Trade and economic cooperation between Mongolia and Russia. To the 100th anniversary of the establishment of diplomatic relations between Mongolia and Russia

A report was presented on the significance and main tendencies of trade and economic cooperation between Mongolia and Russia in connection with the 100th anniversary of the establishment of diplomatic relations between Mongolia and Russia

Post-translational modifications of voltage-gated sodium channels in chronic pain syndromes.

In the peripheral sensory nervous system the neuronal expression of voltage-gated sodium channels (Navs) is very important for the transmission of nociceptive information since they give rise to the upstroke of the action potential (AP). Navs are composed of nine different isoforms with distinct biophysical properties. Studying the mutations associated with the increase or absence of pain sensitivity in humans, as well as other expression studies, have highlighted Nav1.7, Nav1.8, and Nav1.9 as being the most important contributors to the control of nociceptive neuronal electrogenesis. Modulating their expression and/or function can impact the shape of the AP and consequently modify nociceptive transmission, a process that is observed in persistent pain conditions. Post-translational modification (PTM) of Navs is a well-known process that modifies their expression and function. In chronic pain syndromes, the release of inflammatory molecules into the direct environment of dorsal root ganglia (DRG) sensory neurons leads to an abnormal activation of enzymes that induce Navs PTM. The addition of small molecules, i.e., peptides, phosphoryl groups, ubiquitin moieties and/or carbohydrates, can modify the function of Navs in two different ways: via direct physical interference with Nav gating, or via the control of Nav trafficking. Both mechanisms have a profound impact on neuronal excitability. In this review we will discuss the role of Protein Kinase A, B, and C, Mitogen Activated Protein Kinases and Ca++/Calmodulin-dependent Kinase II in peripheral chronic pain syndromes. We will also discuss more recent findings that the ubiquitination of Nav1.7 by Nedd4-2 and the effect of methylglyoxal on Nav1.8 are also implicated in the development of experimental neuropathic pain. We will address the potential roles of other PTMs in chronic pain and highlight the need for further investigation of PTMs of Navs in order to develop new pharmacological tools to alleviate pain

Adenosine A2A receptors: localization and function

Adenosine is an endogenous purine nucleoside present in all mammalian tissues, that originates from the breakdown of ATP. By binding to its four receptor subtypes (A1, A2A, A2B, and A3), adenosine regulates several important physiological functions at both the central and peripheral levels. Therefore, ligands for the different adenosine receptors are attracting increasing attention as new potential drugs to be used in the treatment of several diseases. This chapter is aimed at providing an overview of adenosine metabolism, adenosine receptors localization and their signal transduction pathways. Particular attention will be paid to the biochemistry and pharmacology of A2A receptors, since antagonists of these receptors have emerged as promising new drugs for the treatment of Parkinson's disease. The interactions of A2A receptors with other nonadenosinergic receptors, and the effects of the pharmacological manipulation of A2A receptors on different body organs will be discussed, together with the usefulness of A2A receptor antagonists for the treatment of Parkinson's disease and the potential adverse effects of these drugs

Keratinocytes can modulate and directly initiate nociceptive responses

How thermal, mechanical and chemical stimuli applied to the skin are transduced into signals transmitted by peripheral neurons to the CNS is an area of intense study. Several studies indicate that transduction mechanisms are intrinsic to cutaneous neurons and that epidermal keratinocytes only modulate this transduction. Using mice expressing channelrhodopsin (ChR2) in keratinocytes we show that blue light activation of the epidermis alone can produce action potentials (APs) in multiple types of cutaneous sensory neurons including SA1, A-HTMR, CM, CH, CMC, CMH and CMHC fiber types. In loss of function studies, yellow light stimulation of keratinocytes that express halorhodopsin reduced AP generation in response to naturalistic stimuli. These findings support the idea that intrinsic sensory transduction mechanisms in epidermal keratinocytes can directly elicit AP firing in nociceptive as well as tactile sensory afferents and suggest a significantly expanded role for the epidermis in sensory processing

Regulation of the Spontaneous Augmentation of NaV1.9 in Mouse Dorsal Root Ganglion Neurons: Effect of PKA and PKC Pathways

Sensory neurons in the dorsal root ganglion express two kinds of tetrodotoxin resistant (TTX-R) isoforms of voltage-gated sodium channels, NaV1.8 and NaV1.9. These isoforms play key roles in the pathophysiology of chronic pain. Of special interest is NaV1.9: our previous studies revealed a unique property of the NaV1.9 current, i.e., the NaV1.9 current shows a gradual and notable up-regulation of the peak amplitude during recording (“spontaneous augmentation of NaV1.9”). However, the mechanism underlying the spontaneous augmentation of NaV1.9 is still unclear. In this study, we examined the effects of protein kinases A and C (PKA and PKC), on the spontaneous augmentation of NaV1.9. The spontaneous augmentation of the NaV1.9 current was significantly suppressed by activation of PKA, whereas activation of PKA did not affect the voltage dependence of inactivation for the NaV1.9 current. On the contrary, the finding that activation of PKC can affect the voltage dependence of inactivation for NaV1.9 in the perforated patch recordings, where the augmentation does not occur, suggests that the effects of PMA are independent of the augmentation process. These results indicate that the spontaneous augmentation of NaV1.9 was regulated directly by PKA, and indirectly by PKC

Sciatic lateral popliteal block with clonidine alone or clonidine plus 0.2% ropivacaine: effect on the intra-and postoperative analgesia for lower extremity surgery in children: a randomized prospective controlled study

<p>Abstract</p> <p>Background</p> <p>The effect of adding clonidine to local anesthetics for nerve or plexus blocks remains unclear. Most of the studies in adults have demonstrated the positive effects of clonidine on intra- and postoperative analgesia when used as an adjunctive agent or in some cases as a single to regional techniques. In the pediatric population, there are only few trials involving clonidine as an adjunct to regional anesthesia, and the analgesic benefits are not definite in this group of patients. The evidence concerning perineural administration of clonidine is so far inconclusive in children, as different types and volume of local anesthetic agents have been used in these studies. Moreover, the efficacy of regional anesthesia is largely affected by the operator's technique, accuracy and severity of operation.</p> <p>Methods</p> <p>The use of clonidine alone or combined with 0.2% ropivacaine for effective analgesia after mild to moderate painful foot surgery was assessed in 66 children, after combined sciatic lateral popliteal block (SLPB) plus femoral block. The patients were randomly assigned into three groups to receive placebo, clonidine, and clonidine plus ropivacaine. Time to first analgesic request in the groups was analyzed by using Kaplan-Meier and the log-rank test (mean time, median time, 95% CI).</p> <p>Results</p> <p>In our study, clonidine administered alone in the SLPB seems promising, maintaining intraoperatively the hemodynamic parameters SAP, DAP, HR to the lower normal values so that no patient needed nalbuphine under 0.6 MAC sevoflurane anesthesia, and postoperatively without analgesic request for a median time of 6 hours. In addition, clonidine administered as adjuvant enhances ropivacaine's analgesic effect for the first postoperative day in the majority of children (p = 0.001). Clonidine and clonidine plus ropivacaine groups also didn’t demonstrate PONV, motor blockade, and moreover, the parents of children expressed their satisfaction with the excellent perioperative management of their children, with satisfaction score 9.74 ± 0.45 and 9.73 ± 0.70 respectively. On the contrary all the patients in the control group required rescue nalbuphine in the recovery room, and postoperatively, along with high incidence of PONV, and the parents of children reported a low satisfaction score (7.50 ± 0.70).</p> <p>Conclusions</p> <p>Clonidine appears promising more as an adjuvant in 0.2% ropivacaine and less than alone in the SLPB plus femoral block in children undergoing mild to moderate painful foot surgery, with no side effects.</p> <p>Trial registration</p> <p>ClinicalTrials.gov, <a href="http://www.controlled-trials.com/ISRCTN90832436">ISRCTN90832436</a>, (ref: CCT-NAPN-20886).</p

Importance of Non-Selective Cation Channel TRPV4 Interaction with Cytoskeleton and Their Reciprocal Regulations in Cultured Cells

BACKGROUND: TRPV4 and the cellular cytoskeleton have each been reported to influence cellular mechanosensitive processes as well as the development of mechanical hyperalgesia. If and how TRPV4 interacts with the microtubule and actin cytoskeleton at a molecular and functional level is not known. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated the interaction of TRPV4 with cytoskeletal components biochemically, cell biologically by observing morphological changes of DRG-neurons and DRG-neuron-derived F-11 cells, as well as functionally with calcium imaging. We find that TRPV4 physically interacts with tubulin, actin and neurofilament proteins as well as the nociceptive molecules PKCepsilon and CamKII. The C-terminus of TRPV4 is sufficient for the direct interaction with tubulin and actin, both with their soluble and their polymeric forms. Actin and tubulin compete for binding. The interaction with TRPV4 stabilizes microtubules even under depolymerizing conditions in vitro. Accordingly, in cellular systems TRPV4 colocalizes with actin and microtubules enriched structures at submembranous regions. Both expression and activation of TRPV4 induces striking morphological changes affecting lamellipodial, filopodial, growth cone, and neurite structures in non-neuronal cells, in DRG-neuron derived F11 cells, and also in IB4-positive DRG neurons. The functional interaction of TRPV4 and the cytoskeleton is mutual as Taxol, a microtubule stabilizer, reduces the Ca2+-influx via TRPV4. CONCLUSIONS AND SIGNIFICANCE: TRPV4 acts as a regulator for both, the microtubule and the actin. In turn, we describe that microtubule dynamics are an important regulator of TRPV4 activity. TRPV4 forms a supra-molecular complex containing cytoskeletal proteins and regulatory kinases. Thereby it can integrate signaling of various intracellular second messengers and signaling cascades, as well as cytoskeletal dynamics. This study points out the existence of cross-talks between non-selective cation channels and cytoskeleton at multiple levels. These cross talks may help us to understand the molecular basis of the Taxol-induced neuropathic pain development commonly observed in cancer patients