scholarly journals Dysfunction of Glutamate Delta-1 Receptor-Cerebellin 1 Trans-Synaptic Signaling in the Central Amygdala in Chronic Pain

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2644
Author(s):  
Pauravi J. Gandhi ◽  
Dinesh Y. Gawande ◽  
Gajanan P. Shelkar ◽  
Sukanya G. Gakare ◽  
Takaki Kiritoshi ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Behavioral Effect ◽  
Fear Learning ◽  
Central Amygdala ◽  
Selective Ablation ◽  
Pain Models ◽  
Underlying Mechanisms ◽  
Aversive Behavior ◽  
The Right

Chronic pain is a debilitating condition involving neuronal dysfunction, but the synaptic mechanisms underlying the persistence of pain are still poorly understood. We found that the synaptic organizer glutamate delta 1 receptor (GluD1) is expressed postsynaptically at parabrachio-central laterocapsular amygdala (PB-CeLC) glutamatergic synapses at axo-somatic and punctate locations on protein kinase C δ -positive (PKCδ+) neurons. Deletion of GluD1 impairs excitatory neurotransmission at the PB-CeLC synapses. In inflammatory and neuropathic pain models, GluD1 and its partner cerebellin 1 (Cbln1) are downregulated while AMPA receptor is upregulated. A single infusion of recombinant Cbln1 into the central amygdala led to sustained mitigation of behavioral pain parameters and normalized hyperexcitability of central amygdala neurons. Cbln2 was ineffective under these conditions and the effect of Cbln1 was antagonized by GluD1 ligand D-serine. The behavioral effect of Cbln1 was GluD1-dependent and showed lateralization to the right central amygdala. Selective ablation of GluD1 from the central amygdala or injection of Cbln1 into the central amygdala in normal animals led to changes in averse and fear-learning behaviors. Thus, GluD1-Cbln1 signaling in the central amygdala is a teaching signal for aversive behavior but its sustained dysregulation underlies persistence of pain. Significance statement: Chronic pain is a debilitating condition which involves synaptic dysfunction, but the underlying mechanisms are not fully understood. Our studies identify a novel mechanism involving structural synaptic changes in the amygdala caused by impaired GluD1-Cbln1 signaling in inflammatory and neuropathic pain behaviors. We also identify a novel means to mitigate pain in these conditions using protein therapeutics.

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

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.

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.

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.]

scholarly journals Kappa opioid signaling in the right central amygdala causes hind paw specific loss of diffuse noxious inhibitory controls in experimental neuropathic pain

Pain ◽  
2019 ◽  
Vol 160 (7) ◽  
pp. 1614-1621 ◽  
Author(s):  
Caroline E. Phelps ◽  
Edita Navratilova ◽  
Anthony H. Dickenson ◽  
Frank Porreca ◽  
Kirsty Bannister
Keyword(s):  
Neuropathic Pain ◽  
Central Amygdala ◽  
Diffuse Noxious Inhibitory Controls ◽  
Kappa Opioid ◽  
Specific Loss ◽  
Opioid Signaling ◽  
The Right

Inhibition of Spinal Microglia and Astrocytes Contributes to the Anti-Allodynic Effect of Electroacupuncture in Neuropathic Pain Induced by Spinal Nerve Ligation

2016 ◽  
Vol 34 (1) ◽  
pp. 40-47 ◽  
Author(s):  
Yi Liang ◽  
Yujie Qiu ◽  
Junying Du ◽  
Jin Liu ◽  
Junfan Fang ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Spinal Cord Dorsal Horn ◽  
Control Group ◽  
Sprague Dawley ◽  
Astrocyte Activation ◽  
Gfap Immunoreactivity ◽  
Underlying Mechanisms

Objective Besides neurons, activated microglia and astrocytes in the spinal cord dorsal horn (SCDH) contribute to the pathogenesis of chronic pain. Electroacupuncture (EA) has been used widely to treat various chronic pain diseases, however, the underlying mechanisms of EA are still not fully understood. Methods Male Sprague-Dawley rats were randomly divided into four groups, including an untreated healthy Control group (n=14), a True-spinal nerve ligation (SNL) group that underwent SNL and remained untreated (n=25), a True-SNL+EA group that underwent SNL followed by EA treatment (n=25), and a Sham-SNL group that underwent sham surgery and remained untreated (n=15). SNL was performed unilaterally at L5 and EA was applied to ST36 and BL60 bilaterally once per day. Paw withdrawal thresholds (PWTs) were measured ipsilaterally at baseline and 1, 3, 7, and 14 days after ligation. Activation of microglia and astrocytes in the SCDH were examined bilaterally by immunofluorescence staining, and concentrations of interleukin-1β (IL-1β) and interleukin (IL-6) were measured in the ipsilateral SCDH by ELISA. Results SNL significantly decreased PWTs and activated glial cells in the superficial laminae of the ipsilateral SCDH. In rats with SNL, glial fibrillary acidic protein (GFAP) immunoreactivity peaked at 7 days and was maintained until 14 days post-ligation, while anti-integrin alphaM (OX-42) immunoreactivity peaked at 3 days and declined gradually. EA significantly alleviated SNL-induced mechanical allodynia. Furthermore, EA reduced microglial activation (OX-42 positive ratios) in the lumbar SCDH at 3 days post-ligation and suppressed astrocyte activation (GFAP positive ratios) at all time points observed. Conclusions EA stimulation alleviates SNL-induced neuropathic pain, at least in part through inhibition of spinal glial activation. Moreover, inhibition of spinal microglia and astrocyte activation may contribute to the immediate effects and maintenance of EA analgesia, respectively.

scholarly journals Asprosin, a Novel Therapeutic Candidate for Painful Neuropathy: An Experimental Study in Mice

2021 ◽  
Author(s):  
Sibel Ozcan ◽  
Muhammed Mirac Kelestemur ◽  
Munevver Gizem Hekim ◽  
Ozgur Bulmus ◽  
Ferah Bulut ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Clinical Utility ◽  
Painful Neuropathy ◽  
Hot Plate ◽  
Clear Cut ◽  
Pain Models ◽  
Chronic Pain Conditions ◽  
Thermal Hypersensitivity ◽  
Novel Therapeutic

Abstract Neuropathic pain is primarily caused by nervous system lesions or dysfunction. Evidence strongly suggests that obesity, diabetes and cancer are common in chronic pain conditions, and pain complaints are common in these individuals. Recent studies indicate presence of a strong link between adipokines and neuropathic pain. However, the effects of asprosin, a novel adipokine, on neuropathic pain have not been studied in animal modelsMouse models were employed to investigate the antinociceptive effectiveness of asprosin in the treatment of three types of neuropathic pain, with metabolic (streptozocin/STZ), toxic (oxaliplatin/OXA), and traumatic (sciatic nerve ligation/CCI [chronic constriction nerve injury]) etiologies, respectively. Changes in nociceptive behaviors were assessed relative to controls using thermal (the hot plate and cold plate tests, at 50 °C and 4 °C respectively) and mechanical pain (Von Frey test) tests at baseline and 30, 60, 120 and 180 minutes after asprosin administration. Serum level of asprosin was quantified by ELISA. In all three neuropathic pain models (STZ, OXA and CCI), asprosin administration significantly reduced both mechanical and thermal hypersensitivity, indicating that it exhibits a clear-cut antihypersensitivity effect in the analyzed neuropathic pain models. Asprosin levels were significantly lower in three types of neuropathic pain compare to controls (p < 0.05). The results yielded by the present study suggest that asprosin exhibits an analgesic effect in the neuropathic pain models and may have clinical utility in alleviating chronic pain associated with disease and injury originating from peripheral structures.

scholarly journals Building and Testing PPARγ Therapeutic ELB00824 with an Improved Therapeutic Window for Neuropathic Pain

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1120
Author(s):  
Karin N. Westlund ◽  
Morgan Zhang
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Brain Regions ◽  
Therapeutic Window ◽  
Peroxisome Proliferator ◽  
Preclinical Studies ◽  
Pain Syndromes ◽  
Pparγ Agonist ◽  
Pain Models ◽  
Anti Inflammatory

Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood–brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.

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