Effect of Voluntary Exercise on Endogenous Pain Control Systems and Post-traumatic Headache in Mice.

Traumatic brain injury (TBI) can cause acute and chronic pain along with motor, cognitive, and emotional problems. Although the mechanisms are poorly understood, previous studies suggest disruptions in endogenous pain modulation may be involved. Voluntary exercise after a TBI has been shown to reduce some consequences of injury including cognitive impairment. We hypothesized, therefore, that voluntary exercise could augment endogenous pain control systems in a rodent model of TBI. For these studies, we used a closed-head impact procedure in male mice modeling mild TBI. We investigated the effect of voluntary exercise on TBI-induced hindpaw nociceptive sensitization, diffuse noxious inhibitory control failure, and periorbital sensitization after bright light stress, a model of post-traumatic headache. Furthermore, we investigated the effects of exercise on memory, circulating markers of brain injury, neuroinflammation, and spinal cord gene expression. We observed that exercise significantly reduced TBI-induced hindpaw allodynia and periorbital allodynia in the first week following TBI. We also showed that exercise improved the deficits associated with diffuse noxious inhibitory control and reduced bright light stress-induced allodynia up to 2 months after TBI. In addition, exercise preserved memory and reduced TBI-induced increases in spinal BDNF, CXCL1, CXCL2, and prodynorphin expression, all genes previously linked to TBI-induced nociceptive sensitization. Taken together, our observations suggest that voluntary exercise may reduce pain after TBI by reducing TBI-induced changes in nociceptive signaling and preserving endogenous pain control systems. PERSPECTIVE: This article evaluates the effects of exercise on pain-related behaviors in a preclinical model of traumatic brain injury (TBI). The findings show that exercise reduces nociceptive sensitization, loss of diffuse noxious inhibitory control, memory deficits, and spinal nociception-related gene expression after TBI. Exercise may reduce or prevent pain after TBI.

Impact of Magnesium on Oxytocin Receptor Function.

BACKGROUND AND PURPOSE: The intranasal administration of oxytocin (OT) reduces migraine headaches through activation of the oxytocin receptor (OTR). Magnesium ion (Mg2+) concentration is critical to the activation of the OTR, and a low serum Mg2+ concentration is predictive of a migraine headache. We, therefore, examined the functional impact of Mg2+ concentration on OT-OTR binding efficacy using two complimentary bioassays. EXPERIMENTAL APPROACH: Current clamp recordings of rat trigeminal ganglia (TG) neurons measured the impact of Mg2+ on an OT-induced reduction in excitability. In addition, we assessed the impact of Mg2+ on intranasal OT-induced craniofacial analgesia in rats. KEY RESULTS: While OT alone dose-dependently hyperpolarized TG neurons, decreasing their excitability, the addition of 1.75 mM Mg2+ significantly enhanced this effect. Similarly, while the intranasal application of OT produced dose-dependent craniofacial analgesia, Mg2+ significantly enhanced these effects. CONCLUSIONS AND IMPLICATIONS: OT efficacy may be limited by low ambient Mg2+ levels. The addition of Mg2+ to OT formulations may improve its efficacy in reducing headache pain as well as for other OT-dependent processes.

GdDO3NI Enhanced Magnetic Resonance Imaging Allows Imaging of Hypoxia After Brain Injury.

BACKGROUND: Brain tissue hypoxia is a common consequence of traumatic brain injury (TBI) due to the rupture of blood vessels during impact and it correlates with poor outcome. The current magnetic resonance imaging (MRI) techniques are unable to provide a direct map of tissue hypoxia. PURPOSE: To investigate whether GdDO3NI, a nitroimidazole-based T1 MRI contrast agent allows imaging hypoxia in the injured brain after experimental TBI. STUDY TYPE: Prospective. ANIMAL MODEL: TBI-induced mice (controlled cortical impact model) were intravenously injected with either conventional T1 agent (gadoteridol) or GdDO3NI at 0.3 mmol/kg dose (n = 5 for each cohort) along with pimonidazole (60 mg/kg) at 1 hour postinjury and imaged for 3 hours following which they were euthanized. FIELD STRENGTH/SEQUENCE: 7 T/T2 -weighted spin echo and T1 -weighted gradient echo. ASSESSMENT: Injured animals were imaged with T2 -weighted spin-echo sequence to estimate the extent of the injury. The mice were then imaged precontrast and postcontrast using a T1 -weighted gradient-echo sequence for 3 hours postcontrast. Regions of interests were drawn on the brain injury region, the contralateral brain as well as on the cheek muscle region for comparison of contrast kinetics. Brains were harvested immediately post-imaging for immunohistochemical analysis. STATISTICAL TESTS: One-way analysis of variance and two-sample t-tests were performed with a P < 0.05 was considered statistically significant. RESULTS: GdDO3NI retention in the injury region at 2.5-3 hours post-injection was significantly higher compared to gadoteridol (mean retention fraction 63.95% ± 27.43% vs. 20.68% ± 7.43% for gadoteridol at 3 hours) while it rapidly cleared out of the muscle region. Pimonidazole staining confirmed the presence of hypoxia in both gadoteridol and GdDO3NI cohorts, and the later cohort showed good agreement with MRI contrast enhancement. DATA CONCLUSION: GdDO3NI was successfully shown to visualize hypoxia in the brain post-TBI using T1 -weighted MRI at 2.5-3 hours postcontrast. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Intranasal Administration for Pain: Oxytocin and Other Polypeptides.

Pain, particularly chronic pain, remains one of the most debilitating and difficult-to-treat conditions in medicine. Chronic pain is difficult to treat, in part because it is associated with plastic changes in the peripheral and central nervous systems. Polypeptides are linear organic polymers that are highly selective molecules for neurotransmitter and other nervous system receptors sites, including those associated with pain and analgesia, and so have tremendous potential in pain therapeutics. However, delivery of polypeptides to the nervous system is largely limited due to rapid degradation within the peripheral circulation as well as the blood-brain barrier. One strategy that has been shown to be successful in nervous system deposition of polypeptides is intranasal (IN) delivery. In this narrative review, we discuss the delivery of polypeptides to the peripheral and central nervous systems following IN administration. We briefly discuss the mechanism of delivery via the nasal-cerebral pathway. We review recent studies that demonstrate that polypeptides such as oxytocin, delivered IN, not only reach key pain-modulating regions in the nervous system but, in doing so, evoke significant analgesic effects. IN administration of polypeptides has tremendous potential to provide a non-invasive, rapid and effective method of delivery to the nervous system for chronic pain treatment and management.

A new hypothesis linking oxytocin to menstrual migraine.

OBJECTIVE: To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual-related migraine (MRM). BACKGROUND: MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is lacking. METHODS: We present a narrative literature review on the developing understanding of the role of OT and the OTR in MRM. Literature on MRM on PubMed/MEDLINE database including clinical trials and basic science publications was reviewed using specific keywords. RESULTS: OT is a cyclically released hypothalamic hormone/neurotransmitter that binds to the OTR resulting in inhibition of trigeminal neuronal excitability that can promote migraine pain including that of MRM. Estrogen regulates OT release as well as expression of the OTR. Coincident with menstruation, levels of both estrogen and OT decrease. Additionally, other serum biochemical factors, including magnesium and cholesterol, which positively modulate the affinity of OT for OTRs, both decrease during menstruation. Thus, during menstruation, multiple menstrually associated factors may lead to decreased circulating OT levels, decreased OT affinity for OTR, and decreased expression of the trigeminal OTR. Consistent with the view of migraine as a threshold disorder, these events may collectively result in decreased inhibition promoting lower thresholds for activation of meningeal trigeminal nociceptors and increasing the likelihood of an MRM attack. CONCLUSION: Trigeminal OTR may thus be a novel target for the development of MRM therapeutics.

Platelet-like particles reduce coagulopathy-related and neuroinflammatory pathologies post-experimental traumatic brain injury.

Coagulopathy may occur following traumatic brain injury (TBI), thereby negatively affecting patient outcomes. Here, we investigate the use of platelet-like particles (PLPs), poly(N-isopropylacrylamide-co-acrylic-acid) microgels conjugated with a fibrin-specific antibody, to improve hemostasis post-TBI. The objective of this study was to diminish coagulopathy in a mouse TBI model (controlled cortical impact) via PLP treatment, and subsequently decrease blood-brain barrier (BBB) permeability and neuroinflammation. Following an acute intravenous injection of PLPs post-TBI, we analyzed BBB permeability, ex vivo coagulation parameters, and neuroinflammation at 24 hr and 7 days post-TBI. Both PLP-treatment and control particle-treatment had significantly decreased BBB permeability and improved clot structure 24 hr post-injury. Additionally, no significant change in tissue sparing was observed between 24 hr and 7 days for PLP-treated cohorts compared to that observed in untreated cohorts. Only PLP-treatment resulted in significant reduction of astrocyte expression at 7 days and percent difference from 24 hr to 7 days. Finally, PLP-treatment significantly reduced the percent difference from 24 hr to 7 days in microglia/macrophage density compared to the untreated control. These results suggest that PLP-treatment addressed acute hypocoagulation and decreased BBB permeability followed by decreased neuroinflammation and fold-change tissue loss by 7 days post-injury. These promising results indicate that PLPs could be a potential therapeutic modality for TBI.

Sex-Dependent Macromolecule and Nanoparticle Delivery in Experimental Brain Injury.

The development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NPs) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover, the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24-h postfocal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared with male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 days after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics. Impact statement In this study, we identified a sex-dependent temporal profile of blood/brain barrier disruption in a preclinical mouse model of traumatic brain injury (TBI) that contributes to starkly different macromolecule and nanoparticle delivery profiles post-TBI. The implications and potential impact of this work are profound and far reaching as it indicates that a demand of true personalized medicine for TBI is necessary to deliver the right therapeutic at the right time for the right patient.

Blood-brainbarrier disruption dictates nanoparticle accumulation following experimental brain injury.

Clinically, traumatic brain injury (TBI) results in complex heterogeneous pathology that cannot be recapitulated in single pre-clinical animal model. Therefore, we focused on evaluating utility of nanoparticle (NP)-based therapeutics following three diffuse-TBI models: mildclosed-head injury (mCHI), repetitive-mCHI and midline-fluid percussion injury (FPI). We hypothesized that NP accumulation after diffuse TBI correlates directly with blood-brainbarrier permeability. Mice received PEGylated-NP cocktail (20-500 nm) (intravenously) after single- or repetitive-(1 impact/day, 5 consecutive days) CHI (immediately) and midline-FPI (1 h, 3 h and 6 h). NPs circulated for 1 h before perfusion/brain extraction. NP accumulation was analyzed using fluorescent microscopy in brain regions vulnerable to neuropathology. Minimal/no NP accumulation after mCHI/RmCHI was observed. In contrast, midlineFPI resulted in significant peak accumulation of up to 500 nm NP at 3 h post-injury compared to sham, 1 h, and 6 h groups in the cortex. Therefore, our study provides the groundwork for feasibility of NP-delivery based on NPinjection time and NPsize after mCHI/RmCHI and midline-FPI.

Nanoparticle-Based Therapeutics for Brain Injury.

Brain injuries affect a large patient population with major physical and emotional suffering for patients and their relatives; at a significant cost to the society. Effective diagnostic and therapeutic options available for brain injuries are limited by the complex brain injury pathology involving blood-brain barrier (BBB). Brain injuries, including ischemic stroke and brain trauma, initiate BBB opening for a short period of time, which is followed by a second reopening for an extended time. The leaky BBB and/or the alterations in the receptor expression on BBB may provide opportunities for therapeutic delivery via nanoparticles (NPs). The approaches for therapeutic interventions via NP delivery are aimed at salvaging the pericontusional/penumbra area for possible neuroprotection and neurovascular unit preservation. The focus of this progress report is to provide a survey of NP strategies employed in cerebral ischemia and brain trauma and finally provide insights for improved NP-based diagnostic/treatment approaches.

Temporal assessment of nanoparticle accumulation after experimental brain injury: Effect of particle size.

Nanoparticle (NP) based therapeutic and theranostic agents have been developed for various diseases, yet application to neural disease/injury is restricted by the blood-brain-barrier (BBB). Traumatic brain injury (TBI) results in a host of pathological alterations, including transient breakdown of the BBB, thus opening a window for NP delivery to the injured brain tissue. This study focused on investigating the spatiotemporal accumulation of different sized NPs after TBI. Specifically, animal cohorts sustaining a controlled cortical impact injury received an intravenous injection of PEGylated NP cocktail (20, 40, 100, and 500 nm, each with a unique fluorophore) immediately (0 h), 2 h, 5 h, 12 h, or 23 h after injury. NPs were allowed to circulate for 1 h before perfusion and brain harvest. Confocal microscopy demonstrated peak NP accumulation within the injury penumbra 1 h post-injury. An inverse relationship was found between NP size and their continued accumulation within the penumbra. NP accumulation preferentially occurred in the primary motor and somatosensory areas of the injury penumbra as compared to the parietal association and visual area. Thus, we characterized the accumulation of particles up to 500 nm at different times acutely after injury, indicating the potential of NP-based TBI theranostics in the acute period after injury.