What is the role of fear and escape/avoidance in chronic pain? Models, structural analysis and future directions

Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain.

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Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat

Neuroscience ◽

10.1016/j.neuroscience.2006.10.048 ◽

2007 ◽

Vol 144 (4) ◽

pp. 1477-1485 ◽

Cited By ~ 71

Author(s):

L. Luo ◽

L. Chang ◽

S.M. Brown ◽

H. Ao ◽

D.H. Lee ◽

...

Keyword(s):

Chronic Pain ◽

Cyclic Nucleotide ◽

Pacemaker Channels ◽

Pain Models

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Chronic Orofacial Pain: Models, Mechanisms, and Genetic and Related Environmental Influences

International Journal of Molecular Sciences ◽

10.3390/ijms22137112 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7112

Author(s):

Barry J. Sessle

Keyword(s):

Chronic Pain ◽

Genetic Factors ◽

Orofacial Pain ◽

Trigeminal Neuropathic Pain ◽

Behavioural Characteristics ◽

Pain Models ◽

Chronic Orofacial Pain ◽

Underlying Mechanisms ◽

Animal Strains

Chronic orofacial pain conditions can be particularly difficult to diagnose and treat because of their complexity and limited understanding of the mechanisms underlying their aetiology and pathogenesis. Furthermore, there is considerable variability between individuals in their susceptibility to risk factors predisposing them to the development and maintenance of chronic pain as well as in their expression of chronic pain features such as allodynia, hyperalgesia and extraterritorial sensory spread. The variability suggests that genetic as well as environmental factors may contribute to the development and maintenance of chronic orofacial pain. This article reviews these features of chronic orofacial pain, and outlines findings from studies in animal models of the behavioural characteristics and underlying mechanisms related to the development and maintenance of chronic orofacial pain and trigeminal neuropathic pain in particular. The review also considers the role of environmental and especially genetic factors in these models, focussing on findings of differences between animal strains in the features and underlying mechanisms of chronic pain. These findings are not only relevant to understanding underlying mechanisms and the variability between patients in the development, expression and maintenance of chronic orofacial pain, but also underscore the importance for considering the strain of the animal to model and explore chronic orofacial pain processes.

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Theoretical basis of pain

Oxford Textbook of Pediatric Pain ◽

10.1093/med/9780198818762.003.0010 ◽

2021 ◽

pp. 89-100

Author(s):

Liesbet Goubert ◽

Rebecca Pillai Riddell ◽

Laura Simons ◽

David Borsook

Keyword(s):

Chronic Pain ◽

Theoretical Basis ◽

Theoretical Models ◽

Clinical Implications ◽

Neural Processes ◽

Pain Models ◽

Role Of Parents ◽

Pain Experiences ◽

Resilience Mechanisms

Pain experiences, both acute and chronic, are common in infants, children, and adolescents. The aim of this chapter is to give an overview of different biopsychosocial pediatric pain models that address acute or chronic pain. Recent insights in neural processes are discussed, as well as psychosocial mechanisms across a child’s development. The crucial role of parents in different theoretical conceptualizations is highlighted. We emphasize that both risk factors for the development of chronic pain-related disability and resilience mechanisms for adaptive child functioning should be considered. Finally, clinical implications are outlined ensuing from the different theoretical models discussed in this chapter.

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Neurovascular Unit in Chronic Pain

Mediators of Inflammation ◽

10.1155/2013/648268 ◽

2013 ◽

Vol 2013 ◽

pp. 1-18 ◽

Cited By ~ 19

Author(s):

Beatrice Mihaela Radu ◽

Placido Bramanti ◽

Francesco Osculati ◽

Maria-Luisa Flonta ◽

Mihai Radu ◽

...

Keyword(s):

Chronic Pain ◽

Pain Treatment ◽

Neurovascular Unit ◽

Socioeconomic Impact ◽

Pain Mechanisms ◽

Analgesic Drugs ◽

Pain Models ◽

Chronic Pain Treatment ◽

Blood Spinal Cord Barrier

Chronic pain is a debilitating condition with major socioeconomic impact, whose neurobiological basis is still not clear. An involvement of the neurovascular unit (NVU) has been recently proposed. In particular, the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), two NVU key players, may be affected during the development of chronic pain; in particular, transient permeabilization of the barrier is suggested by several inflammatory- and nerve-injury-based pain models, and we argue that the clarification of molecular BBB/BSCB permeabilization events will shed new light in understanding chronic pain mechanisms. Possible biases in experiments supporting this theory and its translational potentials are discussed. Moving beyond an exclusive focus on the role of the endothelium, we propose that our understanding of the mechanisms subserving chronic pain will benefit from the extension of research efforts to the NVU as a whole. In this view, the available evidence on the interaction between analgesic drugs and the NVU is here reviewed. Chronic pain comorbidities, such as neuroinflammatory and neurodegenerative diseases, are also discussed in view of NVU changes, together with innovative pharmacological solutions targeting NVU components in chronic pain treatment.

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Satellite Glial Cells in Pain Research: A Targeted Viewpoint of Potential and Future Directions

Frontiers in Pain Research ◽

10.3389/fpain.2021.646068 ◽

2021 ◽

Vol 2 ◽

Author(s):

Parisa Gazerani

Keyword(s):

Chronic Pain ◽

Nervous System ◽

Glial Cells ◽

Time Course ◽

Normal Function ◽

Spontaneous Pain ◽

Future Directions ◽

Satellite Glial Cells ◽

Pain Research

Chronic pain is known to be caused by sensitization within the pain circuits. An imbalance occurs between excitatory and inhibitory transmission that enables this sensitization to form. In addition to neurons, the contribution of central glia, especially astrocytes and microglia, to the pathogenesis of pain induction and maintenance has been identified. This has led to the targeting of astrogliosis and microgliosis to restore the normal functions of astrocytes and microglia to help reverse chronic pain. Gliosis is broadly defined as a reactive response of glial cells in response to insults to the central nervous system (CNS). The role of glia in the peripheral nervous system (PNS) has been less investigated. Accumulating evidence, however, points to the contribution of satellite glial cells (SGCs) to chronic pain. Hence, understanding the potential role of these cells and their interaction with sensory neurons has become important for identifying the mechanisms underlying pain signaling. This would, in turn, provide future therapeutic options to target pain. Here, a viewpoint will be presented regarding potential future directions in pain research, with a focus on SGCs to trigger further research. Promising avenues and new directions include the potential use of cell lines, cell live imaging, computational analysis, 3D tissue prints and new markers, investigation of glia–glia and macrophage–glia interactions, the time course of glial activation under acute and chronic pathological pain compared with spontaneous pain, pharmacological and non-pharmacological responses of glia, and potential restoration of normal function of glia considering sex-related differences.

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Nonpharmacological Interventions in Targeting Pain-Related Brain Plasticity

Neural Plasticity ◽

10.1155/2017/2038573 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Maral Tajerian ◽

J. David Clark

Keyword(s):

Chronic Pain ◽

Brain Plasticity ◽

Analgesic Efficacy ◽

Current Review ◽

Global Environmental ◽

Pain Models ◽

Chronic Pain Patients ◽

Psychiatric Conditions ◽

Pain Patients

Chronic pain is a highly prevalent and debilitating condition that is frequently associated with multiple comorbid psychiatric conditions and functional, biochemical, and anatomical alterations in various brain centers. Due to its widespread and diverse manifestations, chronic pain is often resistant to classical pharmacological treatment paradigms, prompting the search for alternative treatment approaches that are safe and efficacious. The current review will focus on the following themes: attentional and cognitive interventions, the role of global environmental factors, and the effects of exercise and physical rehabilitation in both chronic pain patients and preclinical pain models. The manuscript will discuss not only the analgesic efficacy of these therapies, but also their ability to reverse pain-related brain neuroplasticity. Finally, we will discuss the potential mechanisms of action for each of the interventions.

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On Future Directions in Pathology

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053991 ◽

1982 ◽

Vol 40 ◽

pp. 274-277

Author(s):

Benjamin F. Trump ◽

Irene K. Berezesky ◽

Raymond T. Jones

Keyword(s):

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Clinical Pathology ◽

Future Directions ◽

Diagnostic Pathology ◽

The Past ◽

Transmission Electron ◽

Organ Systems ◽

The Many

The role of electron microscopy and associated techniques is assured in diagnostic pathology. At the present time, most of the progress has been made on tissues examined by transmission electron microscopy (TEM) and correlated with light microscopy (LM) and by cytochemistry using both plastic and paraffin-embedded materials. As mentioned elsewhere in this symposium, this has revolutionized many fields of pathology including diagnostic, anatomic and clinical pathology. It began with the kidney; however, it has now been extended to most other organ systems and to tumor diagnosis in general. The results of the past few years tend to indicate the future directions and needs of this expanding field. Now, in addition to routine EM, pathologists have access to the many newly developed methods and instruments mentioned below which should aid considerably not only in diagnostic pathology but in investigative pathology as well.

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