Nerve growth factor (NGF) is elevated in certain chronic pain conditions and is a sufficient stimulus to cause lasting pain in humans, but the actual mechanisms underlying the persistent effects of NGF remain incompletely understood. We developed a rat model of NGFinduced persistent thermal hyperalgesia and mechanical allodynia to determine the role of transient receptor potential vanilloid 1 (TRPV1) and oxidative mechanisms in the persistent effects of NGF. Persistent thermal hypersensitivity and mechanical allodynia require de novo protein translation and are mediated by TRPV1 and oxidative mechanisms. By comparing effects after systemic (subcutaneous), spinal (intrathecal) or hindpaw (intraplantar) injections of test compounds, we determined that TRPV1 and oxidation mediate persistent thermal hypersensitivity via peripheral and spinal sites of action and mechanical allodynia via only a spinal site of action. Therefore, NGF-evoked thermal and mechanical allodynia are mediated by spatially distinct mechanisms. NGF treatment evoked sustained increases in peripheral and central TRPV1 activity, as demonstrated by increased capsaicin-evoked nocifensive responses, increased calcitonin gene-related peptide release from hindpaw skin biopsies, and increased capsaicin-evoked inward current and membrane expression of TRPV1 protein in dorsal root ganglia neurons. Finally, we showed that NGF treatment increased concentrations of linoleic and arachidonic-acid-derived oxidized TRPV1 agonists in spinal cord and skin biopsies. Furthermore, increases in oxidized TRPV1-active lipids were reduced by peripheral and spinal injections of compounds that completely blocked persistent nociception. Collectively, these data indicate that NGF evokes a persistent nociceptive state mediated by increased TRPV1 activity and oxidative mechanisms, including increased production of oxidized lipid TRPV1 agonists.
The transient receptor potential family V1 channel (TRPV1) is activated by multiple stimuli, including capsaicin, acid, endovanilloids, and heat (>42C). Post-translational modifications to TRPV1 result in dynamic changes to the sensitivity of receptor activation. We have previously demonstrated that β-arrestin2 actively participates in a scaffolding mechanism to inhibit TRPV1 phosphorylation, thereby reducing TRPV1 sensitivity. In this study, we evaluated the effect of β-arrestin2 sequestration by G-protein coupled receptors (GPCRs) on thermal and chemical activation of TRPV1. Here we report that activation of mu opioid receptor by either morphine or DAMGO results in β-arrestin2 recruitment to mu opioid receptor in sensory neurons, while activation by herkinorin does not. Furthermore, treatment of sensory neurons with morphine or DAMGO stimulates β-arrestin2 dissociation from TRPV1 and increased sensitivity of the receptor. Conversely, herkinorin treatment has no effect on TRPV1 sensitivity. Additional behavioral studies indicate that GPCR-driven β-arrestin2 sequestration plays an important peripheral role in the development of thermal sensitivity. Taken together, the reported data identify a novel cross-talk mechanism between GPCRs and TRPV1 that may contribute to multiple clinical conditions.
Introduction Dental professionals are at high risk of contracting coronavirus disease 2019 (COVID-19) infection because of their scope of practice with aerosol-generating procedures. Recommendation by the Centers for Disease Control and Prevention to suspend elective dental procedures and avoid aerosol-generating procedures posed significant challenges in the management of patients presenting with endodontic emergencies and uncertainty of outcomes for endodontic procedures initiated, but not completed, before shutdown. The purpose of this study was to evaluate the success of palliative care on endodontic emergencies during the COVID-19 pandemic and to evaluate the stability of teeth with long-term Ca(OH) 2 placement because of delays in treatment completion. Methods Patients presenting for endodontic emergencies during COVID-19 Shelter-in-Place orders received palliative care, including pharmacologic therapy and/or non–aerosol-generating procedural interventions. Part I of the study evaluated the effectiveness of palliative care, and need for aerosol-generating procedures or extractions was quantified. Part II of the study evaluated survivability and rate of adverse events for teeth that received partial or full root canal debridement and placement of calcium hydroxide before shutdown. Results Part I: Twenty-one patients presented with endodontic emergencies in 25 teeth during statewide shutdown. At a follow-up rate of 96%, 83% of endodontic emergencies required no further treatment or intervention after palliative care. Part II: Thirty-one teeth had received partial or full root canal debridement before statewide shutdown. Mean time to complete treatment was 13 weeks. At a recall rate of 100%, 77% of teeth did not experience any adverse events due to delays in treatment completion. The most common adverse event was a fractured provisional restoration (13%), followed by painful and/or infectious flare-up (6.4%), which were managed appropriately and therefore seemed successful. Only 1 tooth was fractured and nonrestorable (3%), leading to a failed outcome of tooth extraction. The remaining 4 outcome failures (13%) were due to patient unwillingness to undergo school-mandated COVID testing or patient unwillingness to continue treatment because of perceived risk of COVID infection. Conclusions Palliative care for management of endodontic emergencies is a successful option when aerosol-generating procedures are restricted. This treatment approach may be considered in an effort to reduce risk of transmission of COVID-19 infection during subsequent shutdowns. Prolonged Ca(OH) 2 medicament because of COVID-19 related delays in treatment completion appeared to have minimal effect on survival of teeth.
Endogenous TRPV1 agonists such as oxidized linoleic acid metabolites (OLAMs) and the enzymes releasing them [e.g., cytochrome P450 (CYP)], are up-regulated following inflammation in the rat. However, it is not known if such agonists are elevated in human inflammatory pain conditions. Since TRPV1 is expressed in human dental pulp nociceptors, we hypothesized that OLAM-CYP machinery is active in this tissue type and is increased under painful inflammatory conditions such as irreversible pulpitis (IP). The aim of this study was to compare CYP expression and linoleic acid (LA) metabolism in normal versus inflamed human dental pulp. Our data showed that exogenous LA metabolism was significantly increased in IP tissues compared to normal tissues and that pretreatment with a CYP inhibitor, ketoconazole, significantly inhibited LA metabolism. Additionally, extracts obtained from LA-treated inflamed tissues, evoked significant inward currents in TG neurons, and were blocked by pretreatment with the TRPV1 antagonist, IRTX. Moreover, extracts obtained from ketoconazole-pretreated inflamed tissues significantly reduced inward currents in TG neurons. These data suggest that LA metabolites produced in human inflamed tissues act as TRPV1 agonists and that the metabolite production can be targeted by CYP inhibition. In addition, immunohistochemical analysis of two CYP isoforms, CYP2J and CYP3A1, were shown to be predominately expressed in immune cells infiltrating the inflamed dental pulp, emphasizing the paracrine role of CYP enzymes in OLAM regulation. Collectively, our data indicates that the machinery responsible for OLAM production is up-regulated during inflammation and can be targeted to develop potential analgesics for inflammatory-induced dental pain.
The left atrial septal pouch (LASP) occurs due to incomplete fusion of septa primum and secundum at the inter-atrial septum, creating an open flap that may serve as a thromboembolic source. Prior studies have demonstrated increased prevalence of LASP in cryptogenic strokes. The aim of the current study was to validate the above findings in a separate, larger group of stroke and non-stroke patients. We examined transesophageal echocardiograms (TEEs) performed between July 2011 and December 2018. LASP prevalence was determined in TEEs referred for ischemic stroke or transient ischemic attack (“stroke”) and compared with LASP prevalence in patients undergoing TEEs for other reasons (“non-stroke”). Stroke subtyping was performed using the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. There were 306 TEEs from 144 non-stroke and 162 stroke patients. Mean age and sex distribution were 56 ± 1 (mean ± SE) and 65% male in the non-stroke group and 58 ± 1 and 54% male in the stroke group. The overall prevalence of LASP was 31%. The prevalence of LASP was 28% (41/144) in non-stroke patients, 25% (24/95) in non-cryptogenic stroke patients, and 43% (29/67) in cryptogenic stroke patients. LASP prevalence was significantly higher in the cryptogenic subgroup compared with the non-cryptogenic subgroup (p = 0.02). These findings demonstrate a significant association of LASP with risk of cryptogenic stroke, suggesting that LASP may serve as a thromboembolic nidus. Additional studies are needed to determine the generalizability of these findings, and their therapeutic implications, supporting LASP as a stroke risk factor.
Quantitative assessment of calcification in different vascular beds demonstrates that extracoronary atherosclerosis is common in patients who have normal MPI. Atherosclerotic calcifications are most common in the iliofemoral arteries and abdominal aorta, which typically predate coronary calcifications. An imaging strategy to detect extracoronary atherosclerosis could lead to greater understanding of the natural history of atherosclerosis in its long pre-clinical phase and possibly to earlier preventive strategies.
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