Microglial Inhibition Influences XCL1/XCR1 Expression and Causes Analgesic Effects in a Mouse Model of Diabetic Neuropathy

2016 ◽  
Vol 125 (3) ◽  
pp. 573-589 ◽  
Author(s):  
Magdalena Zychowska ◽  
Ewelina Rojewska ◽  
Anna Piotrowska ◽  
Grzegorz Kreiner ◽  
Joanna Mika
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Cell Cultures ◽  
Neutralizing Antibody ◽  
Diabetic Neuropathic Pain ◽  
Nociceptive Transmission ◽  
Analgesic Effects ◽  
Primary Microglial Cell ◽  
Neuropathic Pain Model ◽  
Streptozotocin Induced Diabetes

Abstract Background Recent studies indicated the involvement of some chemokines in the development of diabetic neuropathy; however, participation of the chemokine-C-motif ligand (XCL) subfamily remains unknown. The goal of this study was to examine how microglial inhibition by minocycline hydrochloride (MC) influences chemokine-C-motif ligand 1 (XCL1)–chemokine-C-motif receptor 1 (XCR1)/G protein–coupled receptor 5 expression and the development of allodynia/hyperalgesia in streptozotocin-induced diabetic neuropathy. Methods The studies were performed on streptozotocin (200 mg/kg, intraperitoneally)-induced mouse diabetic neuropathic pain model and primary glial cell cultures. The MC (30 mg/kg, intraperitoneally) was injected two times daily until day 21. XCL1 and its neutralizing antibody were injected intrathecally, and behavior was evaluated with von Frey and cold plate tests. Quantitative analysis of protein expression of glial markers, XCL1, and/or XCR1 was performed by Western blot and visualized by immunofluorescence. Results MC treatment diminished allodynia (0.9 ± 0.1 g; n = 7 vs. 3.8 ± 0.7 g; n = 7) and hyperalgesia (6.5 ± 0.6 s; n = 7 vs. 16.5 ± 1 s; n = 7) in the streptozotocin-induced diabetes. Repeated MC administration prevented microglial activation and inhibited the up-regulation of the XCL1/XCR1 levels. XCL1 administration (10 to 500 ng/5 μl; n = 9) in naive mice enhanced nociceptive transmission, and injections of neutralizing XCL1 (4 to 8 μg/5 μl; n = 10) antibody into the mice with diabetic neuropathic pain diminished allodynia/hyperalgesia. Microglia activation evoked in primary microglial cell cultures resulted in enhanced XCL1 release and XCR1 expression. Additionally, double immunofluorescence indicated the widespread coexpression of XCR1-expressing cells with spinal neurons. Conclusions In diabetic neuropathy, declining levels of XCL1 evoked by microglia inhibition result in the cause of analgesia. The putative mechanism corroborating this finding can be related to lower spinal expression of XCR1 together with the lack of stimulation of these XCR1 receptors, which are localized on neurons.

scholarly journals Neuromidin Attenuates Neuropathic Pain in the Streptozocin-Induced Diabetes Model in Rats

2008 ◽  
Vol 62 (3) ◽  
pp. 85-90
Author(s):  
Vija Kluša ◽  
Juris Rumaks ◽  
Ñina Karajeva
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Diabetic Neuropathic Pain ◽  
Cholinergic Mechanism ◽  
Peripheral Neuropathic Pain ◽  
Pain Model ◽  
Diabetes Model ◽  
Neuropathic Pain Model ◽  
New Type ◽  
Anticholinesterase Drug

Neuromidin Attenuates Neuropathic Pain in the Streptozocin-Induced Diabetes Model in Rats Diabetic neuropathy, which affects all peripheral nerves and may cause dramatic pain, is one of the most severe pathologies associated with hyperglycaemia, damage in the blood vessels, and inflammation in nerves. Anticonvulsants and antidepressants are still the most commonly used options to manage diabetic neuropathy. However, to improve clinical benefit in the treatment of diabetic neuropathies, as well as to minimize side effects, search for a new type of drugs to protect/treat neuropathic pain is still important. The aim of this study was to investigate neuromidin (ipidacrine, amiridin, NIK-247), an anticholinesterase drug of tetrahydroaminoacridine series, in the streptozocin (STZ)-induced diabetic neuropathic pain model in rats. Neuromidin was administered per os at daily doses 0.3, 1.0 and 3.0 mg/kg for ten days. The dynamics in the development of hyperalgesia (pain threshold) was measured by algesimeter for five weeks. The data obtained show that neuromidin considerably protects the development of peripheral neuropathic pain caused by STZ. The most active dose was the lowest—0.3 mg/kg. Neuromidin did not affect STZ-hyperglycemia, nor the weight gain in animal groups. Neuromidin per se at the doses 0.3 and 1.0 mg/kg showed a short-term analgesic activity. The cholinergic mechanism of neuromidin may be considered as essential in attenuating of diabetic neuropathic pain; other mechanisms remain to be elucidated.

scholarly journals Biphalin, a Dimeric Enkephalin, Alleviates LPS-Induced Activation in Rat Primary Microglial Cultures in Opioid Receptor-Dependent and Receptor-Independent Manners

2017 ◽  
Vol 2017 ◽  
pp. 1-19 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Anna Piotrowska ◽  
Wioletta Makuch ◽  
Joanna Mika
Keyword(s):  
Neuropathic Pain ◽  
Opioid Receptor ◽  
Pain Therapy ◽  
Cell Activation ◽  
Microglial Cell ◽  
Preclinical Model ◽  
No Production ◽  
Dependent Manner ◽  
Analgesic Effects ◽  
Primary Microglial Cell

Neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by the profound microglial cell activation that underlines neuroinflammation. We demonstrated that intrathecally injected biphalin, a dimeric enkephalin analog, diminished symptoms of neuropathy in a preclinical model of neuropathic pain in rats (CCI, chronic constriction injury of the sciatic nerve) at day 12 postinjury. Using primary microglial cell cultures, we revealed that biphalin did not influence cell viability but diminished NO production and expression of Iba1 in LPS-stimulated cells. Biphalin also diminished MOP receptor level, as well as pronociceptive mediators (iNOS, IL-1β, and IL-18) in an opioid receptor-dependent manner, and it was correlated with diminished p-NF-κB, p-IκB, p-p38MAPK, and TRIF levels. Biphalin reduced IL-6, IL-10, TNFα, p-STAT3, and p-ERK1/2 and upregulated SOCS3, TLR4, and MyD88; however, this effect was not reversed by naloxone pretreatment. Our study provides evidence that biphalin diminishes neuropathy symptoms, which might be partially related to reduced pronociceptive mediators released by activated microglia. Biphalin may be a putative drug for future pain therapy, especially for the treatment of neuropathic pain, when the lower analgesic effects of morphine are correlated with profound microglial cell activation.

Mechanisms of morphine-venlafaxine interaction in diabetic neuropathic pain model

2013 ◽  
Vol 65 ◽  
pp. 35
Author(s):  
Krystyna Cegielska-Perun ◽  
Agata Siwek ◽  
Małgorzata Dybała ◽  
Magdalena Bujalska-Zadrożny ◽  
Helena Makulska-Nowak
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathic Pain ◽  
Pain Model ◽  
Neuropathic Pain Model

scholarly journals Modification of morphine analgesia by venlafaxine in diabetic neuropathic pain model

2012 ◽  
Vol 64 (5) ◽  
pp. 1267-1275 ◽  
Author(s):  
Krystyna Cegielska-Perun ◽  
Magdalena Bujalska-Zadrożny ◽  
Helena E. Makulska-Nowak
Keyword(s):  
Neuropathic Pain ◽  
Morphine Analgesia ◽  
Diabetic Neuropathic Pain ◽  
Pain Model ◽  
Neuropathic Pain Model

scholarly journals Minocycline Enhances the Effectiveness of Nociceptin/Orphanin FQ during Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Katarzyna Popiolek-Barczyk ◽  
Ewelina Rojewska ◽  
Agnieszka M. Jurga ◽  
Wioletta Makuch ◽  
Ferenz Zador ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Cell Activation ◽  
Microglial Cell ◽  
Lumbar Spinal Cord ◽  
Orphanin Fq ◽  
Binding Assays ◽  
Analgesic Effects ◽  
Primary Microglial Cell ◽  
Lumbar Spinal

Nociceptin/orphanin FQ (N/OFQ) antinociception, which is mediated selectively by the N/OFQ peptide receptor (NOP), was demonstrated in pain models. In this study, we determine the role of activated microglia on the analgesic effects of N/OFQ in a rat model of neuropathic pain induced by chronic constriction injury (CCI) to the sciatic nerve. Repeated 7-day administration of minocycline (30 mg/kg i.p.), a drug that affects microglial activation, significantly reduced pain in CCI-exposed rats and it potentiates the analgesic effects of administered N/OFQ (2.5–5 μg i.t.). Minocycline also downregulates the nerve injury-induced upregulation of NOP protein in the dorsal lumbar spinal cord. Ourin vitrostudy showed that minocycline reducedNOPmRNA, but not protein, level in rat primary microglial cell cultures. In [35S]GTPγS binding assays we have shown that minocycline increases the spinal N/OFQ-stimulated NOP signaling. We suggest that the modulation of the N/OFQ system by minocycline is due to the potentiation of its neuronal antinociceptive activity and weakening of the microglial cell activation. This effect is beneficial for pain relief, and these results suggest new targets for the development of drugs that are effective against neuropathic pain.

scholarly journals Psychiatric Underpinnings of Chronic Diabetic Neuropathic Pain

2016 ◽  
Vol 30 (1&2) ◽  
pp. 37
Author(s):  
Syed H. Shabbir
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Psychiatric Illness ◽  
Treatment Options ◽  
Diabetic Polyneuropathy ◽  
Therapeutic Approaches ◽  
Diabetic Neuropathic Pain ◽  
Psychiatric Illnesses ◽  
Axis I

There is increasing evidence that psychosocial factors may be involved in the pathophysiology of chronic diabetic neuropathic pain. Individuals with diabetic polyneuropathy exhibit significantly higher rates of axis I psychiatric disorders, and worsening neuropathic symptoms correlate with worsened psychiatric illness. This association exists even when social-support and quality-of-life measures are controlled. Aberrant supraspinal structures and neuronal networks in diabetic neuropathy mimic those found in other psychiatric illnesses. Response to standard medications and therapeutic approaches remains unsatisfactory, and antidepressants continue to serve as first-line treatment for diabetic neuropathy. The exact interplay between neuropathic pain and psychiatric illness remains unclear and may have a common pathophysiological focus. This area of study needs to be revisited and psychological interventions must be explored as possible treatment options for diabetic neuropathy. 

A Review on Different Analytical Techniques for Determination of DNP Drugs and Their Metabolites in Pharmaceutical Formulations

2020 ◽  
Vol 16 ◽  
Author(s):  
Puja Bag ◽  
Bhupinder Kumar
Keyword(s):  
Mass Spectrometry ◽  
Neuropathic Pain ◽  
Liquid Chromatography ◽  
Diabetic Neuropathy ◽  
Analytical Methods ◽  
Pharmaceutical Formulations ◽  
Diabetic Patients ◽  
Liquid Chromatography Mass Spectrometry ◽  
Diabetic Neuropathic Pain ◽  
Drug Content

Background: Neuropathy is the most common perplexity of diabetes 1 and 2. About 50% diabetic patients develop Diabetic neuropathic pain (DNP). At the beginning of diabetic neuropathy; results loss of sense especially in the lower limb, pain, and difficulty in movement. Glucose regulation effectively prevents the development of diabetic neuropathy in type 1 diabetic patients but the consequences in type 2 diabetic patients are more drastic. Introduction: No single treatment exists to prevent or renovate the pain caused by diabetic neuropathy. The drugs used for the treatment of DNP come in various formulations and with different storage conditions. Till date, the number of analytical methodologies has been reported for analysis of DNP drugs. Few reports are published describing analytical methods of single DNP drugs. Method: The main objective of this review is to compile the different analytical methods developed at UV-Vis (Ultraviolet-visible) spectrophotometer, HPLC (High Performance Liquid Chromatography) and LC-MS (Liquid Chromatography-Mass spectrometry) to identify and quantify the drug content in various formulations which are used to treat or prevent the Diabetic neuropathic pain mainly focusing on γ-aminobutyric acid analogues, anti-depressants, serotonin noradrenaline reuptake inhibitors (SNRIs), aldose reductase inhibitors, opioids, and dietary supplements. Results and Discussion: We have compiled UV-Vis, HPLC and Liquid Chromatography-Mass spectrometry analytical methods developed to study the pharmacokinetic profile, quantify drug content and their metabolites in plasma as well as pharmaceutical formulations. The authors believe that the mentioned studies in the report will help audible readers to select a suitable method for analysis of these drugs and also help researchers to develop a more convenient, fast and sensitive method for these.

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