Repeated Administration of Orexin into the Thalamic Paraventricular Nucleus Inhibits the Development of Morphine-Induced Analgesia.

BACKGROUND: Hypothalamic neuropeptides, orexins, play pivotal roles in nociception and pain modulation. OBJECTIVE: In this study, we investigated the effect of the administration of orexin into the paraventricular nucleus (PVT) on the development of morphine-induced analgesia in rats. METHOD: Male Wistar rats weighing 250-300g received subcutaneous (s.c.) chronic morphine (6, 16, 26, 36, 46, 56 and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two experimental groups in which the orexin (100 µM, 200 nl) and its vehicle were microinjected into the PVT nucleus for 7 days before each morphine injection. Then, the formalin test was performed for the assessment of pain-related behaviors. RESULTS: The results demonstrated that the rats pretreated by intra-PVT orexin exhibited higher pain-related behaviors than the morphine-treated group. The analgesic effects of morphine were significantly lower in orexin plus morphine-treated rats than the vehicle plus morphine-treated ones. CONCLUSION: Our findings suggested that the animals receiving the prolonged intra-PVT application of orexin before morphine injection demonstrated a significant increase in the development of nociceptive behaviors in all phases. There fore, the present study highlighted a new area of the brain involved in the effect of orexin on analgesia induced by morphine.

A review on the role of M2 macrophages in bladder cancer; pathophysiology and targeting.

Tumor-associated macrophages (TAMs) which are often referred to as immunosuppressive cells (M2 macrophage), constitute a subset of tumor microenvironment cells and affect tumor progression in solid tumors. Recently, these cells have gained remarkable importance as therapeutic candidates for solid tumors. In bladder cancer, major studies have focused on evaluating TAMs in response to Bacillus Calmette-Guerin (BCG) therapy. M2 macrophages may directly impact the BCG-induced immune responses against tumor in bladder cancer. They are the main inhibitors of the tumor microenvironment that promotes growth and metastasis of the tumor. However, the clinical significance of M2 macrophages in bladder cancer is controversial. In this review, we will discuss the clinical significance of M2 macrophages in prognosis of bladder cancer as well as worth of their potential targeting in bladder cancer treatment. In the following, we will introduce important factors resulting in M2 macrophage promotion and also experimental therapeutic agents that may cause the inhibition of bladder cancer tumor growth.

A comparative study between platelet-rich plasma and platelet-poor plasma effects on angiogenesis.

Platelet-rich plasma (PRP) has been established as an autologous source for therapeutic angiogenesis. The purpose of this study was to evaluate PRP angiogenic effects compared to platelet-poor plasma (PPP) in vitro and in vivo. The effects of PRP on vascular endothelial growth factor receptor-2 (VEGFR2) and CD34 expression were evaluated using real-time PCR, flow cytometry, western blot, immunocytochemistry and pathological study, as were carried out in both human umbilical endothelial cell culture and rat skin. Our findings indicated significant effect of PRP and PPP on VEGFR2 and CD34 expression by human umbilical vein endothelial cells, which was greater in latter. These effects, however, were confirmed by demonstrating an earlier angiogenic effect of PPP in vivo when compared to PRP. The findings of the present study as the first comparative study of PRP versus PPP are novel. Nevertheless, further studies are needed to clarify the underlying mechanism of these findings to improve the therapeutic effects of PRP and PPP.

Postnatal development changes in excitatory synaptic activity in the rat locus coeruleus neurons.

Glutamatergic synapses are shown to mature during activity and development. In order to further explore how glutamate can change the excitability of noradrenergic neurons of locus coeruleus (LC) and to better understand the involvement of Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors complements across the LC, we investigated developmental changes in their activity during first postnatal weeks. Spontaneous and evoked excitatory postsynaptic currents (sEPSC and eEPSCs) were recorded in neurons of LC slices from 7, 14 and 21 days old rats using the whole cell patch clamp method. Also, the AMPA/NMDA current ratio (A/N) was measured. A pronounced AMPAR and NMDAR components mediated involvement in synaptic transmission were seen from the first postnatal week. Over this period of development, we have demonstrated that AMPA sEPSCs show an increase in frequency without major changes in their amplitude, while NMDA sEPSCs show an increase in frequency with a major change in amplitude. Neither the probability of release nor the AMPA/NMDA ratio was found to change significantly with age. It is concluded that NMDAR activity as well as AMPAR activity may be involved in coerulear excitability and modulatory effect during postnatal development.

Nitric oxide in the nucleus raphe magnus modulates cutaneous blood flow in rats during hypothermia.

OBJECTIVES: Nucleus Raphe Magnus (NRM) that is involved in the regulation of body temperature contains nitric oxide (NO) synthase. Considering the effect of NO on skin blood flow control, in this study, we assessed its thermoregulatory role within the raphe magnus. MATERIALS AND METHODS: To this end, tail blood flow of male Wistar rats was measured by laser doppler following the induction of hypothermia. RESULTS: Intra-NRM injection of SNP (exogenous NO donor, 0.1- 0.2 µl, 0.2 nM) increased the blood flow. Similarly, unilateral microinjection of glutamate (0.1- 0.2 µl, 2.3 nM) into the nucleus increased the blood flow. This effect of L-glutamate was reduced by prior intra NRM administration of NO synthase inhibitor N(G)-methyl-L-arginine or N(G)-nitro-L-arginine methyl ester (L-NAME, 0.1 µl, 100 nM). CONCLUSION: It is concluded that NO modulates the thermoregulatory response of NRM to hypothermia and may interact with excitatory amino acids in central skin blood flow regulation.

Reciprocal Homosynaptic and heterosynaptic long-term plasticity of corticogeniculate projection neurons in layer VI of the mouse visual cortex.

Most neurons in layer VI of the visual cortex project to the dorsal lateral geniculate nucleus (dLGN). These corticogeniculate projection neurons (CG cells) receive top-down synaptic inputs from upper layers (ULs) and bottom-up inputs from the underlying white matter (WM). Use-dependent plasticity of these synapses in layer VI of the cortex has received less attention than in other layers. In the present study, we used a retrograde tracer injected into dLGN to identify CG cells, and, by analyzing EPSPs evoked by electrical stimulation of the UL or WM site, examined whether these synapses show long-term synaptic plasticity. Theta-burst stimulation induced long-term potentiation (LTP) of activated synapses (hom-LTP) and long-term depression (LTD) of nonactivated synapses (het-LTD) in either pathway. The paired-pulse stimulation protocol and the analysis of coefficient variation of EPSPs suggested postsynaptic induction of these changes except UL-induced het-LTD, which may be presynaptic in origin. Intracellular injection of a Ca(2+)-chelator suggested an involvement of postsynaptic Ca(2+) rise in all types of long-term plasticity. Pharmacological analysis indicated that NMDA receptors and type-5 metabotropic glutamate receptors are involved in WM-induced and UL-induced plasticity, respectively. Analysis with inhibitors and/or in transgenic mice suggested an involvement of cannabinoid type 1 receptors and calcineurin in UL-induced and WM-induced het-LTD, respectively. These results suggest that hom-LTP and het-LTD may play a role in switching the top-down or bottom-up regulation of CG cell function and/or in maintaining stability of synaptic transmission efficacy through different molecular mechanisms.

Cell type-specific, presynaptic LTP of inhibitory synapses on fast-spiking GABAergic neurons in the mouse visual cortex.

Properties and plasticity of inhibitory synapses on fast-spiking (FS) GABAergic (FS-GABA) interneurons in layer II/III of the mouse visual cortex were examined in cortical slices by whole-cell recordings of IPSCs or IPSPs evoked by activation of presynaptic FS or non-FS GABAergic interneurons. Unitary IPSCs (uIPSCs) evoked by action potentials of FS-GABA neurons have shorter onset latency, faster rising slope, higher peak amplitude, and faster decay time than those evoked by action potentials of non-FS-GABA neurons. Tetanic activation of presynaptic FS-GABA neurons induced long-term potentiation (LTP) of uIPSCs, whereas that of presynaptic non-FS-GABA neurons did not induce LTP, indicating that long-term plasticity of inhibitory synapses on FS-GABA neurons is pathway specific. For further analysis of inhibitory synaptic plasticity, IPSPs evoked by electrical stimulation of an adjacent site in the cortex were recorded from FS-GABA neurons. Theta burst stimulation induced LTP of IPSPs in 12 of 14 FS-GABA neurons. The paired-pulse stimulation protocol and coefficient of variation analysis indicated that this form of LTP may be presynaptic in origin. Filling postsynaptic cells with a Ca(2+) chelator did not block the induction of LTP, suggesting no involvement of postsynaptic Ca(2+) rise. Also, this form of LTP was dependent neither on metabotropic glutamate receptors nor voltage-gated Ca(2+) channels of the L and T types. Further pharmacological analysis indicated that voltage-gated Ca(2+) channels other than the P/Q type, such as N and R types, were not involved in LTP, suggesting that P/Q-type channels are a candidate for factors inducing LTP of inhibitory synapses between FS-GABA neurons.