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Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury.

ABSTRACT: Opioid-based analgesics are a major component of the lengthy pain management of burn patients, including military service members, but are problematic due to central nervous system-mediated side effects. Peripheral analgesia via targeted ablation of nociceptive nerve endings that express the transient receptor potential vanilloid channel 1 (TRPV1) may provide an improved approach. We hypothesized that local injection of the TRPV1 agonist resiniferatoxin (RTX) would produce long-lasting analgesia in a rat model of pain associated with burn injury.Baseline sensitivities to thermal and mechanical stimuli were measured in male and female Sprague-Dawley rats. Under anesthesia, a 100?°C metal probe was placed on the right hind paw for 30?seconds, and sensitivity was reassessed 72?hours following injury. Rats received RTX (0.25 ?g/100 ?L; ipl) into the injured hind paw, and sensitivity was reassessed across three weeks. Tissues were collected from a separate group of rats at 24?hours and/or one week post-RTX for pathological analyses of the injured hind paw, dorsal spinal cord c-Fos, and primary afferent neuropeptide immunoreactivity.Local RTX reversed burn pain behaviors within 24?hours, which lasted through recovery at three weeks. At one week following RTX, decreased c-Fos and primary afferent neuropeptide immunoreactivities were observed in the dorsal horn, while plantar burn pathology was unaltered.These results indicate that local RTX induces long-lasting analgesia in a rat model of pain associated with burn. While opioids are undesirable in trauma patients due to side effects, RTX may provide valuable long-term, nonopioid analgesia for burn patients.

SUBMITTER: Salas MM

PROVIDER: S-EPMC6279302 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury.

Salas Margaux M MM Clifford John L JL Hayden Jessica R JR Iadarola Michael J MJ Averitt Dayna L DL

Pain medicine (Malden, Mass.) 20171201 12

<h4>Objective</h4>Opioid-based analgesics are a major component of the lengthy pain management of burn patients, including military service members, but are problematic due to central nervous system-mediated side effects. Peripheral analgesia via targeted ablation of nociceptive nerve endings that express the transient receptor potential vanilloid channel 1 (TRPV1) may provide an improved approach. We hypothesized that local injection of the TRPV1 agonist resiniferatoxin (RTX) would produce long ...[more]

PMID: 27794548

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Project description:BackgroundDisruptions of angiogenesis can have a significant effect on the healing of uterine scars. Human endometrial perivascular cells (CD146+PDGFRβ+) function as stem cells in the endometrium. Cysteine-rich angiogenic inducer 61 (CYR61) plays an important role in vascular development. The purpose of this study was to observe the effects of the transplantation of human endometrial perivascular cells (En-PSCs) overexpressing CYR61 on structural and functional regeneration in rat models of partial full-thickness uterine excision.MethodsWe first sorted human En-PSCs from endometrial single-cell suspensions by flow cytometry. Human En-PSCs expressing low or high levels of CYR61 were then generated via transfection with a CYR61-specific small interfering ribonucleic acid (si-CYR61) construct or overexpression plasmid. To establish a rat model of uterine injury, a subset of uterine wall was then resected from each uterine horn in experimental animals. Female rats were randomly assigned to five groups, including a sham-operated group and four repair groups that received either PBS loaded on a collagen scaffold (collagen/PBS), En-PSCs loaded on a collagen scaffold (collagen/En-PSCs), En-PSCs with low CYR61 expression loaded on a collagen scaffold (collagen/si-CYR61 En-PSCs), and En-PSCs overexpressing CYR61 loaded on a collagen scaffold (collagen/ov-CYR61 En-PSCs). These indicated constructs were sutured in the injured uterine area to replace the excised segment. On days 30 and 90 after transplantation, a subset of rats in each group was sacrificed, and uterine tissue was recovered and serially sectioned. Hematoxylin and eosin staining and immunohistochemical staining were then performed. Finally, the remaining rats of each group were mated with fertile male rats on day 90 for a 2-week period.ResultsSorted En-PSCs expressed all recognized markers of mesenchymal stem cells (MSCs), including CD10, CD13, CD44, CD73, CD90, and CD105, and exhibited differentiation potential toward adipocytes, osteoblasts, and neuron-like cells. Compared with En-PSCs and En-PSCs with low CYR61 expression, En-PSCs with elevated CYR61 expression enhanced angiogenesis by in vitro co-culture assays. At day 90 after transplantation, blood vessel density in the collagen/ov-CYR61 En-PSCs group (11.667 ± 1.287) was greater than that in the collagen/En-PSCs group (7.167 ± 0.672) (P < 0.05) and the collagen/si-CYR61 En-PSCs group (3.750 ± 0.906) (P < 0.0001). Pregnancy rates differed among groups, from 40% in the collagen/PBS group to 80% in the collagen/En-PSCs group, 12.5% in the collagen/si-CYR61 En-PSCs group, and 80% in the collagen/ov-CYR61 En-PSCs group. In addition, four embryos were evident in the injured uterine horns of the collagen/ov-CYR61 En-PSCs group, while no embryos were identified in the injured uterine horns of the collagen/PBS group.ConclusionsThe results showed that CYR61 plays an important role in angiogenesis. Collagen/ov-CYR61 En-PSCs promoted endometrial and myometrial regeneration and induced neovascular regeneration in injured rat uteri. The pregnancy rate of rats treated with transplantation of collagen/En-PSCs or collagen/ov-CYR61 En-PSCs was improved. Moreover, the number of embryos implantation on the injured area in uterus was increased after transplantation of collagen/ov-CYR61 En-PSCs.

Project description:UnlabelledResiniferatoxin (RTX) is a potent agonist of TRPV1, which possesses unique properties that can be utilized to treat certain modalities of pain. In the present study, systemic intraperitoneal (i.p.) administration of RTX resulted in a significant decrease in acute thermal pain sensitivity, whereas localized intrathecal (i.t.) administration had no effect on acute thermal pain sensitivity. Both i.p. and i.t. administration of RTX prevented TRPV1-induced nocifensive behavior and inflammatory thermal hypersensitivity. There were no alterations in mechanical sensitivity either by i.p. or i.t. administration of RTX. In spinal dorsal horn (L4-L6), TRPV1 and substance P immunoreactivity were abolished following i.p. and i.t. administration of RTX. In dorsal root ganglia (DRG), TRPV1 immunoreactivity was diminished following i.p. administration, but was unaffected following i.t. administration of RTX. Following i.p. administration, basal and evoked calcitonin gene-related peptide release were reduced both in the spinal cord and peripheral tissues. However, following i.t. administration, basal and evoked calcitonin gene-related peptide release were reduced in spinal cord (L4-L6), but were unaffected in peripheral tissues. Both i.p. and i.t. RTX administration lowered the body temperature acutely, but this effect reversed with time. Targeting TRPV1-expressing nerve terminals at the spinal cord can selectively abolish inflammatory thermal hypersensitivity without affecting acute thermal sensitivity and can preserve the efferent functions of DRG neurons at the peripheral nerve terminals. I.t. administration of RTX can be considered as a strategy for treating certain chronic and debilitating pain conditions.PerspectiveLocalized administration of RTX in spinal cord could be a useful strategy to treat chronic debilitating pain arising from certain conditions such as cancer and at the same time could maintain normal physiological peripheral efferent functions mediated by TRPV1.

Project description:Sleep disordered breathing (SDB) affects 3-5% of the pediatric population, including neonates who are highly susceptible due to an underdeveloped ventilatory control system, and REM-dominated sleep. Although pediatric SDB is associated with poor cognitive outcomes, very little research has focused on models of pediatric SDB, particularly in neonates. In adults and neonates, intermittent hypoxia (IH), a hallmark of SDB, recapitulates multiple physiological aspects of severe SDB, including neuronal apoptosis, sex-specific cognitive deficits, and neuroinflammation. Microglia, resident CNS immune cells, are important mediators of neurodevelopment and neuroinflammation, but to date, no studies have examined the molecular properties of microglia in the context of neonatal IH. Here, we tested the hypothesis that neonatal IH will enhance microglial inflammation and sex-specifically lead to long-term changes in working memory. To test this hypothesis, we exposed post-natal day (P1) neonates with dams to an established adult model of pathological IH consisting of 2 min cycles of 10.5% O2 followed by 21% O2, 8 h/day for 8 days. We then challenged the offspring with bacterial lipopolysaccharide (LPS) at P9 or at 6-8 weeks of age and immunomagnetically isolated microglia for gene expression analyses and RNA-sequencing. We also characterized neonatal CNS myeloid cell populations by flow cytometry analyses. Lastly, we examined working memory performance using a Y-maze in the young adults. Contrary to our hypothesis, we found that neonatal IH acutely augmented basal levels of microglial anti-inflammatory cytokines, attenuated microglial responses to LPS, and sex-specifically altered CNS myeloid populations. We identified multiple sex differences in basal neonatal microglial expression of genes related to chemotaxis, cognition, and aging. Lastly, we found that basal, but not LPS-induced, anti-inflammatory cytokines were augmented sex-specifically in the young adults, and that there was a significant interaction between sex and IH on basal working memory. Our results support the idea that neonates may be able to adapt to IH exposures that are pathological in adults. Further, they suggest that male and female microglial responses to IH are sex-specific, and that these sex differences in basal microglial gene expression may contribute to sexual dimorphisms in vulnerability to IH-induced cognitive disruption.

Project description:The negative side effects of opioid-based narcotics underscore the search for alternative non-opioid bioactive compounds that act on the peripheral nervous system to avoid central nervous system-mediated side effects. The transient receptor potential V1 ion channel (TRPV1) is a peripheral pain generator activated and sensitized by heat, capsaicin, and a variety of endogenous ligands. TRPV1 contributes to peripheral sensitization and hyperalgesia, in part, via triggering the release of proinflammatory peptides, such as calcitonin gene-related peptide (CGRP), both locally and at the dorsal horn of the spinal cord. Ultrapotent exogenous TRPV1 agonists, such as resiniferatoxin identified in the latex of the exotic Euphorbia resinifera, trigger hyperalgesia followed by long lasting, peripheral analgesia. The present study reports on the analgesic properties of Euphorbia bicolor, a relative of E. resinifera, native to the Southern United States. The study hypothesized that E. bicolor latex extract induces long-lasting, non-opioid peripheral analgesia in a rat model of inflammatory pain. Both inflamed and non-inflamed adult male and female rats were injected with the methanolic extract of E. bicolor latex into the hindpaw and changes in pain behaviors were reassessed at various time points up to 4 weeks. Primary sensory neuron cultures also were treated with the latex extract or vehicle for 15 min followed by stimulation with the TRPV1 agonist capsaicin. Results showed that E. bicolor latex extract evoked significant pain behaviors in both male and female rats at 20 min post-injection and lasting around 1-2 h. At 6 h post-injection, analgesia was observed in male rats that lasted up to 4 weeks, whereas in females the onset of analgesia was delayed to 72 h post-injection. In sensory neurons, latex extract significantly reduced capsaicin-evoked CGRP release. Blocking TRPV1, but not opioid receptors, attenuated the onset of analgesia and capsaicin-induced CGRP release. Latex was analyzed by mass spectrometry and eleven candidate compounds were identified and reported here. These findings indicate that phytochemicals in the E. bicolor latex induce hyperalgesia followed by peripheral, non-opioid analgesia in both male and female rats, which occurs in part via TRPV1 and may provide novel, non-opioid peripheral analgesics that warrant further examination.

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Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury.

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Local Resiniferatoxin Induces Long-Lasting Analgesia in a Rat Model of Full Thickness Thermal Injury.

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