Activation of peripheral neuronal FLT3 promotes exaggerated sensorial and emotional pain-related behaviors facilitating the transition from acute to chronic pain

Background. Acute pain events have been associated with persistent pain sensitization of nociceptive pathways increasing the risk of transition from acute to chronic pain. However, it is unclear whether injury-induced persistent pain sensitization can promote long-term mood disorders. The receptor tyrosine kinase FLT3 is causally required for peripheral nerve injury-induced pain chronification, questioning its role in the development of pain-induced mood alterations. Methods. In a model of paw incisional pain, mice underwent single (SI) or double incision (DI) and went through behavioral and molecular phenotyping with the evaluation of both sensorial and emotional pain components. The role of FLT3 was then investigated either by inhibition using transgenic knock-out mice and functional antibodies or by activation with FLT3 ligand (FL) administrations. Results. DI mice showed significant anxiodepressive-like and spontaneous pain behaviors while SI mice did not. DI also promoted and extended mechanical pain hypersensitivity compared to SI. This emotional and sensorial pain exaggeration correlated with a potentiation of spinal microglial activation after DI versus SI. Intrathecal minocycline, a microglial inhibitor, specifically reversed DI induced-mechanical hypersensitivity. Finally, FL injections in naive animals provoked mechanical allodynia and anxiodepressive-like disorders concomitant with a significant microglial activation while FLT3 inhibition blunted the development of persistent pain and depression after DI. Conclusions. Our results show for the first time that the repetition of a peripheral lesion facilitates not only exaggerated nociceptive behaviors but also anxiodepressive disorders. The inhibition of FLT3 could become a promising therapy in the management of pain sensitization and related mood alterations.

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A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.750902 ◽

2021 ◽

Vol 15 ◽

Author(s):

Kathrine Louise Jensen ◽

Gith Noes-Holt ◽

Andreas Toft Sørensen ◽

Kenneth Lindegaard Madsen

Keyword(s):

Chronic Pain ◽

Side Effects ◽

Inflammatory Pain ◽

Pain Treatment ◽

Memory Performance ◽

Current Treatment ◽

Abuse Liability ◽

Spontaneous Pain ◽

Pain Pathways ◽

Pain Sensitization

Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.

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A38 TRPV1 VISCERAL AFFERENTS CONTROL CENTRAL SENSITIZATION IN IBD

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.036 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 278-279

Author(s):

M Defaye ◽

N Abdullah ◽

M Iftinca ◽

C Altier

Keyword(s):

Chronic Pain ◽

Central Sensitization ◽

Microglial Activation ◽

Visceral Pain ◽

Purinergic Signaling ◽

Designer Drugs ◽

Visceral Afferents ◽

Peripheral Sensitization ◽

Specific Expression

Abstract Background Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease, suggesting a high level of plasticity in nociceptive circuits during acute phases. The establishment of chronic visceral pain results from neuroplasticity in nociceptors first, then along the entire neural axis, wherein microglia, the resident immune cells of the central nervous system, are critically involved. Our lab has shown that spinal microglia were key in controlling chronic pain state in IBD. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown. Aims To investigate the role of TRPV1+ visceral afferents in microglial activation and chronic visceral pain. Methods We generated DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice in which TRPV1 sensory neurons can be inhibited (TRPV1-hM4Di) or activated (TRPV1-hM3Dq) in a time and tissue specific manner using the inert ligand Clozapine-N-Oxide (CNO). To test the inhibition of TRPV1 neurons in DSS-induced colitis, TRPV1-hM4Di mice were treated with DSS 2.5% or water for 7 days and received vehicle or CNO i.p. injection twice daily. To activate TRPV1 visceral afferents, TRPV1-hM3Dq mice received vehicle or CNO daily for 7 days, by oral gavage. After 7 days of treatment, visceral pain was evaluated by colorectal distension and spinal cords tissues were harvested to measure microglial activation. Results Our data validated the nociceptor specific expression and function of the DREADD in TRPV1-Cre mice. Inhibition of TRPV1 visceral afferents in DSS TRPV1-hM4Di mice was able to prevent the colitis-induced microglial activation and thus reduce visceral hypersensitivity. In contrast, activation of TRPV1 visceral afferents in TRPV1-hM3Dq mice was sufficient to drive microglial activation in the absence of colitis. Analysis of the proalgesic mediators derived from activated TRPV1-hM3Dq neurons identified ATP as a key factor of microglial activation. Conclusions Overall, these data provide novel insights into the mechanistic understanding of the gut/brain axis in chronic visceral pain and suggest a role of purinergic signaling that could be harnessed for testing effective therapeutic approaches to relieve pain in IBD patients. Funding Agencies CCCACHRI (Alberta Children’s Hospital Research Institute) and CSM (Cumming School of Medicine) postdoctoral fellowship

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Pra-C exerts analgesic effect through inhibiting microglial activation in anterior cingulate cortex in complete Freund’s adjuvant-induced mouse model

Molecular Pain ◽

10.1177/1744806921990934 ◽

2021 ◽

Vol 17 ◽

pp. 174480692199093

Author(s):

Dan-jie Su ◽

Long-fei Li ◽

Sai-ying Wang ◽

Qi Yang ◽

Yu-jing Wu ◽

...

Keyword(s):

Chronic Pain ◽

Mouse Model ◽

Anterior Cingulate Cortex ◽

Analgesic Effect ◽

Microglial Activation ◽

Cingulate Cortex ◽

Anterior Cingulate ◽

Freund’S Adjuvant ◽

Complete Freund's Adjuvant ◽

Freund's Adjuvant

Chronic pain is highly prevalent worldwide and severely affects daily lives of patients and family members. Praeruptorin C (Pra-C) is a main active ingredient derived from Peucedanum praeruptorum Dunn, traditionally used as antibechic, anti-bronchitis and anti-hypertension drug. Here, we evaluated the effects of Pra-C in a chronic inflammatory pain mouse model induced by complete Freund’s adjuvant (CFA) injection. Pra-C (3 mg/kg) treatment for just 3 days after CFA challenge relieved CFA-induced mechanical allodynia and hindpaw edema in mice. In the anterior cingulate cortex (ACC), Pra-C treatment inhibited microglia activation and reduced levels of proinflammatory cytokines, TNF-α and IL-1β, and suppressed upregulation of glutamate receptors caused by CFA injection. In addition, Pra-C attenuated neuronal hyperexcitability in ACC of CFA-injected mice. In vitro studies confirmed the analgesic effect of Pra-C was due to its inhibitory ability on microglial activation. In conclusion, Pra-C administration had a certain effect on relieving chronic pain by inhibiting microglial activation, attenuating proinflammatory cytokine releasing and regulating excitatory synaptic proteins in the ACC of the CFA-injected mice.

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The acquisition and generalization of fear of touch

Scandinavian Journal of Pain ◽

10.1515/sjpain-2019-0177 ◽

2020 ◽

Vol 20 (4) ◽

pp. 809-819 ◽

Cited By ~ 1

Author(s):

Emma E. Biggs ◽

Ann Meulders ◽

Amanda L. Kaas ◽

Rainer Goebel ◽

Johan W. S. Vlaeyen

Keyword(s):

Chronic Pain ◽

Stimulus Generalization ◽

Spontaneous Pain ◽

The Novel ◽

Vibrotactile Stimulation ◽

Differential Acquisition ◽

New Locations ◽

Conditioned Responses ◽

Primary Focus ◽

Post Hoc

AbstractObjectivesContemporary fear-avoidance models of chronic pain posit that fear of pain, and overgeneralization of fear to non-threatening stimuli is a potential pathway to chronic pain. While increasing experimental evidence supports this hypothesis, a comprehensive investigation requires testing in multiple modalities due to the diversity of symptomatology among individuals with chronic pain. In the present study we used an established tactile fear conditioning paradigm as an experimental model of allodynia and spontaneous pain fluctuations, to investigate whether stimulus generalization occurs resulting in fear of touch spreading to new locations.MethodsIn our paradigm, innocuous touch is presented either paired (predictable context) or unpaired (unpredictable context) with a painful electrocutaneous stimulus (pain-US). In the predictable context, vibrotactile stimulation to the index or little finger was paired with the pain-US (CS+), whilst stimulation of the other finger was never paired with pain (CS−). In the unpredictable context, vibrotactile stimulation to the index and little fingers of the opposite hand (CS1 and CS2) was unpaired with pain, but pain-USs occurred unpredictable during the intertrial interval. During the subsequent generalization phase, we tested the spreading of conditioned responses (self-reported fear of touch and pain expectancy) to the (middle and ring) fingers between the CS+ and CS−, and between the CS1 and CS2.ResultsDifferential fear acquisition was evident in the predictable context from increased self-reported pain expectancy and self-reported fear for the CS + compared to the CS−. However, expectancy and fear ratings to the novel generalization stimuli (GS+ and GS−) were comparable to the responses elicited by the CS−. Participants reported equal levels of pain expectancy and fear to the CS1 and CS2 in the unpredictable context. However, the acquired fear did not spread in this context either: participants reported less pain expectancy and fear to the GS1 and GS2 than to the CS1 and CS2. As in our previous study, we did not observe differential acquisition in the startle responses.ConclusionsWhilst our findings for the acquisition of fear of touch replicate the results from our previous study (Biggs et al., 2017), there was no evidence of fear generalization. We discuss the limitations of the present study, with a primary focus on procedural issues that were further investigated with post-hoc analyses, concluding that the present results do not show support for the hypothesis that stimulus generalization underlies spreading of fear of touch to new locations, and discuss how this may be the consequence of a context change that prevented transfer of acquisition.

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Nociceptors and Chronic Pain

10.1093/acrefore/9780190264086.013.339 ◽

2021 ◽

Author(s):

Edgar T. Walters

Keyword(s):

Chronic Pain ◽

Spontaneous Activity ◽

Intracellular Signaling ◽

Chronic Conditions ◽

Spontaneous Pain ◽

Pain Pathways ◽

Low Threshold ◽

Highly Correlated ◽

Hyperalgesic Priming ◽

Peripheral Activation

Chronic pain lasting months or longer is very common, poorly treated, and sometimes devastating. Nociceptors are sensory neurons that usually are silent unless activated by tissue damage or inflammation. In humans their peripheral activation evokes conscious pain, and their spontaneous activity is highly correlated with spontaneous pain. Persistently hyperactive nociceptors mediate increased responses to normally painful stimuli (hyperalgesia) in chronic conditions and promote the sensitization of central pain pathways that allows low-threshold mechanoreceptors to elicit painful responses to innocuous stimuli (allodynia). Investigations of rodent models of neuropathic pain and hyperalgesic priming have revealed many alterations in nociceptors and associated cells that are implicated in the development and maintenance of chronic pain. These include chronic nociceptor hyperexcitability and spontaneous activity, sprouting, synaptic plasticity, changes in intracellular signaling, and modified responses to opioids, along with alterations in the expression and translation of thousands of genes in nociceptors and closely linked cells.

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Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

10.33774/chemrxiv-2021-h5hhv ◽

2021 ◽

Author(s):

Jason Scott ◽

Monica Soto-Velasquez ◽

Michael Hayes ◽

Justin Lavigne ◽

Heath Miller ◽

...

Keyword(s):

Chronic Pain ◽

Physicochemical Properties ◽

Adenylyl Cyclase ◽

Learning And Memory ◽

Inflammatory Pain ◽

Selective Inhibition ◽

Behavioral Studies ◽

Morphine Administration ◽

Ic50 Values ◽

Pain Sensitization

Adenylyl cyclase type 1 is an emerging target for the treatment of chronic pain that is downstream on the analgesic pathway from the traditional µ-opioid receptor. AC1 is expressed in the central nervous system and critical for signaling in pain sensitization. Behavioral studies have revealed AC1 knockout mice exhibit reduced behavioral pain sensitization responses similar to morphine administration. AC1, and a closely related isoform AC8, are also implicated to have a role in learning and memory signaling processes. However, reports suggest selectively targeting AC1 over AC8 may be a viable strategy to eliminate potential deleterious effects on learning and memory. Our team has carried out cellular screening for inhibitors of AC1 that yielded a pyrazolyl-pyrimidinone scaffold with potency comparable to previously published AC1 inhibitors, selectivity versus AC8, and improved drug-like physicochemical properties. Structure-activity relationship (SAR) studies produced 36 analogs that balanced improvements in potency with cellular IC50 values as low as 0.25 µM and selectivity versus AC8. Prioritized analogs were selective for AC1 compared to other AC isoforms and other common neurological targets. A representative analog was assessed for efficacy in a mouse model of inflammatory pain and displayed modest anti-allodynic effects. This series of compounds represents the most potent and selective inhibitors of Ca2+/Calmodulin-stimulated AC1 activity to date with reduced off-target liabilities and improved drug-like physicochemical properties making them promising lead compounds for the treatment of inflammatory pain.

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Optogenetic activation of spinal microglia triggers chronic pain in mice

PLoS Biology ◽

10.1371/journal.pbio.3001154 ◽

2021 ◽

Vol 19 (3) ◽

pp. e3001154

Author(s):

Min-Hee Yi ◽

Yong U. Liu ◽

Anthony D. Umpierre ◽

Tingjun Chen ◽

Yanlu Ying ◽

...

Keyword(s):

Chronic Pain ◽

Microglial Activation ◽

Red Light ◽

Inflammasome Activation ◽

Pain Hypersensitivity ◽

Microglial Phenotype ◽

C Fiber ◽

Inward Currents ◽

Calcium Elevation

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been any direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1β production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.

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Catastrophizing in Comorbid Chronic Pain and Mental Illness

Overlapping Pain and Psychiatric Syndromes ◽

10.1093/med/9780190248253.003.0017 ◽

2020 ◽

pp. 234-248

Author(s):

Cynthia O. Townsend ◽

Donald R. Townsend

Keyword(s):

Chronic Pain ◽

Mental Illness ◽

Prognostic Factor ◽

Pain Catastrophizing ◽

Psychological Interventions ◽

Clinical Implications ◽

Specific Situation ◽

Negative Consequences ◽

Pain Chronification

Catastrophizing, or the tendency to emphasize and exaggerate the occurrence of negative consequences in a specific situation, has been shown to play an important role in the development and maintenance of chronic pain. Dynamically viewed as a contributor, mediator, and result of chronic pain suffering, catastrophizing has notable importance for clinicians treating patients’ comorbid chronic pain and mental illness. Exciting research on catastrophizing and neuroplasticity in persons with chronic pain promises to expand our understanding of pain catastrophizing, pain chronification, and cortical structural neuroplasticity in response to psychological interventions. This chapter provides a selective review of the assessment and neural correlates of pain catastrophizing as well as the role of catastrophizing as a prognostic factor for pain-related outcomes. The interactions between catastrophizing and chronic pain are also explored in the context of key comorbid mental conditions: depression and insomnia. Clinical implications for the practicing clinician are discussed.

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