scholarly journals Zerumbone-Induced Analgesia Modulated via Potassium Channels and Opioid Receptors in Chronic Constriction Injury-Induced Neuropathic Pain

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3880 ◽  
Author(s):  
Banulata Gopalsamy ◽  
Jasmine Siew Min Chia ◽  
Ahmad Akira Omar Farouk ◽  
Mohd Roslan Sulaiman ◽  
Enoch Kumar Perimal
Keyword(s):  
Neuropathic Pain ◽  
Potassium Channels ◽  
Opioid Receptors ◽  
Channel Blocker ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
K Channel ◽  
Mice Model ◽  
Opioid Receptor Antagonists ◽  
Voltage Dependent

Zerumbone, a monocyclic sesquiterpene from the wild ginger plant Zingiber zerumbet (L.) Smith, attenuates allodynia and hyperalgesia. Currently, its mechanisms of action in neuropathic pain conditions remain unclear. This study examines the involvement of potassium channels and opioid receptors in zerumbone-induced analgesia in a chronic constriction injury (CCI) neuropathic pain mice model. Male Institute of Cancer Research (ICR) mice were subjected to CCI and behavioral responses were tested on day 14. Responses toward mechanical allodynia and thermal hyperalgesia were tested with von Frey’s filament and Hargreaves’ tests, respectively. Symptoms of neuropathic pain were significantly alleviated following treatment with zerumbone (10 mg/kg; intraperitoneal, i.p.). However, when the voltage-dependent K+ channel blocker tetraethylammonium (TEA, 4 mg/kg; i.p.), ATP-sensitive K+ channel blocker, glibenclamide (GLIB, 10 mg/kg; i.p.); small-conductance Ca2+-activated K+ channel inhibitor apamin (APA, 0.04 mg/kg; i.p.), or large-conductance Ca2+-activated K+ channel inhibitor charybdotoxin (CHAR, 0.02 mg/kg; i.p.) was administered prior to zerumbone (10 mg/kg; i.p.), the antiallodynic and antihyperalgesic effects of zerumbone were significantly reversed. Additionally, non-specific opioid receptors antagonist, naloxone (NAL, 10 mg/kg; i.p.), selective µ-, δ- and κ-opioid receptor antagonists; β-funaltrexamine (β-FN, 40 mg/kg; i.p.), naltrindole (20 mg/kg; s.c.), nor-binaltorphamine (10 mg/kg; s.c.) respectively attenuated the antiallodynic and antihyperalgesic effects of zerumbone. This outcome clearly demonstrates the participation of potassium channels and opioid receptors in the antineuropathic properties of zerumbone. As various clinically used neuropathic pain drugs also share this similar mechanism, this compound is, therefore, a highly potential substitute to these therapeutic options.

Anti-Neuropathic Pain Activity of Ageratum conyzoides L due to The Essential Oil Components

2020 ◽  
Vol 19 ◽  
Author(s):  
Yedy Purwandi Sukmawan ◽  
Kusnandar Anggadiredja ◽  
I Ketut Adnyana
Keyword(s):  
Neuropathic Pain ◽  
Essential Oil ◽  
Opioid Receptor ◽  
Steam Distillation ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Ageratum Conyzoides ◽  
Safety And Efficacy ◽  
Activity Test ◽  
Oil Components

Background: Neuropathic pain is one of the contributors to the global burdens of illness. At present many patients do not achieve satisfactory pain relief even with synthetic pain-killers. Taking this into consideration, it is necessary to search for natural product-derived alternative treatment with confirmed safety and efficacy. Ageratum conyzoides L is a plant often used as analgesic in Indonesia, however, anti-neuropathic pain activity of this plant is still unknown. Objective: To determine the anti-neuropathic pain activity of the essential oil and non-essential oil component (distillation residue) of A. conyzoides L. Methods: We conducted separation of the essential oil component from other secondary metabolites through steam distillation. Both components were tested for anti-neuropathic pain activity using chronic constriction injury animal models with thermal hyperalgesia and allodynia tests. The animals were divided into 7 test groups namely normal, sham, negative, positive (pregabalin at 0.195 mg/20 g BW of mice), essential oil component (100 mg/kg BW), and non-essential oil component (100 mg/kg BW). Naloxone was tested against the most potent anti-neuropathic pain component (essential oil or nonessential oil) to investigate the involvement of opioid receptor. Results: The GC-MS of the essential oil component indicated the presence of 60 compounds. Meanwhile, non-essential oil components contained alkaloid, flavonoid, polyphenol, quinone, steroid, and triterpenoid. This non-essential oil component contained a total flavonoid equivalent to 248.89 ppm quercetin. The anti-neuropathic pain activity test showed significantly higher activity of the essential oil component compared to the non-essential oil component and negative groups (p<0.05). Furthermore, the essential oil component showed equal activity to pregabalin (p>0.05). However, this activity was abolished by naloxone, indicating the involvement of opioid receptor in the action of the essential oil component. Conclusion: The essential oil component of A. conyzoides L is a potential novel substance for use as anti-neuropathic pain.

scholarly journals Alpha lipoic acid attenuated neuropathic pain induced by chronic constriction Injury of sciatic nerve in rats

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Prasad Neerati ◽  
Harika Prathapagiri
Keyword(s):  
Neuropathic Pain ◽  
Peripheral Neuropathy ◽  
Sciatic Nerve ◽  
Lipoic Acid ◽  
Normal Saline ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Alpha Lipoic Acid ◽  
Chronic Neuropathic Pain ◽  
Neuropathic Pain Syndrome

Abstract Background Chronic neuropathic pain syndrome is associated with impaired quality of life and is poorly manageable. Alpha lipoic acid (ALA) is a powerful antioxidant and showed its effectiveness on diabetic neuropathy and other acute peripheral nerve injuries but it was not evaluated in the chronic neuropathic pain, chronic constriction injury (CCI) in rat model by using duloxetine (DLX) as standard. Methodology The main objective of the study was to expedite ALA effect on chronic peripheral neuropathy induced by CCI of sciatic nerve in rats. In this study, male Wister rats were randomly divided into six groups (n = 8) including, normal saline, sham operated, surgery control, DLX 30mg/kg treated, ALA treated 25mg/kg, and ALA+DLX. The CCI of sciatic nerve was conducted on all animals except normal saline group and studied for 21 days (i.e. 14 days treatment period & 7 days treatment free period) by using different behavioral, biochemical and, histopathology studies. Results ALA showed minor but significant decrease of thermal hyperalgesia, cold allodynia, malondialdehyde (MDA), total protein, lipid peroxidation, and nitric oxide levels and significant increase of motor coordination, glutathione level and decreased axonal degeneration significantly. These effects sustained even during treatment free period. ALA enhanced the effect of DLX when given in combination by showing sustained effect. In conclusion, ALA acted as potent antioxidant may be this activity is responsible for the potent neuroprotective effect. Conclusion Hence, ALA attenuated the nueroinflammation mediated by chronic peripheral neuropathy. Further studies are warranted with ALA to develop as a clinically relevant therapeutic agent for the treatment of neuropathic pain.

scholarly journals Comparative efficacy of pregabalin and baclofen in the rodent chronic constriction injury model of neuropathic pain

2018 ◽  
Vol 8 (1) ◽  
pp. 133
Author(s):  
Saurabh Kohli ◽  
Taruna Sharma ◽  
Juhi Kalra ◽  
Dilip C. Dhasmana
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Mechanical Hyperalgesia ◽  
Comparative Efficacy ◽  
First Line ◽  
Injury Model ◽  
Different Types ◽  
Chronic Constriction Injury Model

Background: Neuropathic pain is associated with prolonged disability and is usually not responsive to conventional analgesics like NSAIDs and opioids. Even the recommended first-line drugs are effective in less than 50% patients. Thus, drugs with different mechanisms of action are needed. Baclofen, a GABA-B agonist has shown benefit in different types of neuropathic pains and is compared against pregabalin.Methods: The sciatic nerve was ligated in 2 groups of 6 rats each as per the chronic constriction injury model of neuropathic pain on day 0. After 14 days the effect of single doses of pregabalin (30mg/kg) and baclofen (5mg/kg) intraperitoneally were assessed over a 2 hours period. Thermal and mechanical hyperalgesia were assessed as measures of neuropathic pain by the hotplate and pin-prick method respectively.Results: Significant thermal and mechanical hyperalgesia was produced 14 days after sciatic nerve ligation in both the groups (p <0.05). Both pregabalin (p <0.001) and baclofen (p <0.01) were effective in decreasing thermal hyperalgesia throughout the two hours study period, but pregabalin was more effective as compared to baclofen (p <0.05) at 30, 60 and 120minutes. Both the drugs produced a significant decrease in mechanical hyperalgesia (p <0.01) throughout the study period. Again, pregabalin was the more effective drug (p <0.05) at all time points.Conclusions: Significant thermal and mechanical hyperalgesia was seen 14 days after sciatic nerve ligation. Both pregabalin and baclofen were effective in reversing the hyperalgesia, but pregabalin was the more effective of the two drugs at all time points.

Differential distribution of potassium channels in acutely demyelinated, primary-auditory neurons in vitro

1996 ◽  
Vol 76 (1) ◽  
pp. 438-447 ◽  
Author(s):  
R. L. Davis
Keyword(s):  
Potassium Channels ◽  
Potassium Channel ◽  
Myelin Sheath ◽  
Lucifer Yellow ◽  
The Other ◽  
K Channel ◽  
Channel Activity ◽  
Auditory Neurons ◽  
Axonal Membrane ◽  
Voltage Dependent

1. Single-channel recordings of potassium channel activity were made from two populations of primary-auditory neurons maintained in tissue culture. The saccular nerve, which is the auditory component of the eighth cranial nerve in goldfish, was separated into two branches according to its peripheral innervation pattern. Neurons which innervated the rostral saccular macula corresponded to a class of cells that showed spike frequency adaptation; whereas, neurons which innervated the caudal macula were consistent with another type of cell that demonstrated bursting spontaneous firing patterns in vivo. Both somatic and internodal axonal membranes from each of these neuronal classes were studied after acute removal of the myelin sheath by microdissection. 2. Dye injections were used to discriminate neuronal from myelin membrane. After successful removal of the myelin, patch electrodes containing Lucifer yellow were used to fill a neuron and reveal its morphology within the myelin sheath. Patches on myelin led to filling of Schwann cells that surrounded the neuron. 3. Four kinds of potassium channels were observed and characterized according to unitary conductance, inactivation, and sensitivity to internal calcium. Three voltage-dependent K+ channel types were found on the somatic and axonal membrane of the two neuronal populations. Two channel types showed voltage-dependent inactivation and had average conductances of 32 and 19 pS, each with distinctive subconductance states. The third type of channel activity had an estimated conductance of 12 pS and was noninactivating. 4. The fourth type of channel was the Ca2(+)-activated K+ channel (k(Ca)), which was classified by the dependence of its activity on the calcium concentration at its cytoplasmic surface. Unlike the other three potassium channel types, this kind of channel was found exclusively on neurons that innervated the caudal sensory epithelium. As with the other kinds of potassium channels, it was found on both somatic and axonal internodal membranes.

NO causes perinatal pulmonary vasodilation through K+-channel activation and intracellular Ca2+release

1999 ◽  
Vol 276 (6) ◽  
pp. L925-L932 ◽  
Author(s):  
Connie B. Saqueton ◽  
Robert B. Miller ◽  
Valerie A. Porter ◽  
Carlos E. Milla ◽  
David N. Cornfield
Keyword(s):  
Channel Blocker ◽  
Control Period ◽  
Left Pulmonary Artery ◽  
Competitive Inhibitor ◽  
Late Gestation ◽  
K Channel ◽  
Channel Activation ◽  
Pulmonary Vasodilation ◽  
Voltage Dependent ◽  
Intracellular Ca

Evidence suggests that nitric oxide (NO) causes perinatal pulmonary vasodilation through K+-channel activation. We hypothesized that this effect worked through cGMP-dependent kinase-mediated activation of Ca2+-activated K+ channel that requires release of intracellular Ca2+ from a ryanodine-sensitive store. We studied the effects of 1) K+-channel blockade with tetraethylammonium, 4-aminopyridine, a voltage-dependent K+-channel blocker, or glibenclamide, an ATP-sensitive K+-channel blocker; 2) cyclic nucleotide-sensitive kinase blockade with either KT-5823, a guanylate-sensitive kinase blocker, or H-89, an adenylate-sensitive kinase blocker; and 3) blockade of intracellular Ca2+ release with ryanodine on NO-induced pulmonary vasodilation in acutely prepared late-gestation fetal lambs. N-nitro-l-arginine, a competitive inhibitor of endothelium-derived NO synthase, was infused into the left pulmonary artery, and tracheotomy was placed. The animals were ventilated with 100% oxygen for 20 min, followed by ventilation with 100% oxygen and inhaled NO at 20 parts/million (ppm) for 20 min. This represents the control period. In separate protocols, the animals received an intrapulmonary infusion of the different blockers and were ventilated as above. Tetraethylammonium ( n = 6 animals) and KT-5823 ( n = 4 animals) attenuated the response, whereas ryanodine ( n = 5 animals) blocked NO-induced perinatal pulmonary vasodilation. 4-Aminopyridine ( n = 5 animals), glibenclamide ( n = 5 animals), and H-89 ( n = 4 animals) did not affect NO-induced pulmonary vasodilation. We conclude that NO causes perinatal pulmonary vasodilation through cGMP-dependent kinase-mediated activation of Ca2+-activated K+ channels and release of Ca2+ from ryanodine-sensitive stores.

scholarly journals Endothelium-Independent Vasodilatory Effects of Isodillapiolglycol Isolated from Ostericum citriodorum

Molecules ◽  
2020 ◽  
Vol 25 (4) ◽  
pp. 885 ◽  
Author(s):  
Tengshuo Luo ◽  
Zewei Chen ◽  
Fengyun Wang ◽  
Shanshan Yin ◽  
Pan Liu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Channel Blocker ◽  
Ethyl Acetate Extract ◽  
K Channel ◽  
Krebs Solution ◽  
Native Range ◽  
Sprague Dawley ◽  
Independent Manner ◽  
High K ◽  
Voltage Dependent

Ostericum citriodorum is a plant with a native range in China used in herbal medicine for treating angina pectoris. In this study, we investigated the vasodilatory effects of isodillapiolglycol (IDG), which is one of the main ingredients isolated from O. citriodorum ethyl acetate extract, in Sprague–Dawley rat aortic rings, and measured intracellular Ca2+ ([Ca2+]in) using a molecular fluo-3/AM probe. The results show that IDG dose-dependently relaxed endothelium-intact or -denuded aortic rings pre-contracted with noradrenaline (NE) or potassium chloride (KCl), and inhibited CaCl2-induced contraction in high K+ depolarized aortic rings. Tetraethyl ammonium chloride (a Ca2+-activated K+ channel blocker) or verapamil (an L-type Ca2+ channel blocker) significantly reduced the relaxation of IDG in aortic rings pre-contracted with NE. In vascular smooth muscle cells, IDG inhibited the increase in [Ca2+]in stimulated by KCl in Krebs solution; likewise, IDG also attenuated the increase in [Ca2+]in induced by NE or subsequent supplementation of CaCl2. These findings demonstrate that IDG relaxes aortic rings in an endothelium-independent manner by reducing [Ca2+]in, likely through inhibition of the receptor-gated Ca2+ channel and the voltage-dependent Ca2+ channel, and through opening of the Ca2+-activated K+ channel.

scholarly journals Evaluation of the GABAA Receptor Expression and the Effects of Muscimol on the Activity of Wide Dynamic Range Neurons Following Chronic Constriction Injury of the Sciatic Nerve in Rats

2021 ◽  
Author(s):  
Mehdi Sadeghi ◽  
◽  
Homa Manaheji ◽  
Jalal Zaringhalam ◽  
Abbas Haghparast ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Gabaa Receptor ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Dynamic Range ◽  
Thermal Hyperalgesia ◽  
Receptor Expression ◽  
Wide Dynamic Range ◽  
Wdr Neurons ◽  
Α1 Subunit

Introduction: The modality of γ-aminobutyric acid receptors (GABAA) in control of dorsal horn neuronal excitability and inhibition of sensory information is ambiguous. The aim of the present study was to investigate the expression of GABAA receptor and the effects of its agonist muscimol on wide dynamic range (WDR) neuronal activity in the chronic constriction injury (CCI) model of neuropathic pain. Methods: Adult male Wistar rats weighing 200 to 250 g were used for the induction of CCI neuropathy. 14 days after surgery, muscimol (0.5, 1, and 2 mg/kg i.p.) was injected. Then, the behavioral tests were performed. Thereafter, the animals were sacrificed, and the lumbar segments of the spinal cords were collected for Western blot analysis of the GABAA receptor α1 subunit expression. The electrophysiological properties of WDR neurons were studied by single unit recordings in separate groups on the 14th day after CCI. Results: The outcomes indicated the development of thermal hyperalgesia and mechanical allodynia after neuropathy; nonetheless, the expression of GABAA receptor α1 subunit did not change significantly. Moreover, the evoked responses of the WDR neurons to electrical, mechanical, and thermal stimuli were significantly increased. 14 days after CCI, muscimol administration decreased thermal hyperalgesia, mechanical allodynia, and hyper-responsiveness of the WDR neurons in CCI rats. Conclusion: It confirms that the modulation of the spinal GABAA receptors after nerve injury can offer further insights to design new therapeutic agents in order to reduce the neuropathic pain symptoms.

scholarly journals The Involvement of l-Arginine-Nitric Oxide-cGMP-ATP-Sensitive K+ Channel Pathway in Antinociception of BBHC, a Novel Diarylpentanoid Analogue, in Mice Model

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7431
Author(s):  
Hui Ming Ong ◽  
Ahmad Farhan Ahmad Azmi ◽  
Sze Wei Leong ◽  
Faridah Abas ◽  
Enoch Kumar Perimal ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Channel Blocker ◽  
Antinociceptive Effect ◽  
Soluble Guanylyl Cyclase ◽  
K Channel ◽  
Mice Model ◽  
Chemically Induced ◽  
Pre Treatment ◽  
Oxide Synthase ◽  
Abdominal Constriction

The present study focuses on the possible involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was attenuated by the intraperitoneal pre-treatment of l-arginine (a nitric oxide synthase precursor) and glibenclamide (an ATP-sensitive K+ channel blocker) in acetic acid-induced abdominal constriction tests. Interestingly, BBHC’s antinociception was significantly enhanced by the i.p. pre-treatment of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase (p < 0.05). Altogether, these findings suggest that the systemic administration of BBHC is able to establish a significant antinociceptive effect in a mice model of chemically induced pain. BBHC’s antinociception is shown to be mediated by the involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K+ channel pathway, without any potential sedative or muscle relaxant concerns.

scholarly journals Nrf2 Activation Attenuates Chronic Constriction Injury-induced Neuropathic Pain via Induction of PGC-1α-mediated Mitochondrial Biogenesis in the Spinal Cord

2021 ◽  
Author(s):  
Jia Sun ◽  
Jia-Yan Li ◽  
Long-Qing Zhang ◽  
Dan-Yang Li ◽  
Jia-Yi Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Biogenesis ◽  
Chronic Constriction Injury ◽  
Clinical Investigation ◽  
Thermal Hyperalgesia ◽  
Related Factor ◽  
Dependent Manner

Abstract BackgroundNeuropathic pain is a debilitating disease with few effective treatments. Emerging evidence indicates the involvement of mitochondrial dysfunction and oxidative stress in neuropathic pain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a potent regulator of antioxidant response system. In this study, we investigated whether RTA-408 (a novel synthetic triterpenoid under clinical investigation) could activate Nrf2 and promote mitochondrial biogenesis (MB) to reverse neuropathic pain and the underlying mechanisms.MethodsNeuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Pain behaviors were measured via the von-Frey test and Hargreaves plantar test. The L4-6 spinal cord was collected to examine the activation of Nrf2 and MB.ResultsRTA-408 treatment significantly reversed mechanical allodynia and thermal hyperalgesia in CCI mice in a dose-dependent manner. Furthermore, RTA-408 increased the activity of Nrf2 and significantly restored MB that was impaired in CCI mice in an Nrf2 dependent manner. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) is the key regulator of MB. We found that PGC-1α activator also exhibited a potent analgesic effect in CCI mice. Moreover, the antinociceptive effect of RTA-408 was reversed by the pre-injection of PGC-1α inhibitor.ConclusionsNrf2 activation attenuates chronic constriction injury-induced neuropathic pain via induction of PGC-1α-mediated mitochondrial biogenesis in the spinal cord. Our results indicate that Nrf2 may be a potential therapeutic strategy to ameliorate neuropathic pain and many other disorders with oxidative stress and mitochondrial dysfunction.

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