Opioid Receptors in Immune and Glial Cells-Implications for Pain Control

Opioid receptors comprise μ (MOP), δ (DOP), κ (KOP), and nociceptin/orphanin FQ (NOP) receptors. Opioids are agonists of MOP, DOP, and KOP receptors, whereas nociceptin/orphanin FQ (N/OFQ) is an agonist of NOP receptors. Activation of all four opioid receptors in neurons can induce analgesia in animal models, but the most clinically relevant are MOP receptor agonists (e.g., morphine, fentanyl). Opioids can also affect the function of immune cells, and their actions in relation to immunosuppression and infections have been widely discussed. Here, we analyze the expression and the role of opioid receptors in peripheral immune cells and glia in the modulation of pain. All four opioid receptors have been identified at the mRNA and protein levels in immune cells (lymphocytes, granulocytes, monocytes, macrophages) in humans, rhesus monkeys, rats or mice. Activation of leukocyte MOP, DOP, and KOP receptors was recently reported to attenuate pain after nerve injury in mice. This involved intracellular Ca2+-regulated release of opioid peptides from immune cells, which subsequently activated MOP, DOP, and KOP receptors on peripheral neurons. There is no evidence of pain modulation by leukocyte NOP receptors. More good quality studies are needed to verify the presence of DOP, KOP, and NOP receptors in native glia. Although still questioned, MOP receptors might be expressed in brain or spinal cord microglia and astrocytes in humans, mice, and rats. Morphine acting at spinal cord microglia is often reported to induce hyperalgesia in rodents. However, most studies used animals without pathological pain and/or unconventional paradigms (e.g., high or ultra-low doses, pain assessment after abrupt discontinuation of chronic morphine treatment). Therefore, the opioid-induced hyperalgesia can be viewed in the context of dependence/withdrawal rather than pain management, in line with clinical reports. There is convincing evidence of analgesic effects mediated by immune cell-derived opioid peptides in animal models and in humans. Together, MOP, DOP, and KOP receptors, and opioid peptides in immune cells can ameliorate pathological pain. The relevance of NOP receptors and N/OFQ in leukocytes, and of all opioid receptors, opioid peptides and N/OFQ in native glia for pain control is yet to be clarified

A Performance Measurement Framework and Solution Approach for the Integrated Facility Layout Problem With Uncertain Demand

The integrated facility layout problem (IFLP) focuses on the simultaneous determination of the relative locations of multiple copies of capacitated equip- ment or machinery in a facility, as well as the material ow between these units. In this paper, we consider the IFLP in the existence of uncertain demand for the products of the facility. Motivated by the framework for next generation facility layouts by Benjaafar et al. (2002), we extend the approaches in the lit- erature for distributed facility layouts to the case of dynamic demand and the possibility of relayouts, and propose a heuristic solution approach to minimize the expected total material handling cost over the planning horizon. We also analyze the performance of the resulting solutions in terms of empty travel of the material handling equipment and waiting time. Our computational results reveal that when demand is dynamic and stochastic, the relationship between the level of uncertainty and relayout cost plays an important role in determin- ing layout performance, and therefore a priori assumption of using a certain layout type may lead to detrimental results

The Storage Replenishment Problem in Rectangular Warehouses

In warehouses, storage replenishment operations involve the transportation of items to capacitated item slots in forward storage area from reserve storage. These items are later picked from these slots as their demand arises. While order picking constitutes the majority of warehouse operating costs, replenishment operations might be as costly in warehouses where pick lists generally consist of only a few lines (e.g., order fulfillment warehouses). In this study, we consider the storage replenishment problem in a parallel-aisle warehouse, where replenishment and order picking operations are carried out in successive waves with time limits. The aim is to determine the item slots that will be replenished and the route of the replenishment worker in each replenishment wave, so as to minimize the total labor and travel costs, and ensure the availability of items at the start of the wave they will be picked. The problem is analogous to the inventory routing problem due to the inherent trade-o between labor and travel costs. We present complexity results on different variants of the problem and show that the problem is NP-hard in general. Consequently, we use a heuristic approach inspired by those from the inventory routing literature. We use randomly generated warehouse instances to analyze the elect of different storage policies (random and turnover-based) and demand patterns (highly skewed or uniform) on replenishment performance, and to compare the proposed replenishment approach to those in practice

Warehousing efficiency in a small warehouse

Small warehouses generally have different needs than large warehouses. They usually do not have warehouse management systems that are data intensive and involve high capital investment. Operational procedures are more nebulous and management control is less rigid. Because of the difference in operational approach, different measures are needed in order to enhance productivity. This paper describes the results and insights gained from a study of the inventory control and warehouse operations at an industrial distributor of maintenance and repair items. The accuracy of the inventory and the efficiency of order picking are studied and appropriate measures are proposed in order to improve operations. Improvements are in the areas of process organization, inventory accuracy, inventory control, and order picking. Implementations and results are reported. Major improvements include lowering inventory levels and more efficient order picking

Order picking in parallel-aisle warehouses with multiple blocks::complexity and a graph theory-based heuristic

In this paper, we consider the order picking problem (OPP), which constitutes one of the special cases of the Steiner travelling salesperson problem and addresses the costliest operation in a warehouse. Given a list of items to be picked and their locations in the warehouse layout, the OPP aims to find the shortest route that starts from a depot point, picks all the items in the list, and returns to the depot. This paper fills two important gaps regarding the OPP. First, to the best of our knowledge, we present the first complexity results on the problem. Second, we propose a heuristic approach that makes use of its graph-theoretic properties. Computational experiments on randomly generated instances show that the heuristic not only outperforms its state-of-the-art counterparts in the literature, but it is also robust in terms of changing problem parameters

Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain

Neuropathic pain often results from peripheral nerve damage, which can involve immune response. Local leukocyte-derived opioid peptides or exogenous opioid agonists inhibit neuropathy-induced mechanical hypersensitivity in animal models. Since neuropathic pain can also be augmented by heat, in this study we investigated the role of opioids in the modulation of neuropathy-evoked heat hypersensitivity. We used a chronic constriction injury of the sciatic nerve in wild-type and opioid peptide-knockout mice, and tested opioid effects in heat and mechanical hypersensitivity using Hargreaves and von Frey tests, respectively. We found that although perineural exogenous opioid agonists, including peptidergic ligands, were effective, the endogenous opioid peptides β-endorphin, Met-enkephalin and dynorphin A did not alleviate heat hypersensitivity. Specifically, corticotropin-releasing factor, an agent triggering opioid peptide secretion from leukocytes, applied perineurally did not attenuate heat hypersensitivity in wild-type mice. Exogenous opioids, also shown to release opioid peptides via activation of leukocyte opioid receptors, were equally analgesic in wild-type and opioid peptide-knockout mice, indicating that endogenous opioids do not contribute to exogenous opioid analgesia in heat hypersensitivity. Furthermore, exogenously applied opioid peptides were ineffective as well. Conversely, opioid peptides relieved mechanical hypersensitivity. Thus, both opioid type and sensory modality may determine the outcome of neuropathic pain treatment

Mu-Opioid Receptor Agonist Induces Kir3 Currents in Mouse Peripheral Sensory Neurons - Effects of Nerve Injury

Neuropathic pain often arises from damage to peripheral nerves and is difficult to treat. Activation of opioid receptors in peripheral sensory neurons is devoid of respiratory depression, sedation, nausea, and addiction mediated in the brain, and ameliorates neuropathic pain in animal models. Mechanisms of peripheral opioid analgesia have therefore gained interest, but the role of G protein-coupled inwardly rectifying potassium (Kir3) channels, important regulators of neuronal excitability, remains unclear. Whereas functional Kir3 channels have been detected in dorsal root ganglion (DRG) neurons in rats, some studies question their contribution to opioid analgesia in inflammatory pain models in mice. However, neuropathic pain can be diminished by activation of peripheral opioid receptors in mouse models. Therefore, here we investigated effects of the selective μ-opioid receptor (MOR) agonist [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on potassium conductance in DRG neurons upon a chronic constriction injury (CCI) of the sciatic nerve in mice. For verification, we also tested human embryonic kidney (HEK) 293 cells transfected with MOR and Kir3.2. Using patch clamp, we recorded currents at -80 mV and applied voltage ramps in high extracellular potassium concentrations, which are a highly sensitive measures of Kir3 channel activity. We found a significantly higher rate of HEK cells responding with potassium channel blocker barium-sensitive inward current (233 +/- 51 pA) to DAMGO application in transfected than in untransfected group, which confirms successful recordings of inward currents through Kir3.2 channels. Interestingly, DAMGO induced similar inward currents (178 +/- 36-207 +/- 56 pA) in 15-20% of recorded DRG neurons from naive mice and in 4-27% of DRG neurons from mice exposed to CCI, measured in voltage clamp or voltage ramp modes. DAMGO-induced currents in naive and CCI groups were reversed by barium and a more selective Kir3 channel blocker tertiapin-Q. These data indicate the coupling of Kir3 channels with MOR in mouse peripheral sensory neuron cell bodies, which was unchanged after CCI. A comparative analysis of opioid-induced potassium conductance at the axonal injury site and peripheral terminals of DRG neurons could clarify the role of Kir3 channel-MOR interactions in peripheral nerve injury and opioid analgesia

Usporedba performansi modela ARIMAX, ANN i hibridizacije ARIMAX-ANN u predviđanju prodaje za industriju namještaja

Manufacturing firms aim to increase their profits and reduce costs in a competitive and rapidly changing market. One of the most important ways to reach these goals is to forecast sales correctly. Furniture manufacturing, which is considered a prosperous and growing industry in Turkey, has an increasing trend related to the growth in construction and associated industries, increase in urban migration and increase in per capita income. Accuracy of sales forecasting in furniture industry is affected by external factors, such as consumer confidence index, producer price index, month of the year and number of vacation days as well as the time factor itself. This study aims to develop an Autoregressive Integrated Moving Average with external variables (ARIMAX) to forecast the total monthly sales of furniture products of a well-known manufacturer in Turkey. As a follow up study, a performance comparison between ARIMAX, artificial neural networks (ANNs) and ARIMAX-ANN hybridization is performed. In conclusion, results of performance measures demonstrate that hybrid model developed for each amount of product sales give better accuracy values than single methods. Overall, it is proved that using the ARIMAX and hybridization of this method with ANN are applicable for forecasting monthly sales of furniture products

An analysis of 214 cases of rib fractures

INTRODUCTION: Rib fractures are the most common type of injury associated with trauma to the thorax. In this study, we investigated whether morbidity and mortality rates increased in correlation with the number of fractured ribs. MATERIALS AND METHODS: Data from 214 patients with rib fractures who applied or were referred to our clinic between January 2007 and December 2008 were retrospectively evaluated. The patients were allocated into three groups according to the number of fractures: 1) patients with an isolated rib fracture (RF1) (n = 50, 23.4%), 2) patients with two rib fractures (RF2) (n = 53, 24.8%), and 3) patients with more than two rib fractures (RF3) (n = 111, 51.9%). The patients were evaluated and compared according to the number of rib fractures, mean age, associated chest injuries (hemothorax, pneumothorax, and/or pulmonary contusion), and co-existing injuries to other systems. FINDINGS: The mean age of the patients was 51.5 years. The distribution of associated chest injuries was 30% in group RF1, 24.6% in group RF2, and 75.6% in group RF3 (p<0.05). Co-existing injuries to other systems were 24% in group RF1, 23.2% in group RF2, and 52.6% in group RF3 (p<0.05). Two patients (4%) in group RF1, 2 patients (3.8%) in group RF2, and 5 patients (4.5%) in group RF3 (total n = 9; 4.2%) died. CONCLUSION: Patients with any number of rib fractures should be carefully screened for co-existing injuries in other body systems and hospitalized to receive proper treatment