Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states

<p>Abstract</p> <p>Background</p> <p>Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα₂δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.</p> <p>Results</p> <p>We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaVα₂δ-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaVα₂δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaVα₂δ-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaVα₂δ-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation.</p> <p>Conclusions</p> <p>Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaVα₂δ-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states.</p

Why conservation biology can benefit from sensory ecology

Global expansion of human activities is associated with the introduction of novel stimuli, such as anthropogenic noise, artificial lights and chemical agents. Progress in documenting the ecological effects of sensory pollutants is weakened by sparse knowledge of the mechanisms underlying these effects. This severely limits our capacity to devise mitigation measures. Here, we integrate knowledge of animal sensory ecology, physiology and life history to articulate three perceptual mechanisms—masking, distracting and misleading—that clearly explain how and why anthropogenic sensory pollutants impact organisms. We then link these three mechanisms to ecological consequences and discuss their implications for conservation. We argue that this framework can reveal the presence of ‘sensory danger zones’, hotspots of conservation concern where sensory pollutants overlap in space and time with an organism’s activity, and foster development of strategic interventions to mitigate the impact of sensory pollutants. Future research that applies this framework will provide critical insight to preserve the natural sensory world

Ndel1 Promotes Axon Regeneration via Intermediate Filaments

Failure of axons to regenerate following acute or chronic neuronal injury is attributed to both the inhibitory glial environment and deficient intrinsic ability to re-grow. However, the underlying mechanisms of the latter remain unclear. In this study, we have investigated the role of the mammalian homologue of aspergillus nidulans NudE, Ndel1, emergently viewed as an integrator of the cytoskeleton, in axon regeneration. Ndel1 was synthesized de novo and upregulated in crushed and transected sciatic nerve axons, and, upon injury, was strongly associated with neuronal form of the intermediate filament (IF) Vimentin while dissociating from the mature neuronal IF (Neurofilament) light chain NF-L. Consistent with a role for Ndel1 in the conditioning lesion-induced neurite outgrowth of Dorsal Root Ganglion (DRG) neurons, the long lasting in vivo formation of the neuronal Ndel1/Vimentin complex was associated with robust axon regeneration. Furthermore, local silencing of Ndel1 in transected axons by siRNA severely reduced the extent of regeneration in vivo. Thus, Ndel1 promotes axonal regeneration; activating this endogenous repair mechanism may enhance neuroregeneration during acute and chronic axonal degeneration

Experimental River Noise Alters Arthropod Abundance

Anthropogenic noise has received considerable recent attention, but we know little about the role that sources of natural noise have on wildlife abundance and distributions. Rivers and streams represent an ancient source of natural noise that is widespread and covers much of Earth. We sought to understand the role that whitewater river noise plays on arthropod abundance in riparian habitats across a desert landscape. For two summers, we continuously broadcasted whitewater river noise and spectrally-altered river noise (shifted upwards in frequency, but maintaining the same temporal profile) to experimentally tease apart the effects of two characteristics of noise – sound levels and background spectral frequency – on arthropod abundances. We used five types of trapping methods, placed across 20 sites within the Pioneer Mountains of Idaho, USA, to collect and identify 151 992 specimens to the order level. We built Bayesian generalized linear mixed-effects models with noise characteristics and other habitat variables such as riparian vegetation, elevation, temperature, and moonlight. Of the 42 models we built (one for each order-trap type combination), 26 (62%) indicated a substantial response to at least one noise variable – sound pressure level, background spectral frequency, or an interaction between the two. Fourteen of 17 (82%) arthropod orders responded to noise in some capacity: Araneae, Coleoptera, Collembola, Dermaptera, Hemiptera, Hymenoptera, Lepidoptera, Neuroptera, Opiliones, Orthoptera, Plecoptera, Raphidioptera, Thysanoptera and Trichoptera. Only three groups appeared to be unaffected, Acari, Archaeognatha and Diptera. Results from this study suggest that the natural acoustic environment can shape arthropod abundances both directly and indirectly (via predator–prey relationships). Future work should further examine the role that the indirect effects of noise play in food webs. Natural noise should be considered an important ecological niche axis, especially as we continue to alter natural acoustic environments and replace them with anthropogenic ones

The nature and identification of quantitative trait loci: a community’s view

This white paper by eighty members of the Complex Trait Consortium presents a community’s view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?