Experimental pain models and clinical chronic pain: Is plasticity enough to link them?

1997 ◽  
Vol 20 (3) ◽  
pp. 458-459 ◽  
Author(s):  
Paolo Marchettini ◽  
Marco Lacerenza ◽  
Fabio Formaglio
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Animal Models ◽  
Experimental Pain ◽  
Experimental Models ◽  
Basic Information ◽  
Pain Models ◽  
Clinical Conditions

The central hyperexcitability observed in animal models supports a pathophysiological explanation for chronic human pain. Novel information on cholecystokinin (CCK) upregulation offers a rationale for reduced opioid response in neuropathic pain. However, the basic information provided by scientists should not lead clinicians to equate experimental models to chronic human conditions. Clinicians should provide careful reports and attempt to classify pathophysiologically clinical conditions that have so far been grouped generically. [blumberg et al.; coderre & katz; dickenson; wiesenfeld-hallin et al.]

Neuropathic pain models in the development of analgesic drugs

2011 ◽  
Vol 2 (4) ◽  
pp. 172-177 ◽  
Author(s):  
Per Hartvig Honoré ◽  
Anna Basnet ◽  
Laila Eljaja ◽  
Pernille Kristensen ◽  
Lene Munkholm Andersen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Animal Models ◽  
Nerve Injury ◽  
Clinical Manifestations ◽  
Pharmacological Intervention ◽  
Special Focus ◽  
Surgical Performance ◽  
Neuropathic Pain Syndrome ◽  
Pain Models ◽  
Rats And Mice

AbstractIntroductionAnimal disease models are predictive for signs seen in disease. They may rarely mimic all signs in a specific disease in humans with respect to etiology, cause or development. Several models have been developed for different pain states and the alteration of behavior has been interpreted as a response to external stimulus or expression of pain or discomfort. Considerable attention must be paid not to interpret other effects such as somnolence or motor impairment as a pain response and similarly not to misinterpret the response of analgesics.Neuropathic pain is caused by injury or disease of the somatosensory system. The clinical manifestations of neuropathic pain vary including both stimulus-evoked and non-stimulus evoked (spontaneous) symptoms. By pharmacological intervention, the threshold for allodynia and hyperalgesia in the various pain modalities can be modulated and measured in animals and humans. Animal models have been found most valuable in studies on neuropathic pain and its treatment.Aim of the studyWith these interpretation problems in mind, the present text aims to describe the most frequently used animal models of neuropathic pain induced by mechanical nerve injury.MethodsThe technical surgical performance of these models is described as well as pain behavior based on the authors own experience and from a literature survey.ResultsNerve injury in the hind limb of rats and mice is frequently used in neuropathic pain models and the different types of lesion may afford difference in the spread and quality of the pain provoked. The most frequently used models are presented, with special focus on the spared nerve injury (SNI) and the spinal nerve ligation/transection (SNL/SNT) models, which are extensively used and validated in rats and mice. Measures of mechanical and thermal hypersensitivity with von Frey filaments and Hargreaves test, respectively, are described and shown in figures.ConclusionsA number of animal models have been developed and described for neuropathic pain showing predictive value in parallel for both humans and animals. On the other hand, there are still large knowledge gaps in the pathophysiologic mechanisms for the development, maintenance and progression of the neuropathic pain syndromeImplicationsBetter understanding of pathogenic mechanisms of neuropathic pain in animal models may support the search for new treatment paradigms in patients with complex neuropathic pain conditions

Sympathetic component of neuropathic pain: Animal models and clinical diagnosis

1997 ◽  
Vol 20 (3) ◽  
pp. 468-469
Author(s):  
Laszlo A. Urban
Keyword(s):  
Experimental Data ◽  
Chronic Pain ◽  
Neuropathic Pain ◽  
Animal Models ◽  
Clinical Diagnosis ◽  
Inflammatory Pain ◽  
Ongoing Debate ◽  
Pain Syndromes ◽  
Sympathetic Nervous

Although clinical studies and animal models seem to establish an important role for the sympathetic nervous system in many forms of neuropathic and inflammatory pain, there is an ongoing debate on the classification of pain syndromes with sympathetic components. The confusion originates from several sources: failure to acknowledge that the pathomechanism of chronic pain can change during the progress of the disease, which is now strongly underlined by experimental data from suitable animal models. Neuropathic pain is a vaguely defined collection of pain syndromes which includes painful conditions with diverse and largely unknown patho-mechanisms. Clinical diagnosis is difficult and well designed, placebo controlled sympathectomy is rarely performed. [blumberg et al.]

scholarly journals Pathogenic Role of iNOs+ M1 Effector Macrophages in Fibromyalgia

2020 ◽  
Author(s):  
Vishwas Tripathi ◽  
Amaresh Mishra ◽  
Yamini Pathak ◽  
Aklank Jain ◽  
Hridayesh Prakash
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Neurodegenerative Disorder ◽  
Specific Treatment ◽  
The Body ◽  
World Population ◽  
Pain Models ◽  
Chronic Pain Conditions ◽  
Inflammatory Macrophages ◽  
The Impact

Fibromyalgia (FM) or Fibromyalgia Syndrome (FMS) is a neurodegenerative disorder causing musculoskeletal pain, tenderness, stiffness, fatigue, and sleep disorder in the body. It is one of the most common chronic pain conditions, affecting about 6% of the world population. Being refractory, till date, no specific treatment of this disease is available. Accumulating evidences over the last few decades indicate that proinflammatory macrophages, cytokines, & chemokines as the key players in this disease. Recent findings suggest activation of Microglial cells and associated pro-inflammatory signals as one of the major causes of chronic pain in patients suffering from fibromyalgia. Increased density of iNOs/CD68+ M1 effector macrophages has been associated with neuropathic pain models. In light of this, depletion of these pro-inflammatory macrophages has been shown to reduce sensitivity to neuropathic pain. On the other hand, modulating pattern of AGEs (Advanced Glycation End-Products) can also contribute to inactivation of macrophages. These findings strongly suggest that macrophages are critical in both inflammatory and neuropathic pain. Therefore, this chapter highlights the impact of macrophage plasticity in various immunopathological aspects of fibromyalgia.

scholarly journals Modulation of Glia-Mediated Processes by Spinal Cord Stimulation in Animal Models of Neuropathic Pain

2021 ◽  
Vol 2 ◽  
Author(s):  
David L. Cedeño ◽  
Courtney A. Kelley ◽  
Krishnan Chakravarthy ◽  
Ricardo Vallejo
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Animal Models ◽  
Glial Cells ◽  
Mechanism Of Action ◽  
Spinal Cord Stimulation ◽  
Expression Levels ◽  
Gate Control Theory

Glial cells play an essential role in maintaining the proper functioning of the nervous system. They are more abundant than neurons in most neural tissues and provide metabolic and catabolic regulation, maintaining the homeostatic balance at the synapse. Chronic pain is generated and sustained by the disruption of glia-mediated processes in the central nervous system resulting in unbalanced neuron–glial interactions. Animal models of neuropathic pain have been used to demonstrate that changes in immune and neuroinflammatory processes occur in the course of pain chronification. Spinal cord stimulation (SCS) is an electrical neuromodulation therapy proven safe and effective for treating intractable chronic pain. Traditional SCS therapies were developed based on the gate control theory of pain and rely on stimulating large Aβ neurons to induce paresthesia in the painful dermatome intended to mask nociceptive input carried out by small sensory neurons. A paradigm shift was introduced with SCS treatments that do not require paresthesia to provide effective pain relief. Efforts to understand the mechanism of action of SCS have considered the role of glial cells and the effect of electrical parameters on neuron–glial interactions. Recent work has provided evidence that SCS affects expression levels of glia-related genes and proteins. This inspired the development of a differential target multiplexed programming (DTMP) approach using electrical signals that can rebalance neuroglial interactions by targeting neurons and glial cells differentially. Our group pioneered the utilization of transcriptomic and proteomic analyses to identify the mechanism of action by which SCS works, emphasizing the DTMP approach. This is an account of evidence demonstrating the effect of SCS on glia-mediated processes using neuropathic pain models, emphasizing studies that rely on the evaluation of large sets of genes and proteins. We show that SCS using a DTMP approach strongly affects the expression of neuron and glia-specific transcriptomes while modulating them toward expression levels of healthy animals. The ability of DTMP to modulate key genes and proteins involved in glia-mediated processes affected by pain toward levels found in uninjured animals demonstrates a shift in the neuron–glial environment promoting analgesia.

Translational animal models using veterinary patients – An example of canine osteoarthritis (OA)

2012 ◽  
Vol 3 (2) ◽  
pp. 84-89 ◽  
Author(s):  
Outi Vainio
Keyword(s):  
Chronic Pain ◽  
Animal Models ◽  
Laboratory Animal ◽  
The United States ◽  
Reference List ◽  
Pain Research ◽  
Drug Molecules ◽  
Animal Pain ◽  
Pain Models ◽  
Privately Owned

AbstractBackground and purposeThe use of laboratory animals in pain research has powerfully contributed to our detailed understanding of the physiological mechanisms of pain. Animal models also represent an essential tool to screen and select novel drug molecules with potentially analgesic properties. Despite of the inevitable input of laboratory animal trials, recent studies have shown that animal pain models have repeatedly failed to predict clinical analgesic efficacy and adverse side effects of potential drug molecules in human pain patients. This paper provides a review of the laboratory animal models of OA, which have been developed to test efficacy of novel analgesics. The paper also presents spontaneous OA in canine veterinary patients, and methods to observe chronic pain in nonverbal dogs.MethodsPubMed data base was searched as a reference list to locate most relevant articles. A number of 118 articles including 4 reviews were located. Web pages of 4 establishments and 2 private organizations were also accessed.ResultsThe clinical expression and pathogenesis of naturally occurring OA in dogs is considered an analogous disease that occurs in humans, including pain and lameness. OA may occur in any joint in dogs as well as in humans. Primary idiopathic OA in dogs is rare, but certain breeds may be predisposed to it. For the most part, canine OA is considered secondary to acquired or congenital musculoskeletal disorders. Concomitant factors, such as aging and obesity, likely accelerate progression. However, mechanical factors appear to predominate in the etiopathogenesis of canine spontaneous OA. Both subjective (validated questionnaire) and objective (gait analysis) tools are available to measure OA related pain in dogs. Information on the prevalence of canine OA is limited, but rough surveys suggest that 11 million dogs in the United States and 5 million in Europe could suffer from OA. Ethical considerations concerning the use of privately owned dogs can be resolved by a careful experimental design.ConclusionCanine spontaneous OA could serve as a translational animal model that would more closely mimick clinical OA related pain conditions in humans. Privately owned dogs would make a solution to fix the gap between animal pain models and clinical trials when testing potential analgesic drug molecules. Close interdisciplinary cooperation would guarantee that both scientific and ethical intentions would be achieved.ImplicationsThe predictability of translational pain research would improve by using privately owned dogs as chronic pain models when testing novel analgesics.

scholarly journals mTOR Kinase: A Possible Pharmacological Target in the Management of Chronic Pain

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Lucia Lisi ◽  
Paola Aceto ◽  
Pierluigi Navarra ◽  
Cinzia Dello Russo
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Mammalian Target Of Rapamycin ◽  
Public Health Problem ◽  
Experimental Models ◽  
Major Public Health Problem ◽  
Major Mechanism ◽  
Mtor Kinase ◽  
Pain Transmission ◽  
Pharmacological Target

Chronic pain represents a major public health problem worldwide. Current pharmacological treatments for chronic pain syndromes, including neuropathic pain, are only partially effective, with significant pain relief achieved in 40–60% of patients. Recent studies suggest that the mammalian target of rapamycin (mTOR) kinase and downstream effectors may be implicated in the development of chronic inflammatory, neuropathic, and cancer pain. The expression and activity of mTOR have been detected in peripheral and central regions involved in pain transmission. mTOR immunoreactivity was found in primary sensory axons, in dorsal root ganglia (DRG), and in dorsal horn neurons. This kinase is a master regulator of protein synthesis, and it is critically involved in the regulation of several neuronal functions, including the synaptic plasticity that is a major mechanism leading to the development of chronic pain. Enhanced activation of this pathway is present in different experimental models of chronic pain. Consistently, pharmacological inhibition of the kinase activity turned out to have significant antinociceptive effects in several experimental models of inflammatory and neuropathic pain. We will review the main evidence from animal and human studies supporting the hypothesis that mTOR may be a novel pharmacological target for the management of chronic pain.

scholarly journals Opioid-Induced Glial Activation: Mechanisms of Activation and Implications for Opioid Analgesia, Dependence, and Reward

2007 ◽  
Vol 7 ◽  
pp. 98-111 ◽  
Author(s):  
Mark R. Hutchinson ◽  
Sondra T. Bland ◽  
Kirk W. Johnson ◽  
Kenner C. Rice ◽  
Steven F. Maier ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Experimental Pain ◽  
Glial Activation ◽  
Opioid Analgesia ◽  
Dopamine Level ◽  
Clinical Method ◽  
Pain Models ◽  
Activation Mechanisms ◽  
Agonistic Activity ◽  
Level Of Analysis

This review will introduce the concept of toll-like receptor (TLR)–mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward). Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical (nucleus accumbens microdialysis of morphine-induced elevations in dopamine) level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (˗)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial (analgesia) and unwanted (tolerance, dependence, and reward) actions of opioids, thereby improving the safety and efficacy of their use.

Efficacy of the ketamine metabolite (2R,6R)-hydroxynorketamine in mice models of pain

2019 ◽  
Vol 44 (1) ◽  
pp. 111-117 ◽  
Author(s):  
Jeffrey S Kroin ◽  
Vaskar Das ◽  
Mario Moric ◽  
Asokumar Buvanendran
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Postoperative Pain ◽  
Mechanical Allodynia ◽  
Pain Syndrome ◽  
Saline Control ◽  
Pain Model ◽  
Time Period ◽  
Pain Models ◽  
Neuropathic Pain Model

Background and objectivesKetamine has been shown to reduce chronic pain; however, the adverse events associated with ketamine makes it challenging for use outside of the perioperative setting. The ketamine metabolite (2R,6R)-hydroxynorketamine ((2R,6R)-HNK) has a therapeutic effect in mice models of depression, with minimal side effects. The objective of this study is to determine if (2R,6R)-HNK has efficacy in both acute and chronic mouse pain models.MethodsMice were tested in three pain models: nerve-injury neuropathic pain, tibia fracture complex regional pain syndrome type-1 (CRPS1) pain, and plantar incision postoperative pain. Once mechanical allodynia had developed, systemic (2R,6R)-HNK or ketamine was administered as a bolus injection and compared with saline control in relieving allodynia.ResultsIn all three models, 10 mg/kg ketamine failed to produce sustained analgesia. In the neuropathic pain model, a single intraperitoneal injection of 10 mg/kg (2R,6R)-HNK elevated von Frey thresholds over a time period of 1–24hours compared with saline (F=121.6, p<0.0001), and three daily (2R,6R)-HNK injections elevated von Frey thresholds for 3 days compared with saline (F=33.4, p=0.0002). In the CRPS1 model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 4 days compared with saline (F=116.1, p<0.0001). In the postoperative pain model, three (2R,6R)-HNK injections elevated von Frey thresholds for 3 days and then an additional 5 days compared with saline (F=60.6, p<0.0001).ConclusionsThis study demonstrates that (2R,6R)-HNK is superior to ketamine in reducing mechanical allodynia in acute and chronic pain models and suggests it may be a new non-opioid drug for future therapeutic studies.

scholarly journals Animal Pain Models for Spinal Cord Stimulation

2021 ◽  
Author(s):  
Joseph M. Williams ◽  
Courtney A. Kelley ◽  
Ricardo Vallejo ◽  
David C. Platt ◽  
David L. Cedeño
Keyword(s):  
Spinal Cord ◽  
Chronic Pain ◽  
Neuropathic Pain ◽  
Mechanism Of Action ◽  
Spinal Cord Stimulation ◽  
Spinal Nerve ◽  
Animal Pain ◽  
Injury Model ◽  
Pain Models ◽  
Electrical Neuromodulation

Spinal cord stimulation (SCS) is an electrical neuromodulation technique with proven effectiveness and safety for the treatment of intractable chronic pain in humans. Despite its widespread use, the mechanism of action is not fully understood. Animal models of chronic pain, particularly rodent-based, have been adapted to study the effect of SCS on pain-like behavior, as well as on the electrophysiology and molecular biology of neural tissues. This chapter reviews animal pain models for SCS, emphasizing on findings relevant to advancing our understanding of the mechanism of action of SCS, and highlighting the contribution of the animal model to advance clinical outcomes. The models described include those in which SCS has been coupled to neuropathic pain models in rats and sheep based on peripheral nerve injuries, including the chronic constriction injury (CCI) model and the spared nerve injury model (SNI). Other neuropathic pain models described are the spinal nerve ligation (SNL) for neuropathic pain of segmental origin, as well as the chemotherapy-induced and diabetes-induced peripheral neuropathy models. We also describe the use of SCS with inflammatory pain and ischemic pain models.

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