Nociceptors and Chronic Pain

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.

scholarly journals A Novel Peripheral Action of PICK1 Inhibition in Inflammatory Pain

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.

Chemo- and Optogenetic Strategies for the Elucidation of Pain Pathways

2019 ◽  
pp. 816-832 ◽  
Author(s):  
Sascha R. A. Alles ◽  
Anne-Marie Malfait ◽  
Richard J. Miller
Keyword(s):  
Chronic Pain ◽  
Pain Response ◽  
Conscious Perception ◽  
Novel Therapies ◽  
The Past ◽  
Nociceptive Pathways ◽  
Pain Pathways ◽  
Technical Advances ◽  
The Brain

Pain is not a simple phenomenon and, beyond its conscious perception, involves circuitry that allows the brain to provide an affective context for nociception, which can influence mood and memory. In the past decade, neurobiological techniques have been developed that allow investigators to elucidate the importance of particular groups of neurons in different aspects of the pain response, something that may have important translational implications for the development of novel therapies. Chemo- and optogenetics represent two of the most important technical advances of recent times for gaining understanding of physiological circuitry underlying complex behaviors. The use of these techniques for teasing out the role of neurons and glia in nociceptive pathways is a rapidly growing area of research. The major findings of studies focused on understanding circuitry involved in different aspects of nociception and pain are highlighted in this article. In addition, attention is drawn to the possibility of modification of chemo- and optogenetic techniques for use as potential therapies for treatment of chronic pain disorders in human patients.

scholarly journals The acquisition and generalization of fear of touch

2020 ◽  
Vol 20 (4) ◽  
pp. 809-819 ◽  
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.

Chronic Estrogen Sensitizes a Subset of Mechanosensitive Afferents Innervating the Uterine Cervix

2005 ◽  
Vol 93 (4) ◽  
pp. 2167-2173 ◽  
Author(s):  
Baogang Liu ◽  
James C. Eisenach ◽  
Chuanyao Tong
Keyword(s):  
Spontaneous Activity ◽  
Uterine Cervix ◽  
Firing Frequency ◽  
High Threshold ◽  
Group 13 ◽  
Ovx Rats ◽  
Afferent Fibers ◽  
Low Threshold ◽  
Group 5 ◽  
Afferent Response

Estrogen increases reflex nocifensive responses to distension of the uterus and the urinary bladder, but estrogen's effects on afferent response to distension of the uterine cervix, the site of obstetric and some gynecologic pain, has not been studied. Here, single fiber recording of hypogastric nerve responses to uterine cervical distension were obtained from ovariectomized (OVX) rats and OVX rats treated with estrogen (ES). Spontaneous activity was greater in the ES group (13 of 24 units; 54%) than in the OVX group (6 of 27 units; 22%). ES differentially altered the response of low- and high-threshold units to distension. For high-threshold units, firing frequency was increased two- to fourfold with 60–100 gm distension in ES compared with OVX groups ( P < 0.05). In contrast, the response of low-threshold units to distension was not altered by ES. About one-half of units tested in each group responded to a temperature increase from 35 to 49°C. A greater proportion of thermosensitive units were also mechanosensitive in the ES group (7 of 8 afferents, 88%) than in the OVX group (5 of 11 afferents, 45%). Acute application of ES in OVX rats failed to evoke or increase distension-induced responses. These data show the polymodal nature of afferent fibers innervating the uterine cervix. Increased spontaneous activity with ES may play a part in remodeling of the cervical tissue, whereas selective sensitization of high-threshold units by ES might underlie increased pain responses to cervical distension. Failure of acute ES treatment to mimic this suggests a genomic effect.

Dorsal Root Ganglion Neuron Types and Their Functional Specialization

2018 ◽  
pp. 127-155 ◽  
Author(s):  
Edward C. Emery ◽  
Patrik Ernfors
Keyword(s):  
Chronic Pain ◽  
Dorsal Root Ganglion ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drg Neurons ◽  
Low Threshold

Primary sensory neurons of the dorsal root ganglion (DRG) respond and relay sensations that are felt, such as those for touch, pain, temperature, itch, and more. The ability to discriminate between the various types of stimuli is reflected by the existence of specialized DRG neurons tuned to respond to specific stimuli. Because of this, a comprehensive classification of DRG neurons is critical for determining exactly how somatosensation works and for providing insights into cell types involved during chronic pain. This article reviews the recent advances in unbiased classification of molecular types of DRG neurons in the perspective of known functions as well as predicted functions based on gene expression profiles. The data show that sensory neurons are organized in a basal structure of three cold-sensitive neuron types, five mechano-heat sensitive nociceptor types, four A-Low threshold mechanoreceptor types, five itch-mechano-heat–sensitive nociceptor types and a single C–low-threshold mechanoreceptor type with a strong relation between molecular neuron types and functional types. As a general feature, each neuron type displays a unique and predicable response profile; at the same time, most neuron types convey multiple modalities and intensities. Therefore, sensation is likely determined by the summation of ensembles of active primary afferent types. The new classification scheme will be instructive in determining the exact cellular and molecular mechanisms underlying somatosensation, facilitating the development of rational strategies to identify causes for chronic pain.

scholarly journals User Experience and Potential Health Effects of a Conversational Agent-Based Electronic Health Intervention: Protocol for an Observational Cohort Study

10.2196/16641 ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. e16641
Author(s):  
Marian Z M Hurmuz ◽  
Stephanie M Jansen-Kosterink ◽  
Harm op den Akker ◽  
Hermie J Hermens
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Chronic Pain ◽  
User Experience ◽  
Chronic Conditions ◽  
Healthy Lifestyle ◽  
Observational Cohort Study ◽  
Potential Health ◽  
Observational Cohort

Background While the average human life expectancy has increased remarkably, the length of life with chronic conditions has also increased. To limit the occurrence of chronic conditions and comorbidities, it is important to adopt a healthy lifestyle. Within the European project “Council of Coaches,” a personalized coaching platform was developed that supports developing and maintaining a healthy lifestyle. Objective The primary aim of this study is to assess the user experience with and the use and potential health effects of a fully working Council of Coaches system implemented in a real-world setting among the target population, specifically older adults or adults with type 2 diabetes mellitus or chronic pain. Methods An observational cohort study with a pretest-posttest design will be conducted. The study population will be a dynamic cohort consisting of older adults, aged ≥55 years, as well as adults aged ≥18 years with type 2 diabetes mellitus or chronic pain. Each participant will interact in a fully automated manner with Council of Coaches for 5 to 9 weeks. The primary outcomes are user experience, use of the program, and potential effects (health-related factors). Secondary outcomes include demographics, applicability of the virtual coaches, and user interaction with the virtual coaches. Results Recruitment started in December 2019 and is conducted through mass mailing, snowball sampling, and advertisements in newspapers and social media. This study is expected to conclude in August 2020. Conclusions The results of this study will either confirm or reject the hypothesis that a group of virtual embodied conversational coaches can keep users engaged over several weeks of interaction and contribute to positive health outcomes. Trial Registration The Netherlands Trial Register: NL7911; https://www.trialregister.nl/trial/7911 International Registered Report Identifier (IRRID) PRR1-10.2196/16641

scholarly journals The effects of propranolol on heart rate variability and quantitative, mechanistic, pain profiling: a randomized placebo-controlled crossover study

2018 ◽  
Vol 18 (3) ◽  
pp. 479-489 ◽  
Author(s):  
Kristian Kjær Petersen ◽  
Hjalte Holm Andersen ◽  
Masato Tsukamoto ◽  
Lincoln Tracy ◽  
Julian Koenig ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Chronic Pain ◽  
Pain Sensitivity ◽  
Experimental Pain ◽  
Central Pain ◽  
Healthy Male ◽  
Pain Pathways ◽  
Β Blocker ◽  
Chronic Pain Conditions

AbstractBackground and aimsThe autonomic nervous system (ANS) is capable of modulating pain. Aberrations in heart rate variability (HRV), reflective of ANS activity, are associated with experimental pain sensitivity, chronic pain, and more recently, pain modulatory mechanisms but the underlying mechanisms are still unclear. HRV is lowered during experimental pain as well as in chronic pain conditions and HRV can be increased by propranolol, which is a non-selective β-blocker. Sensitization of central pain pathways have been observed in several chronic pain conditions and human mechanistic pain biomarkers for these central pain pathways include temporal summation of pain (TSP) and conditioned pain modulation (CPM). The current study aimed to investigate the effect of the β-blocker propranolol, and subsequently assessing the response to standardized, quantitative, mechanistic pain biomarkers.MethodsIn this placebo-controlled, double-blinded, randomized crossover study, 25 healthy male volunteers (mean age 25.6 years) were randomized to receive 40 mg propranolol and 40 mg placebo. Heart rate, blood pressure, and HRV were assessed before and during experimental pain tests. Cuff pressure pain stimulation was used for assessment of pain detection (cPDTs) and pain tolerance (cPTTs) thresholds, TSP, and CPM. Offset analgesia (OA) was assessed using heat stimulation.ResultsPropranolol significantly reduced heart rate (p<0.001), blood pressure (p<0.02) and increased HRV (p<0.01) compared with placebo. No significant differences were found comparing cPDT (p>0.70), cPTT (p>0.93), TSP (p>0.70), OA-effect (p>0.87) or CPM (p>0.65) between propranolol and placebo.ConclusionsThe current study demonstrated that propranolol increased HRV, but did not affect pressure pain sensitivity or any pain facilitatory or modulatory outcomes.ImplicationsAnalgesic effects of propranolol have been reported in clinical pain populations and the results from the current study could indicate that increased HRV from propranolol is not associated with peripheral and central pain pathways in healthy male subjects.

scholarly journals P2X receptor channels in chronic pain pathways

2017 ◽  
Vol 175 (12) ◽  
pp. 2219-2230 ◽  
Author(s):  
Louis-Philippe Bernier ◽  
Ariel R Ase ◽  
Philippe Séguéla
Keyword(s):  
Chronic Pain ◽  
P2x Receptor ◽  
Pain Pathways

Pain medicine

2014 ◽  
Author(s):  
Jeremy Prout ◽  
Tanya Jones ◽  
Daniel Martin
Keyword(s):  
Chronic Pain ◽  
Pain Management ◽  
Management Strategies ◽  
Multidisciplinary Management ◽  
Pain Medicine ◽  
Pain Pathways ◽  
Patient Groups ◽  
Chronic Pain Conditions ◽  
Sites Of Action ◽  
Specific Management

This chapter summarizes the assessment and management of acute and chronic pain for FRCA. Pain pathways and physiological consequences of pain are considered along with sites of action and the pharmacology of common analgesics. Assessment of pain for different patient groups and settings is explained. Pain management strategies, pharmacological, non-interventional and interventional techniques are described, including multidisciplinary management of chronic pain. Specific management of some common chronic pain conditions, such as trigeminal neuralgia, are discussed in more detail.

Pain Pathways and Nervous System Plasticity: Learning and Memory in Pain

Pain Medicine ◽  
2019 ◽  
Vol 20 (12) ◽  
pp. 2421-2437 ◽  
Author(s):  
Bill McCarberg ◽  
John Peppin
Keyword(s):  
Chronic Pain ◽  
Neural Plasticity ◽  
Central Sensitization ◽  
Long Term Potentiation ◽  
Functional Changes ◽  
Pain Pathways ◽  
Term Potentiation ◽  
Pain Chronification ◽  
Longitudinal Imaging

Abstract Objective This article reviews the structural and functional changes in pain chronification and explores the association between memory and the development of chronic pain. Methods PubMed was searched using the terms “chronic pain,” “central sensitization,” “learning,” “memory,” “long-term potentiation,” “long-term depression,” and “pain memory.” Relevant findings were synthesized into a narrative of the processes affecting pain chronification. Results Pain pathways represent a complex sensory system with cognitive, emotional, and behavioral influences. Anatomically, the hippocampus, amygdala, and anterior cortex—central to the encoding and consolidation of memory—are also implicated in experiential aspects of pain. Common neurotransmitters and similar mechanisms of neural plasticity (eg, central sensitization, long-term potentiation) suggest a mechanistic overlap between chronic pain and memory. These anatomic and mechanistic correlates indicate that chronic pain and memory intimately interact on several levels. Longitudinal imaging studies suggest that spatiotemporal reorganization of brain activity accompanies the transition to chronic pain, during which the representation of pain gradually shifts from sensory to emotional and limbic structures. Conclusions The chronification of pain can be conceptualized as activity-induced plasticity of the limbic–cortical circuitry resulting in reorganization of the neocortex. The state of the limbic–cortical network determines whether nociceptive signals are transient or chronic by extinguishing pathways or amplifying signals that intensify the emotional component of nociceptive inputs. Thus, chronic pain can be seen as the persistence of the memory of pain and/or the inability to extinguish painful memories. Ideally, pharmacologic, physical, and/or psychological approaches should reverse the reorganization accompanying chronic pain.

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