The search for translational pain outcomes to refine analgesic development: Where did we come from and where are we going?

Pain measures traditionally used in rodents record mere reflexes evoked by sensory stimuli; the results thus may not fully reflect the human pain phenotype. Alterations in physical and emotional functioning, pain-depressed behaviors and facial pain expressions were recently proposed as additional pain outcomes to provide a more accurate measure of clinical pain in rodents, and hence to potentially enhance analgesic drug development. We aimed to review how preclinical pain assessment has evolved since the development of the tail flick test in 1941, with a particular focus on a critical analysis of some nonstandard pain outcomes, and a consideration of how sex differences may affect the performance of these pain surrogates. We tracked original research articles in Medline for the following periods: 1973-1977, 1983-1987, 1993-1997, 2003-2007, and 2014-2018. We identified 606 research articles about alternative surrogate pain measures, 473 of which were published between 2014 and 2018. This indicates that preclinical pain assessment is moving toward the use of these measures, which may soon become standard procedures in preclinical pain laboratories.FPU grant from the Spanish Ministry of Education, Culture and SportsSpanish Ministry of Economy and Competitiveness (MINECO, grant SAF2016-80540-R)Ramón Areces FoundationJunta de Andalucía (grant CTS 109)Esteve PharmaceuticalsEuropean Regional Development Fund (ERDF

Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model

Peripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7–8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg−1) was administered i.p . at 8 h intervals for 3 days starting at 18 h post‐SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme‐linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post‐SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)‐1α, IL‐1β and IL‐10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro‐inflammatory (IL‐1β and IL‐1α) and anti‐inflammatory (IL‐10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP

Bridges and Their Avant-Garde Architecture

Throughout the history of our civilization peopleconstructed bridges, viaducts, overpasses and other types ofengineering structures designed to overcome deep gorges andvast rivers. The reasons for doing it were functional necessities.But on the other hand new big structural forms and their newaesthetics values intrigue observers, mostly because of theinnovativeness. New forms emanating its technical beauty, free ofdecorations or decorative details, with the charm of repeatedhuge arches, anchor ropes or riveting rhythm have impressedpeople both two thousands year ago and now

The Role of Some Chemokines from the CXC Subfamily in a Mouse Model of Diabetic Neuropathy

The mechanism involved in the development of diabetic neuropathy is complex. Currently, it is thought that chemokines play an important role in this process. The aim of this study was to determine how the level of some chemokines from the CXC subfamily varies in diabetic neuropathy and how the chemokines affect nociceptive transmission. A single intraperitoneal (i.p.) injection of streptozotocin (STZ; 200 mg/kg) resulted in an increased plasma glucose. The development of allodynia and hyperalgesia was measured at day 7 after STZ administration. Using Antibody Array techniques, the increases in CXCL1 (KC), CXCL5 (LIX), CXCL9 (MIG), and CXCL12 (SDF-1) protein levels were detected in STZ-injected mice. No changes in CXCL11 (I-TAC) or CXCL13 (BLC) protein levels were observed. The single intrathecal (i.t.) administration of CXCL1, CXCL5, CXCL9, and CXCL12 (each in doses of 10, 100, and 500 ng/5 L) shows their pronociceptive properties as measured 1, 4, and 24 hours after injection using the tail-flick, von Frey, and cold plate tests. These findings indicate that the chemokines CXCL1, CXCL5, CXCL9, and CXCL12 are important in nociceptive transmission and may play a role in the development of diabetic neuropathy