scholarly journals Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 864
Author(s):  
Christopher L. Cioffi
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Therapeutic Potential ◽  
Opioid Analgesic ◽  
Critical Role ◽  
Analgesic Efficacy ◽  
Standard Of Care ◽  
Current Standard ◽  
Glycine Transporters ◽  
Pathological Pain

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na+/Cl−-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain.

scholarly journals Left Atrial Appendage Exclusion for Stroke Prevention in Atrial Fibrillation

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Taral K. Patel ◽  
Clyde W. Yancy ◽  
Bradley P. Knight
Keyword(s):  
Atrial Fibrillation ◽  
Oral Anticoagulation ◽  
Stroke Prevention ◽  
Left Atrial ◽  
Left Atrial Appendage ◽  
Critical Role ◽  
Standard Of Care ◽  
Atrial Appendage ◽  
Current Standard ◽  
Public Health Burden

The public health burden of atrial fibrillation (AF) and associated thromboembolic stroke continues to grow at alarming rates. AF leads to a fivefold increase in the risk of stroke. Therefore, stroke prevention remains the most critical aspect of AF management. Current standard of care focuses on oral systemic anticoagulation, most commonly with warfarin and now with newer agents such as dabigatran, rivaroxaban, and apixaban. However, the challenges and limitations of oral anticoagulation have been well documented. Given the critical role of the left atrial appendage (LAA) in the genesis of AF-related thromboembolism, recent efforts have targeted removal or occlusion of the LAA as an alternative strategy for stroke prevention, particularly in patients deemed unsuitable for oral anticoagulation. This paper highlights recent advances in mechanical exclusion of the LAA. The problem of AF and stroke is briefly summarized, followed by an explanation for the rationale behind LAA exclusion for stroke prevention. After briefly reviewing the history of LAA exclusion, we highlight the most promising LAA exclusion devices currently available. Finally, we discuss future challenges and opportunities in this growing field.

Regulation of Glutamate Release From Primary Afferents and Interneurons in the Spinal Cord by Muscarinic Receptor Subtypes

2007 ◽  
Vol 97 (1) ◽  
pp. 102-109 ◽  
Author(s):  
Hong-Mei Zhang ◽  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Acetylcholine Receptors ◽  
Glutamate Release ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Primary Afferents ◽  
Muscarinic Acetylcholine Receptors ◽  
Receptor Subtypes ◽  
Dorsal Horn Neurons

Activation of spinal muscarinic acetylcholine receptors (mAChRs) produces analgesia and inhibits dorsal horn neurons through potentiation of GABAergic/glycinergic tone and inhibition of glutamatergic input. To investigate the mAChR subtypes involved in the inhibitory effect of mAChR agonists on glutamate release, evoked excitatory postsynaptic currents (eEPSCs) were recorded in lamina II neurons using whole cell recordings in rat spinal cord slices. The nonselective mAChR agonist oxotremorine-M concentration-dependently inhibited the monosynaptic and polysynaptic EPSCs elicited by dorsal root stimulation. Interestingly, oxotromorine-M caused a greater inhibition of polysynaptic EPSCs (64.7%) than that of monosynaptic EPSCs (27.9%). In rats pretreated with intrathecal pertussis toxin, oxotremorine-M failed to decrease monosynaptic EPSCs but still partially inhibited the polysynaptic EPSCs in some neurons. This remaining effect was blocked by a relatively selective M3 antagonist 4-DAMP. Himbacine, an M2/M4 antagonist, or AFDX-116, a selective M2 antagonist, completely blocked the inhibitory effect of oxotremorine-M on monosynaptic EPSCs. However, the specific M4 antagonist MT-3 did not alter the effect of oxotremorine-M on monosynaptic EPSCs. Himbacine also partially attenuated the effect of oxotremorine-M on polysynaptic EPSCs in some cells and this effect was abolished by 4-DAMP. Furthermore, oxotremorine-M significantly decreased spontaneous EPSCs in seven of 22 (31.8%) neurons, an effect that was blocked by 4-DAMP. This study provides new information that the M2 mAChRs play a critical role in the control of glutamatergic input from primary afferents to dorsal horn neurons. The M3 and M2/M4 subtypes on a subpopulation of interneurons are important for regulation of glutamate release from interneurons in the spinal dorsal horn.

scholarly journals Age-related gene expression changes in lumbar spinal cord: Implications for neuropathic pain

2020 ◽  
Vol 16 ◽  
pp. 174480692097191
Author(s):  
Jack A Mayhew ◽  
Mitchell J Cummins ◽  
Ethan T Cresswell ◽  
Robert J Callister ◽  
Doug W Smith ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Dorsal Spinal Cord ◽  
Age Related ◽  
Pathological Pain ◽  
The Impact ◽  
Dorsal Spinal ◽  
Young Mice

Clinically, pain has an uneven incidence throughout lifespan and impacts more on the elderly. In contrast, preclinical models of pathological pain have typically used juvenile or young adult animals to highlight the involvement of glial populations, proinflammatory cytokines, and chemokines in the onset and maintenance of pathological signalling in the spinal dorsal horn. The potential impact of this mismatch is also complicated by the growing appreciation that the aged central nervous system exists in a state of chronic inflammation because of enhanced proinflammatory cytokine/chemokine signalling and glial activation. To address this issue, we investigated the impact of aging on the expression of genes that have been associated with neuropathic pain, glial signalling, neurotransmission and neuroinflammation. We used qRT-PCR to quantify gene expression and focussed on the dorsal horn of the spinal cord as this is an important perturbation site in neuropathic pain. To control for global vs region-specific age-related changes in gene expression, the ventral half of the spinal cord was examined. Our results show that expression of proinflammatory chemokines, pattern recognition receptors, and neurotransmitter system components was significantly altered in aged (24–32 months) versus young mice (2–4 months). Notably, the magnitude and direction of these changes were spinal-cord region dependent. For example, expression of the chemokine, Cxcl13, increased 119-fold in dorsal spinal cord, but only 2-fold in the ventral spinal cord of old versus young mice. Therefore, we propose the dorsal spinal cord of old animals is subject to region-specific alterations that prime circuits for the development of pathological pain, potentially in the absence of the peripheral triggers normally associated with these conditions.

scholarly journals Evans Blue Reduces Neuropathic Pain Behavior by Inhibiting Spinal ATP Release

2019 ◽  
Vol 20 (18) ◽  
pp. 4443 ◽  
Author(s):  
Yin ◽  
Hong ◽  
Phạm ◽  
Shin ◽  
Gwon ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Evans Blue ◽  
Spinal Dorsal Horn ◽  
Critical Role ◽  
Atp Release ◽  
Pain Behavior ◽  
Dependent Manner ◽  
Spinal Dorsal

Upon peripheral nerve injury, vesicular ATP is released from damaged primary afferent neurons. This extracellular ATP subsequently activates purinergic receptors of the spinal cord, which play a critical role in neuropathic pain. As an inhibitor of the vesicular nucleotide transporter (VNUT), Evans blue (EB) inhibits the vesicular storage and release of ATP in neurons. Thus, we tested whether EB could attenuate neuropathic pain behavior induced by spinal nerve ligation (SNL) in rats by targeting VNUT. An intrathecal injection of EB efficiently attenuated mechanical allodynia for five days in a dose-dependent manner and enhanced locomotive activity in an SNL rat model. Immunohistochemical analysis showed that EB was found in VNUT immunoreactivity on neurons in the dorsal root ganglion and the spinal dorsal horn. The level of ATP in cerebrospinal fluid in rats with SNL-induced neuropathic pain decreased upon administration of EB. Interestingly, EB blocked ATP release from neurons, but not glial cells in vitro. Eventually, the loss of ATP decreased microglial activity in the ipsilateral dorsal horn of the spinal cord, followed by a reduction in reactive oxygen species and proinflammatory mediators, such as interleukin (IL)-1β and IL-6. Finally, a similar analgesic effect of EB was demonstrated in rats with monoiodoacetate-induced osteoarthritis (OA) pain. Taken together, these data demonstrate that EB prevents ATP release in the spinal dorsal horn and reduces the ATP/purinergic receptor-induced activation of spinal microglia followed by a decline in algogenic substances, thereby relieving neuropathic pain in rats with SNL.

scholarly journals Updates on clinical trials evaluating the regenerative potential of allogenic mesenchymal stem cells in COVID-19

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Dhavan Sharma ◽  
Feng Zhao
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Adaptive Immune Response ◽  
Standard Of Care ◽  
Multiple Organ ◽  
Current Standard ◽  
Number Of Patients ◽  
Standard Of Care Treatment

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected nearly 118 million people and caused ~2.6 million deaths worldwide by early 2021, during the coronavirus disease 2019 (COVID-19) pandemic. Although the majority of infected patients show mild-to-moderate symptoms, a small fraction of patients develops severe symptoms. Uncontrolled cytokine production and the lack of substantive adaptive immune response result in hypoxia, acute respiratory distress syndrome (ARDS), or multiple organ failure in severe COVID-19 patients. Since the current standard of care treatment is insufficient to alleviate severe COVID-19 symptoms, many clinics have been prompted to perform clinical trials involving the infusion of mesenchymal stem cells (MSCs) due to their immunomodulatory and therapeutic properties. Several phases I/II clinical trials involving the infusion of allogenic MSCs have been performed last year. The focus of this review is to critically evaluate the safety and efficacy outcomes of the most recent, placebo-controlled phase I/II clinical studies that enrolled a larger number of patients, in order to provide a statistically relevant and comprehensive understanding of MSC’s therapeutic potential in severe COVID-19 patients. Clinical outcomes obtained from these studies clearly indicate that: (i) allogenic MSC infusion in COVID-19 patients with ARDS is safe and effective enough to decreases a set of inflammatory cytokines that may drive COVID-19 associated cytokine storm, and (ii) MSC infusion efficiently improves COVID-19 patient survival and reduces recovery time. These findings strongly support further investigation into MSC-infusion in larger clinical trials for COVID-19 patients with ARDS, who currently have a nearly 50% of mortality rate.

scholarly journals Treating ADHD With Suggestion: Neurofeedback and Placebo Therapeutics

2018 ◽  
Vol 22 (8) ◽  
pp. 707-711 ◽  
Author(s):  
Robert T. Thibault ◽  
Samuel Veissière ◽  
Jay A. Olson ◽  
Amir Raz
Keyword(s):  
Medical Literature ◽  
Therapeutic Potential ◽  
Standard Of Care ◽  
Current Standard ◽  
Full Disclosure ◽  
Pilot Experiment ◽  
Eeg Neurofeedback ◽  
Potential Alternative

Objective: We propose that clinicians can use suggestion to help treat conditions such as ADHD. Methods: We use EEG neurofeedback as a case study, alongside evidence from a recent pilot experiment utilizing a sham MRI scanner to highlight the therapeutic potential of suggestion-based treatments. Results: The medical literature demonstrates that many practitioners already prescribe treatments that hardly outperform placebo comparators. Moreover, the sham MRI experiment showed that, even with full disclosure of the procedure, suggestion alone can reduce the symptomatology of ADHD. Conclusion: Non-deceptive suggestion-based treatments, especially those drawing on accessories from neuroscience, may offer a safe complement and potential alternative to current standard of care for individuals with ADHD.

scholarly journals Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Kelly M Smith ◽  
Tyler J Browne ◽  
Olivia C Davis ◽  
A Coyle ◽  
Kieran A Boyle ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Calcium Binding ◽  
Spinal Cord Dorsal Horn ◽  
Projection Neurons ◽  
Spinal Interneurons ◽  
Nociceptive Information ◽  
Spinal Cord Dorsal ◽  
Pathological Pain

Nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate spinal interneurons that express the calcium-binding protein calretinin (CR). We show that these interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relay signals to lamina I projection neurons. Photoactivation of CR interneurons in vivo resulted in a significant nocifensive behavior that was morphine sensitive, caused a conditioned place aversion, and was enhanced by spared nerve injury. Furthermore, halorhodopsin-mediated inhibition of these interneurons elevated sensory thresholds. Our results suggest that dorsal horn circuits that involve excitatory CR neurons are important for the generation and amplification of pain and identify these interneurons as a future analgesic target.

scholarly journals The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Beatriz Subtil ◽  
Alessandra Cambi ◽  
Daniele V. F. Tauriello ◽  
I. Jolanda M. de Vries
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Critical Role ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Future Research ◽  
The Impact

Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.

scholarly journals Calretinin positive neurons form an excitatory amplifier network in the spinal cord dorsal horn

2019 ◽  
Author(s):  
KM Smith ◽  
TJ Browne ◽  
O Davis ◽  
A Coyle ◽  
KA Boyle ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Calcium Binding ◽  
Spinal Cord Dorsal Horn ◽  
Projection Neurons ◽  
Neuronal Circuits ◽  
Nociceptive Information ◽  
Spinal Cord Dorsal ◽  
Pathological Pain

AbstractThe passage of nociceptive information is relayed through the spinal cord dorsal horn, a critical area in sensory processing. The neuronal circuits in this region that underpin sensory perception must be clarified to better understand how dysfunction can lead to pathological pain. This study used an optogenetic approach to selectively activate neurons that contain the calcium-binding protein calretinin (CR). We show that CR+ interneurons form an interconnected network that can initiate and sustain enhanced excitatory signaling, and directly relays signals to lamina I projection neurons. In vivo photoactivation of CR+ interneurons resulted in a significant nocifensive behavior that was morphine sensitive and cause a conditioned place aversion. Furthermore, halorhodopsin-mediated inhibition of CR+ interneurons elevated sensory thresholds. These results suggest that neuronal circuits in the superficial dorsal horn that involve excitatory CR+ neurons are important for the generation and amplification of pain, and identify these interneurons as a future analgesic target.

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