Biology subjects

Bree, D.

Publications and source records attributed to Bree, D..

5 recordsLinked to original sources

bioRxiv2025

Cortical astrocyte activation triggers meningeal nociception and migraine-like pain

Migraine attacks are believed to originate in the brain, but the exact mechanisms by which the brain generates peripheral nociceptive signals that drive migraine pain remain unclear. Sensory cortex hyperexcitability has been observed consistently across different migraine subtypes. Astrocytes detect aberrant increases in cortical activity via their Gq-coupled receptors and respond by releasing gliotransmitters and other factors with proinflammatory and nociceptive properties. In the present study, we used a rat model to investigate whether heightened cortical astrocyte Gq-coupled signaling is sufficient to drive peripheral trigeminal meningeal nociceptive responses linked to the generation of migraine headaches. We used an AAV-based chemogenetic approach that allows selective activation of cortical astrocyte Gq-GPCR signaling. We targeted astrocytes in the visual cortex as hyperexcitability in this region has been implicated in migraine. Furthermore, the meninges overlying the visual cortex are densely innervated by nociceptive fibers. We combined this chemogenetic approach with in vivo single-unit recording of meningeal nociceptors to assess changes in their ongoing activity and mechanosensitivity, along with testing of migraine-like behaviors. We further targeted calcitonin gene-related peptide (CGRP), using a monoclonal antibody (anti-CGRP mAb), to assess the relevance of cortical astrocyte activation to migraine. We discovered that heightened activation of Gq-coupled signaling in visual cortex astrocytes drives persistent discharge and increased mechanosensitivity of meningeal nociceptors. Cortical astrocytic activation also generated cephalic mechanical pain hypersensitivity, reduced exploratory behavior, and anxiety-like behaviors linked to migraine headaches. Blocking calcitonin gene-related peptide signaling suppressed astrocyte-mediated increases in meningeal nociceptor discharge and alleviated associated migraine-related behaviors. Our findings reveal a previously unappreciated role for augmented visual cortex astrocyte signaling as a triggering factor sufficient to generate meningeal nociception and migraine pain and greatly expand our understanding of migraine pathophysiology.

neuroscience↗

bioRxiv2023

Targeting NGF but not VEGF or BDNF signaling reduces endometriosis-associated pain in mice

IntroductionEndometriosis is a chronic inflammatory disease that affects [~]10% of women. A significant fraction of patients experience limited or no efficacy with current therapies. Tissue adjacent to endometriosis lesions often exhibits increased neurite and vascular density, suggesting that disease pathology involves neurotrophic activity and angiogenesis. ObjectivesWe aim to evaluate the potential for key tyrosine-kinase-receptor-coupled neurotrophic molecules to contribute to endometriosis-associated pain in mice. MethodsThe levels of VEGFR1 regulators (VEGFA, VEGFB, PLGF, and sVEGFR1) were quantified by ELISA in peritoneal fluid from endometriosis patients undergoing surgery and used to calculate VEGFR1 occupancy. We used genetic depletion, neutralizing antibody, and pharmacological approaches to specifically block ligand (NGF or BDNF) or neurotrophic receptor (VEGFR1, TRKs) in a murine model of endometriosis-associated pain. Endometriosis-associated pain was determined using the von Frey filaments method, quantification of spontaneous abdominal pain-related behavior, and thermal discomfort. Diseases parameters were evaluated by lesion size and prevalence. ResultsWe found that entrectinib (pan-Trk inhibitor) or anti-NGF treatments reduced evoked pain, spontaneous pain, and thermal discomfort. In contrast, even though receptor occupancy revealing that VEGFR1 agonist levels are sufficient to support pain, blocking VEGFR1 signaling via antibody or tamoxifen-induced knockout did not reduce pain or lesion size in mice. Targeting BDNF-TrkB with an anti-BDNF antibody also proved ineffective. ConclusionsThis suggests NGF-TrkA signaling, but not BDNF-TrkB or VEGF-VEGFR1, mediates endometriosis-associated pain. Moreover, entrectinib blocks endometriosis-associated pain and reduces lesion sizes. Our results also indicated that entrectinib-like molecules are promising candidates for endometriosis treatment. Credit author statementConceptualization: T.H. Zaninelli, V. Fattori, and M.S. Rogers; investigation and data curation: T.H. Zaninelli, V. Fattori, O.K. Heintz, K.R. Wright; A.C. Andrello, W.A. Verri Jr, M.S. Rogers; funding acquisition: M.S. Rogers,, S.A. Missmer, R.M. Anchan; methodology: T.H. Zaninelli, V. Fattori, and M.S. Rogers; human sample collection: S.A. Missmer, A.F. Vitonis, K.L. Terry, R.M. Anchan; animal breading and VEGFR1 ablation: D. Sim and H. Bukhari; resources: A.C. Andrello; D. Bree, T. Zheng, J. Wagner, W.A. Verri Jr, and M.S. Rogers; project administration: T.H. Zaninelli; supervision: V. Fattori, W.A. Verri Jr, and M.S. Rogers; visualization: T.H. Zaninelli, V. Fattori, W.A. Verri Jr, and M.S. Rogers; writing-original draft: T.H. Zaninelli; writing - editing and reviewing: all authors. All authors have read and approved the final version of the manuscript.

pharmacology and toxicology↗

bioRxiv2020

Increased severity of closed head injury or repetitive subconcussive head impacts enhances post-traumatic headache-like behaviors in a rat model.

IntroductionPosttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a traumatic head injury. The development of novel therapeutic approaches is nevertheless hampered by the paucity of preclinical models and poor understanding of the mechanisms underlying PTH. To address these shortcomings, we previously characterized the development of PTH-like pain behaviors in rats subjected to a single mild closed head injury using a 250 g weight drop. Here, we conducted a follow-up study to further develop this preclinical model by exploring the development of headache-like pain behaviors in male rats subjected to a single, but more severe head trauma (450 g) as well as following repetitive, subconcussive head impacts (150 g). In addition, we tested whether these behaviors involve peripheral CGRP signaling by testing the effect of systemic anti-CGRP monoclonal antibody (anti-CGRP mAb). MethodsAdult male Sprague Dawley rats (total n=138) were subjected to diffuse closed head injury using a weight-drop device, or a sham procedure. Three injury paradigms were employed: a single hit, using 450 g or 150 g weight drop, and three successive 150 g weight drop events conducted 72 hours apart. Changes in open field activity and development of headache-related cephalic and extracephalic mechanical pain hypersensitivity were assessed up to 42 days post head trauma. Treatment included systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody (30 mg/kg.). ResultsRats subjected to 450 g closed head injury displayed an acute decrease in rearing and increased thigmotaxis, together with cephalic and extracephalic mechanical pain hypersensitivity that resolved by 6 weeks post-injury. Repetitive subconcussive head impacts using the 150 g weight drop, but not a single event, led to decreased vertical rearing as well as prolonged cephalic and extracephalic mechanical pain hypersensitivity. Early and prolonged anti-CGRP mAb treatment inhibited the development of the cephalic, but not extracephalic pain hypersensitivities in both the severe and repetitive subconcussive head impact models. ConclusionsWhen compared to the data obtained from male rats in the previous study, a more severe head injury gives rise to a prolonged state of cephalic and extracephalic hyperalgesia. Such enhanced headache-like behaviors also occur following repetitive, subconcussive head impacts. Extended headache-like behaviors following severe and repetitive mild closed head injury are ameliorated by early and prolonged anti-CGRP mAb treatment, suggesting a mechanism linked to peripheral CGRP signaling.

neuroscience↗

bioRxiv2019

Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury

IntroductionFemales are thought to have increased risk of developing posttraumatic headache (PTH) following a traumatic head injury, or concussion. However, the processes underlying this susceptibility remain unclear. We previously explored the development of PTH-like pain behaviors in a novel rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we explored the development of PTH-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. MethodsAdult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device. Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of systemic administration of a low-dose of glyceryl trinitrate (GTN). Treatments included acute systemic administration of sumatriptan and repeated systemic administration of a mouse anti-calcitonin-gene-related peptide monoclonal antibody. Serum levels of calcitonin-gene-related peptide were measured at various time points in females and males after the head injury. ResultsFemale rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, that was limited to the cephalic region, and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan, but was resistant to an early and prolonged treatment with the anti-CGRP monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of GTN produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-CGRP treatment. CGRP serum levels were elevated in females but not in males at 7 days post head injury. ConclusionsDevelopment of PTH-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to males, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-CGRP treatment. The increased risk of females to develop PTH may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral CGRP signaling.

neuroscience↗

bioRxiv2018

Intact mast cell content during mild head injury is required for the development of latent pain sensitization - implications for mechanisms underlying posttraumatic headache

Posttraumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a traumatic head injury. While the mechanisms underlying PTH remain elusive, recent studies in rodent models suggest the potential involvement of calcitonin gene-related peptide (CGRP), a mediator of neurogenic inflammation, and the ensuing activation of meningeal mast cells (MCs), pro-algesic resident immune cells that can lead to the activation of the headache pain pathway. Here, we investigated the relative contribution of MCs to the development of PTH-like pain behaviors in a model of mild closed head injury (mCHI) in male rats. We initially tested the relative contribution of peripheral CGRP signaling to the activation of meningeal MCs following mCHI using an anti-CGRP monoclonal antibody. We then employed a prophylactic MC granule depletion approach to address the hypotheses that intact meningeal MC granule content is necessary for the development of PTH-related pain-like behaviors. The data suggest that following mCHI, ongoing activation of meningeal MCs is not mediated by peripheral CGRP signaling, and does not contribute to development of the mCHI-evoked cephalic mechanical pain hypersensitivity. Our data, however, also reveals that the development of latent sensitization, manifested as persistent hypersensitivity upon the recovery from mCHI-evoked acute cranial hyperalgesia to the headache trigger glyceryl trinitrate requires intact MC content during and immediately after mCHI. Collectively, our data implicate the acute activation of meningeal MCs as mediator of chronic pain hypersensitivity following a concussion or mCHI. Targeting MCs may be explored for early prophylactic treatment of PTH.

neuroscience↗