceptive afferent neurons could be a potential strategy for inflammatory pain therapy.

Deletion of MyD88 adaptor in nociceptor alleviates low-dose formalin-induced acute pain and persistent pain in mice.

The myeloid differentiation factor 88 (MyD88) adaptor mediates signaling by Toll-like receptors and some interleukins (ILs) in neural and non-neuronal cells. Recently, MyD88 protein was found to express in primary sensory neurons and be involved in the maintenance of persistent pain induced by complete Freund's adjuvant, chronic constriction injury and chemotherapy treatment in rodents. However, whether MyD88 in nociceptive neurons contributes to persistent pain induced by intraplantar injection of formalin remains elusive. Here, using conditional knockout (CKO) mice, we found that selective deletion of Myd88 in Nav1.8-expressing primary nociceptive neurons led to reduced pain response in the recovery phase of 1% formalin-induced mechanical pain and impaired the persistent thermal pain. Moreover, CKO mice exhibited reduced phase II pain response in 1%, but not 5%, formalin-induced acute inflammatory pain. Finally, nociceptor MyD88 deletion resulted in less neuronal c-Fos activation in spinal dorsal horns following 1% formalin stimulation. These data suggest that MyD88 in nociceptive neurons is not only involved in persistent mechanical pain but also promotes the transition from acute inflammatory pain to persistent thermal hyperalgesia induced by low-dose formalin stimulation.

Cytokine activin C ameliorates chronic neuropathic pain in peripheral nerve injury rodents by modulating the TRPV1 channel.

BACKGROUND AND PURPOSE: The cytokine activin C is mainly expressed in small-diameter dorsal root ganglion (DRG) neurons and suppresses inflammatory pain. However, the effects of activin C in neuropathic pain remain elusive. EXPERIMENTAL APPROACH: Male rats and wild-type and TRPV1 knockout mice with peripheral nerve injury - sciatic nerve axotomy and spinal nerve ligation in rats; chronic constriction injury (CCI) in mice - provided models of chronic neuropathic pain. Ipsilateral lumbar (L)4-5 DRGs were assayed for activin C expression. Chronic neuropathic pain animals were treated with intrathecal or locally pre-administered activin C or the vehicle. Nociceptive behaviours and pain-related markers in L4-5 DRGs and spinal cord were evaluated. TRPV1 channel modulation by activin C was measured. KEY RESULTS: Following peripheral nerve injury, expression of activin ßC subunit mRNA and activin C protein was markedly up-regulated in L4-5 DRGs of animals with axotomy, SNL or CCI. [Correction added on 26 November 2020, after first online publication: The preceding sentence has been corrected in this current version.] Intrathecal activin C dose-dependently inhibited neuropathic pain in spinal nerve ligated rats. Local pre-administration of activin C decreased neuropathic pain, macrophage infiltration into ipsilateral L4-5 DRGs and microglial reaction in L4-5 spinal cords of mice with CCI. In rat DRG neurons, activin C enhanced capsaicin-induced TRPV1 currents. Pre-treatment with activin C reduced capsaicin-evoked acute hyperalgesia and normalized capsaicin-evoked persistent hypothermia in mice. Finally, the analgesic effect of activin C was abolished in TRPV1 knockout mice with CCI. CONCLUSION AND IMPLICATIONS: Activin C inhibits neuropathic pain by modulating TRPV1 channels, revealing potential analgesic applications in chronic neuropathic pain therapy.

A central neural circuit for itch sensation.

Although itch sensation is an important protective mechanism for animals, chronic itch remains a challenging clinical problem. Itch processing has been studied extensively at the spinal level. However, how itch information is transmitted to the brain and what central circuits underlie the itch-induced scratching behavior remain largely unknown. We found that the spinoparabrachial pathway was activated during itch processing and that optogenetic suppression of this pathway impaired itch-induced scratching behaviors. Itch-mediating spinal neurons, which express the gastrin-releasing peptide receptor, are disynaptically connected to the parabrachial nucleus via glutamatergic spinal projection neurons. Blockade of synaptic output of glutamatergic neurons in the parabrachial nucleus suppressed pruritogen-induced scratching behavior. Thus, our studies reveal a central neural circuit that is critical for itch signal processing.

[Cell penetrating peptides enhance intracellular translocation and function of siRNA encapsulated in Pegylated liposomes].

AIM: To prepare the PEGylated liposomes modified with cell penetrating peptides, which protect siRNA from nuclease degradation and deliver efficiently siRNA into cells to facilitate silencing of target gene. METHODS: The purity of R8-PEG-PE and pNP-PEG-PE was detected by HPLC; the quantity of R8, PEG-DPPE modified R8, and R8 attached to the out membrane surface of the liposomal siRNA by transfer from R8-PEG-DPPE micelles to the liposomes was tested by fluorescence; Size and size distribution of siRNA loaded liposomes with and without attached R8 were determined by Zetasizer 5000; A comparison of mediated siRNA transfection efficiency between R8-liposomes and lipofectamine 2000 was examined by individual inside cell fluorescence intensity; The growth inhibition of small cell lung carcinoma NCI-H446 cells treated with R8-liposomal hdm2-siRNA or lipofectamine 2000-hdm2-siRNA complex was tested by MTT assay. RESULTS: The retention times of PEG-DPPE and R8-PEG-DPPE were 9.0 min and 7.8 min, respectively. Fluorescence scanning indicated that lipids composed of liposomes and siRNAs didn't interfere to the determination of R8 when it was attached to the liposomal siRNA. The cells treated with R8-liposomal hdm2-siRNA significantly enhanced the cellular uptake of hdm2-siRNA and facilitated the functions of hdm2-siRNA through silencing of target gene which, in turn, inhibited tumor cell growth, compared with lipofectamine 2000. CONCLUSION: The R8 attached liposomes are shown to be powerful carriers for delivery siRNAs into cell to silence targeted gene.

TLR signaling adaptor protein MyD88 in primary sensory neurons contributes to persistent inflammatory and neuropathic pain and neuroinflammation.

Increasing evidence suggests that neuro-immune and neuro-glial interactions are critically involved in chronic pain sensitization. It is well studied how immune/glial mediators sensitize pain, but how sensory neurons control neuroinflammation remains unclear. We employed Myd88 conditional knockout (CKO) mice, in which Myd88 was deleted in sodium channel subunit Nav1.8-expressing primary sensory neurons, to examine the unique role of neuronal MyD88 in regulating acute and chronic pain, and possible underlying mechanisms. We found that baseline pain and the formalin induced acute inflammatory pain were intact in CKO mice. However, the late phase inflammatory pain following complete Freund's adjuvant injection and the late phase neuropathic pain following chronic constriction injury (CCI), were reduced in CKO mice. CCI induced up-regulation of MyD88 and chemokine C-C motif ligand 2 expression in DRG neurons and macrophage infiltration into DRGs, and microglia activation in spinal dorsal horns in wild-type mice, but all these changes were compromised in CKO mice. Finally, the pain hypersensitivity induced by intraplantar IL-1ß was reduced in CKO mice. Our findings suggest that MyD88 in primary sensory neurons plays an active role in regulating IL-1ß signaling and neuroinflammation in the peripheral and the central nervous systems, and contributes to the maintenance of persistent pain.

Colocalization of insulin-like growth factor-1 receptor and T type Cav3.2 channel in dorsal root ganglia in chronic inflammatory pain mouse model.

Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays important roles in the nervous system. Increasing evidence supports that IGF-1 contributes to pain hypersensitivity through its insulin-like growth factor-1 receptor (IGF-1R) by activating IGF-1R/Akt or MAPK signaling pathways, whereas T-type Cav3.2 channel can facilitate and amplify pain signals originating from the sensory periphery. A recent study showed that activated IGF-1R can increase T-type Cav3.2 channel currents and further activate the G protein-dependent PKCα pathway to contribute to inflammatory pain sensitivity. However, the colocalization of IGF-1R and Cav3.2 in mouse dorsal root ganglion (DRG) under chronic inflammatory pain conditions remains elusive. In this study, we investigated changes in the expression of IGF-1R and the Cav3.2 channel, and their colocalization in mouse DRGs in chronic inflammatory pain condition (induced by complete Freund's adjuvant intraplanter injection) using real-time RT-PCR and immunohistochemistry approaches to confirm that Cav3.2 channel can mediate pain facilitation following IGF-1/IGF-1R signaling. We found that IGF-1R was expressed extensively in DRG neurons including small-, medium-, and large-sized neurons, whereas Cav3.2 channel was expressed exclusively in small-sized DRG neurons of naive mice. Expression of Cav3.2, but not IGF-1R, and colocalization of Cav3.2 and IGF-1R were increased in lumbar (L)4-L6 primary sensory neurons in DRGs of mice in chronic inflammatory pain. Moreover, the increased colocalization of IGF-1R and Cav3.2 is exclusively localized in small- and medium-sized primary sensory neurons. Our findings provided morphological evidence that T-type Cav3.2 channel, at least partially, mediates the pain facilitation of IGF-1/IGF-1R signaling in chronic inflammatory pain condition.

Expression patterns of T-type Cav3.2 channel and insulin-like growth factor-1 receptor in dorsal root ganglion neurons of mice after sciatic nerve axotomy.

Substantial evidence indicates that T-type Cav3.2 channel and insulin-like growth factor-1 (IGF-1) contribute to pain hypersensitivity within primary sensory nerves. A recent study suggested that activation of IGF-1 receptor (IGF-1R) could increase Cav3.2 channel currents and further contribute to inflammatory pain sensitivity. However, the expression patterns of Cav3.2 and IGF-1R and their colocalization in dorsal root ganglion (DRG) in chronic neuropathic pain condition remain unknown. In this study, we explored expression patterns of Cav3.2, IGF-1R and their colocalization, and whether phenotypic switch occurs in a subpopulation of Cav3.2 or IGF-1R neurons in mouse DRGs after sciatic nerve axotomy with immunofluorescence, real-time reverse transcription-PCR, and western blot assays. We found that expressions of Cav3.2 and IGF-1R, and their colocalization were not increased in DRGs of mice following axotomy. In addition, Cav3.2 or IGF-1R subpopulation neurons did not acquire significant switch in expression phenotype after sciatic nerve axotomy. Our findings argue for an upregulation of Cav3.2 and IGF-1R expression in lumbar DRGs post-sciatic nerve axotomy and provided an insight for understanding the functions of peripheral afferent Cav3.2 channel and IGF-1/IGF-1R signaling in chronic neuropathic pain.

Influence of microstructural features on thermal expansion coefficient in graphene/epoxy composites.

In this paper, theoretical calculations were conducted to determine the coefficient of thermal expansion (CTE) based on the effective medium approach using Green's function method. The influences of microstructural features were investigated, including volume fraction, aspect ratio, and the orientation of graphene fillers. Calculated results demonstrated strong anisotropy of CTE when all graphene sheets in the composite were aligned in the in-plane direction due to the large difference between the elastic moduli of the graphene and epoxy. The in-plane CTE in the graphene/epoxy composite can be effectively reduced with small additions of graphene additive. Orientation dispersion among the graphene fillers significantly decreases the anisotropy of CTE. Accounting for the influences of all microstructural features, simulation results closely align with current experimental results. This work will provide a general guideline and a solid foundation for the optimal design and preparation of graphene/polymer composites.

Fibroblast growth factor 7 is a nociceptive modulator secreted via large dense-core vesicles.

Fibroblast growth factor (FGF) 7, a member of FGF family, is initially found to be secreted from mesenchymal cells to repair epithelial tissues. However, its functions in the nervous system are largely unknown. The present study showed that FGF7 was a neuromodulator localized in the large dense-core vesicles (LDCVs) in nociceptive neurons. FGF7 was mainly expressed in small-diameter neurons of the dorsal root ganglion and could be transported to the dorsal spinal cord. Interestingly, FGF7 was mostly stored in LDCVs that did not contain neuropeptide substance P. Electrophysiological recordings in the spinal cord slice showed that buffer-applied FGF7 increased the amplitude of excitatory post-synaptic current evoked by stimulating the sensory afferent fibers. Behavior tests showed that intrathecally applied FGF7 potentiated the formalin-induced acute nociceptive response. Moreover, both acute and inflammatory nociceptive responses were significantly reduced in Fgf7-deficient mice. These results suggest that FGF7 exerts an excitatory modulation of nociceptive afferent transmission.

Alkylglyceronephosphate synthase (AGPS) alters lipid signaling pathways and supports chemotherapy resistance of glioma and hepatic carcinoma cell lines.

Chemotherapy continues to be a mainstay of cancer treatment, although drug resistance is a major obstacle. Lipid metabolism plays a critical role in cancer pathology, with elevated ether lipid levels. Recently, alkylglyceronephosphate synthase (AGPS), an enzyme that catalyzes the critical step in ether lipid synthesis, was shown to be up-regulated in multiple types of cancer cells and primary tumors. Here, we demonstrated that silencing of AGPS in chemotherapy resistance glioma U87MG/DDP and hepatic carcinoma HepG2/ADM cell lines resulted in reduced cell proliferation, increased drug sensitivity, cell cycle arrest and cell apoptosis through reducing the intracellular concentration of lysophosphatidic acid (LPA), lysophosphatidic acid-ether (LPAe) and prostaglandin E2 (PGE2), resulting in reduction of LPA receptor and EP receptors mediated PI3K/AKT signaling pathways and the expression of several multi-drug resistance genes, like MDR1, MRP1 and ABCG2. ß-catenin, caspase-3/8, Bcl-2 and survivin were also found to be involved. In summary, our studies indicate that AGPS plays a role in cancer chemotherapy resistance by mediating signaling lipid metabolism in cancer cells.

Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1.

Intracellular microRNAs (miRNAs) are key regulators of gene expression. The role of extracellular miRNAs in neuronal activation and sensory behaviors are unknown. Here we report an unconventional role of extracellular miRNAs for rapid excitation of nociceptor neurons via toll-like receptor-7 (TLR7) and its coupling to TRPA1 ion channel. miRNA-let-7b induces rapid inward currents and action potentials in dorsal root ganglion (DRG) neurons. These responses require the GUUGUGU motif, only occur in neurons coexpressing TLR7 and TRPA1, and are abolished in mice lacking Tlr7 or Trpa1. Furthermore, let-7b induces TLR7/TRPA1-dependent single-channel activities in DRG neurons and HEK293 cells overexpressing TLR7/TRPA1. Intraplantar injection of let-7b elicits rapid spontaneous pain via TLR7 and TRPA1. Finally, let-7b can be released from DRG neurons by neuronal activation, and let-7b inhibitor reduces formalin-induced TRPA1 currents and spontaneous pain. Thus, secreted extracellular miRNAs may serve as novel pain mediators via activating TLR7/TRPA1 in nociceptor neurons.

Transcriptional profiles of TGF-β superfamily members in the lumbar DRGs and the effects of activins A and C on inflammatory pain in rats

Signaling by the transforming growth factor (TGF)-β superfamily is necessary for proper neural development and is involved in pain processing under both physiological and pathological conditions. Sensory neurons that reside in the dorsal root ganglia (DRGs) initially begin to perceive noxious signaling from their innervating peripheral target tissues and further convey pain signaling to the central nervous system. However, the transcriptional profile of the TGF-β superfamily members in DRGs during chronic inflammatory pain remains elusive. We developed a custom microarray to screen for transcriptional changes in members of the TGF-β superfamily in lumbar DRGs of rats with chronic inflammatory pain and found that the transcription of the TGF-β superfamily members tends to be downregulated. Among them, signaling of the activin/inhibin and bone morphogenetic protein/growth and differentiation factor (BMP/GDF) families dramatically decreased. In addition, peripherally pre-local administration of activins A and C worsened formalin-induced acute inflammatory pain, whereas activin C, but not activin A, improved formalin-induced persistent inflammatory pain by inhibiting the activation of astrocytes. This is the first report of the TGF-β superfamily transcriptional profiles in lumbar DRGs under chronic inflammatory pain conditions, in which transcriptional changes in cytokines or pathway components were found to contribute to, or be involved in, inflammatory pain processing. Our data will provide more targets for pain research. (AU)

Prognostic factors for differentiated thyroid carcinoma and review of the literature.

OBJECTIVE: Prognostic factors of differentiated thyroid carcinoma (DTC) are analyzed to justify the diagnostic and therapeutic modalities of DTC in current practice. METHODS: Patients undergoing curative resection for histologically diagnosed DTC (n = 150) were consecutively enrolled, and the clinical and pathological data were retrospectively reviewed. RESULTS: The DTC patient cohort consisted of 113 females (75.3%; mean age at the time of onset, 40.1 ± 12.0 yr) and 37 males (24.7%; 47.5 ± 16.2 yr). The pathological types of DTC included papillary thyroid carcinoma (n = 131, 87.3%) and follicular thyroid carcinoma (n = 19, 12.7%). The follow-up period ranged from 4.2 to 31 years, in which period 140 (93.3%) patients survived, 30 (20.0%) patients relapsed, and 10 (6.7%) patients died of DTC. Surgical procedures used for the curative resection consisted of near-total or subtotal thyroidectomy (n = 83, 55.3%), partial thyroidectomy (n = 64, 42.7%) and total thyroidectomy (n = 3, 2.0%). Out of those patients undergoing concomitant lymph node dissection (n = 63, 42.0%), 45 patients (71.4%) had detectable lymph node metastases. Postoperatively, 12 patients (8.0%) received external beam radiotherapy, 16 patients (10.7%) received chemotherapy, 37 patients (24.7%) received 131I therapy, and 66 patients (44.0%) received additional long-term L-T4 or thyroid hormone treatment. Age of onset, tumor size at initial visit, and rate of early metastasis showed statistically significant differences between the mortality group and the survival group (P <0.05) and between the recurrence group and the recurrence-free group (P <0.05). CONCLUSIONS: Age, tumor size at initial visit, and early metastasis are prognostic factors for DTC, requiring a stratified management in clinical practice.