Opioids alter paw placement during walking, confounding assessment of analgesic efficacy in a postsurgical pain model in mice

Introduction: Hind paw-directed assays are commonly used to study the analgesic effects of opioids in mice. However, opioid-induced hyperlocomotion can obscure results of such assays. Objectives: We aimed to overcome this potential confound by using gait analysis to observe hind paw usage during walking in mice. Methods: We measured changes in the paw print area after induction of postsurgical pain (using the paw incision model) and treatment with oxycodone. Results: Paw incision surgery reduced the paw print area of the injured hind paw as mice avoided placing the incised section of the paw on the floor. Surprisingly, oxycodone caused a tiptoe-like gait in mice, reducing the paw print area of both hind paws. Further investigation of this opioid-induced phenotype revealed that analgesic doses of oxycodone or morphine dose-dependently reduced the hind paw print area in uninjured mice. The gait changes were not dependent on opioid-induced increases in the locomotor activity; speed and paw print area had no correlation in opioid-treated mice, and other analgesic compounds that alter locomotor activity did not affect the paw print area. Conclusion: Unfortunately, the opioid-induced tiptoe gait phenotype prevented gait analysis from being a viable metric for demonstrating opioid analgesia in injured mice. However, this work reveals an important, previously uncharacterized effect of treatment with analgesic doses of opioids on paw placement. Our characterization of how opioids affect gait has important implications for the use of mice to study opioid pharmacology and suggests that scientists should use caution when using hind paw-directed nociceptive assays to test opioid analgesia in mice

Sex, drugs and pain control

A study finds that pain hypersensitivity in male and female mice is differentially dependent on microglia and T cells, and describes a sex-specific response to microglia-targeted pain treatments

Vascular channels formed by subpopulations of PECAM1+ melanoma cells

Targeting the vasculature remains a promising approach for treating solid tumors; however, the mechanisms of tumor neovascularization are diverse and complex. Here we uncover a new subpopulation of melanoma cells that express the vascular cell adhesion molecule PECAM1, but not VEGFR-2, and participate in a PECAM1-dependent form of vasculogenic mimicry (VM). Clonally-derived PECAM1+ tumor cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, VEGF-independent channels in mice. The neural crest specifier AP-2α is diminished in PECAM1+ melanoma cells and is a transcriptional repressor of PECAM1. Reintroduction of AP-2α into PECAM1+ tumor cells represses PECAM1 and abolishes tube-forming ability whereas AP-2α knockdown in PECAM1− tumor cells up-regulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumor, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF

Wireless, Battery-Free Implants for Electrochemical Catecholamine Sensing and Optogenetic Stimulation

Neurotransmitters and neuromodulators mediate communication between neurons and other cell types; knowledge of release dynamics is critical to understanding their physiological role in normal and pathological brain function. Investigation into transient neurotransmitter dynamics has largely been hindered due to electrical and material requirements for electrochemical stimulation and recording. Current systems require complex electronics for biasing and amplification and rely on materials that offer limited sensor selectivity and sensitivity. These restrictions result in bulky, tethered, or battery-powered systems impacting behavior and that require constant care of subjects. To overcome these challenges, we demonstrate a fully implantable, wireless, and battery-free platform that enables optogenetic stimulation and electrochemical recording of catecholamine dynamics in real time. The device is nearly 1/10th the size of previously reported examples and includes a probe that relies on a multilayer electrode architecture featuring a microscale light emitting diode (μ-LED) and a carbon nanotube (CNT)-based sensor with sensitivities among the highest recorded in the literature (1264.1 nA μM-1 cm-2). High sensitivity of the probe combined with a center tapped antenna design enables the realization of miniaturized, low power circuits suitable for subdermal implantation even in small animal models such as mice. A series of in vitro and in vivo experiments highlight the sensitivity and selectivity of the platform and demonstrate its capabilities in freely moving, untethered subjects. Specifically, a demonstration of changes in dopamine concentration after optogenetic stimulation of the nucleus accumbens and real-time readout of dopamine levels after opioid and naloxone exposure in freely behaving subjects highlight the experimental paradigms enabled by the platform.Fil: Stuart, Tucker. University of Arizona; Estados UnidosFil: Jeang, William J.. Northwestern University; Estados UnidosFil: Slivicki, Richard A.. University of Washington; Estados UnidosFil: Brown, Bobbie J.. University of Washington; Estados UnidosFil: Burton, Alex. University of Arizona; Estados UnidosFil: Brings, Victoria E.. University of Washington; Estados UnidosFil: Agyare, Prophecy. Northwestern University; Estados UnidosFil: Alarcon Segovia, Lilian Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Matemática Aplicada del Litoral. Universidad Nacional del Litoral. Instituto de Matemática Aplicada del Litoral; ArgentinaFil: Ruiz, Savanna. Northwestern University; Estados UnidosFil: Tyree, Amanda. University of Arizona; Estados UnidosFil: Pruitt, Lindsay. University of Arizona; Estados UnidosFil: Madhvapathy, Surabhi. Northwestern University; Estados UnidosFil: Niemiec, Martin. University of Arizona; Estados UnidosFil: Zhuang, James. University of Arizona; Estados UnidosFil: Krishnan, Siddharth. Northwestern University; Estados UnidosFil: Copits, Bryan A.. University of Washington; Estados UnidosFil: Rogers, John A.. Northwestern University; Estados UnidosFil: Gereau, Robert W.. Washington University in St. Louis; Estados UnidosFil: Samineni, Vijay K.. University of Washington; Estados UnidosFil: Bandodkar, Amay J.. No especifíca;Fil: Gutruf, Philipp. University of Arizona; Estados Unido