scholarly journals Effect of xylopic acid on alloxan-induced diabetic neuropathy in rats

2021 ◽  
Vol 10 (4) ◽  
pp. 333
Author(s):  
Elvis Ofori Ameyaw ◽  
Ernest Obese ◽  
Du-Bois Asante ◽  
Robert P. Biney ◽  
Akua A. Karikari ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Cold Water ◽  
Thermal Hyperalgesia ◽  
Hot Water ◽  
Male Rats ◽  
Major Constituent ◽  
Diabetic Patients ◽  
Cold Allodynia ◽  
Liver And Kidney

Background: Neuropathic pain is a very disturbing condition commonly found in diabetic patients. This study investigated xylopic acid (XA), the major constituent of Xylopia aethiopica in diabetic neuropathy as well as established possible toxicity of the compound on some selected tissues.Methods: Diabetes was induced in six groups of male rats with 120 mg/kg alloxan monohydrate. Diabetes was confirmed as a blood glucose level >15 mmol/dl. Neuropathic pain was confirmed on day three post-diabetes induction and treatment with 10 mg/kg, 30 mg/kg or 100 mg/kg xylopic acid, 10 mg/kg glibenclamide, 10 mg/kg morphine, and 10 ml/kg normal saline were initiated and continued for the next 15 days. The effects of the treatments on cold allodynia (cold water at 4°C) and thermal hyperalgesia (hot water at 55 ± 1°C) were evaluated within the duration of treatments. Histology of the liver and kidney, as well as haematological, serum biochemical, and semen analyses, were done after the fifteenth day of the experiment.Results: Xylopic acid produced significant anti-hyperglycaemic and analgesic effects in the cold allodynia and thermal hyperalgesia tests. Sperm motility, viability and count were significantly restored at 10 mg/kg XA as compared higher doses and negative control. The outcome of haematological analysis revealed a protective effect of XA although histological damage liver and kidney due to alloxan treatment was observable.Conclusions: Xylopic acid ameliorates diabetic neuropathy in rats and does not exert detrimental effects at low doses.

A hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn ameliorates hyperalgesia and allodynia in vincristine-induced neuropathic pain in rats

2015 ◽  
Vol 26 (4) ◽  
Author(s):  
Patrick Amoateng ◽  
Samuel Adjei ◽  
Dorcas Osei-Safo ◽  
Elvis Ofori Ameyaw ◽  
Believe Ahedor ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Cold Water ◽  
Thermal Hyperalgesia ◽  
Ethanolic Extract ◽  
Mechanical Hyperalgesia ◽  
Sprague Dawley ◽  
Cold Allodynia ◽  
Sprague Dawley Rats ◽  
Vincristine Sulphate ◽  
Synedrella Nodiflora

Abstract: The hydro-ethanolic extract of: Neuropathic pain was induced in Sprague-Dawley rats by injecting 100 μg/kg of vincristine sulphate on alternative days for 6 days (days 0, 2, 4, 8, 10 and 12). Vincristine-induced cold allodynia, mechanical hyperalgesia and thermal hyperalgesia were measured pre-vincristine administration and on days 15, 17 and 19 post-vincristine administration. The rats were then treated withSNE and pregabalin produced analgesic properties observed as increased paw withdrawal latencies to mechanical, tactile, cold water stimuli and thermal hyperalgesic tests during the 5 days of treatment.: The findings suggest that hydro-ethanolic extract of

scholarly journals Evaluation of Neuroprotective Effect of Ficus benghalensis against Alloxan Induced Diabetic Neuropathy in Rats

2016 ◽  
Vol 4 ◽  
pp. 52-60
Author(s):  
Chandrasekeran Stalin ◽  
V. Gunasekaran ◽  
G. Jayabalan
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Cold Water ◽  
Methanolic Extract ◽  
Neuroprotective Effect ◽  
Thermal Hyperalgesia ◽  
Control Group ◽  
Albino Rats ◽  
Hot Plate Test ◽  
Ficus Benghalensis

Neuropathic pain in diabetics is characterized by both hyperalgesia and allodynia. This is attributed to both uncontrolled glycemia and the further complications which it leads to. The objective of the study was to evaluate the neuroprotective effect of methanolic leaf extract of Ficus benghalensis against alloxan induced diabetic neuropathy in rats.Material and methods:Experimental diabetes was induced in wistar albino rats by single intraperitoneal injection of Alloxan monohydrate (150 mg/kg). The methanolic extract of leaves of Ficus benghalensis at a dose of 200 and 400 mg/kg body weight was administered at single dose per day to diabetes induced rats for a period of 28 days. Neuropathic pain was assessed in diabetic rats with various painful procedures. hot and cold water tail immersion test, pinprick test, cold allodynia, hot plate test, actophotometer and rota-rod tests were performed to assess the degree of thermal, mechanical, cold hyperalgesia and locomotor activity as well as motor co-ordination.Results:Animals treated with methanolic extract of Ficus benghalensis (200, and 400 mg/kg p.o.) showed good results in different parameters such as thermal allodynia (hot and cold), thermal hyperalgesia and motor co-ordination in comparison with diabetic control group. Thus, from this study we conclude that Ficus benghalensis exhibits significant neuroprotective activities against Alloxan-induced diabetic neuropathy in rats.

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.

scholarly journals Demographic Characteristics of Diabetic Neuropathy Patients Attended at a Tertiary Care Hospital in Dhaka City

2019 ◽  
Vol 31 (1) ◽  
pp. 27-30
Author(s):  
Mohammad Mashudur Rahman ◽  
Abu Nasir Rizvi ◽  
Mohammad Nazim Uddin ◽  
Rashida Akter Khanam ◽  
Muhammad Abdul Momen Khan ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Diabetic Neuropathy ◽  
Demographic Characteristics ◽  
Outpatient Department ◽  
Diabetic Patients ◽  
Type I ◽  
Care Hospital ◽  
Type Ii ◽  
Study Population ◽  
The Mean

Introduction: Diabetic neuropathy is one of the early complications of diabetes mellitus patients which is very difficult to face in the daily living activities. The purpose of the present study was to see the demographic characteristics of diabetic neuropathy patients. Metarials & Methods: This descriptive type of cross-sectional study was conducted in the Department of Neurology including Neuropathy Clinic and in collaboration with department of Endocrinology at Banghabandhu Sheikh Mujib Medical University, Dhaka from January 2012 to December 2013 for a period of two (2) years. Adult diabetic patients presented with neuropathic pain with symmetrical involvement of distal limbs from indoor and outpatient department of Neurology including Neuropathy clinic as well as indoor and outpatient department of Endocrinology, BSMMU were enrolled in the study population. Data was collected by face to face interview. Information was collected by taking medical history and clinical examinations and subsequent laboratory investigations. Results: A total number of 102 cases were recruited for this study who were clinically diagnosed as painful diabetic polyneuropathy. Female was predominant than male 55(53.9%) cases and 47(46.1%) cases respectively. The male and female ratio was 1:1.2. Majority were in the age group of more than 55 years which was 55(53.9%) cases. The mean age with SD of the study population was 52.79±9.42 years. Among 102 patients type II DM was predominate than type I patients which were 95(92.2%) cases and 8(7.8%) cases respectively. The mean duration of DM with SD was 6.51±3.6 years. However the mean duration of neuropathic pain was 1.68±1.155 years. Conclusion: In conclusion majority of the diabetic neuropathy patients are female suffering from type II DM in the middle age. Medicine Today 2019 Vol.31(1): 27-30

scholarly journals EFFECT OF ETHANOLIC FLOWER EXTRACT OF SPATHODEA CAMPANULATA ON STREPTOZOTOCIN INDUCED DIABETIC NEUROPATHY

2018 ◽  
Vol 10 (5) ◽  
pp. 64
Author(s):  
Rishikesh Bachhav ◽  
Ravindranath Saudagar
Keyword(s):  
Body Weight ◽  
Reaction Time ◽  
Diabetic Neuropathy ◽  
Aldose Reductase ◽  
Thermal Hyperalgesia ◽  
Test Group ◽  
Male Rats ◽  
Cellulose Solution ◽  
Aldose Reductase Inhibition

Objective: To evaluate the effect of ethanolic extract of the flower of Spathodea camapanulata (EFESC) on streptozotocin-induced diabetic neuropathy.Methods: Non-insulin dependent diabetes mellitus (NIDDM) was induced in overnight fasted adult wistar strain albino male rats weighing 160-200g by a single intraperitoneal injection (i. p) of streptozotocin (STZ-65 mg/kg). The rats were randomized into six groups, with six animals each, namely normal control (NC) (Treated with 1% carboxymethyl cellulose solution), diabetic control (DC) (65 mg/kg., i. p. STZ), test group treated at various doses of EFESC250, EFESC500, and EFESC750, standard control-glibenclamide0.25 mg/kg b.w.(SCG) and the treatment has begun from the day of blood sugar level (BSL) detection after the STZ treatment. Body weight was checked daily and serum glucose levels were measured at 48 h, 15th and 28th d of study. Reaction time to thermal hyperalgesia and cold allodynia were measured after induction of diabetes. In vitro, aldose reductase inhibition assay was carried out.Results: The preliminary phytochemical screening revealed the steroids, terpenoids, coumarins, carbohydrates, tannins, glycosides, and flavonoids in EFESC. DC group showed decreased in reaction time (hyperalgesia) compared to NC while a significant increase in reaction time was observed at various doses EFESC250, EFESC500, EFESC750 and SCG0.25. EFESC at various doses showed the significant reduction in BSL and body weight on 15th and 28th d in STZ diabetic rat at various dose levels. In vitro, aldose reductase inhibition was observed with an IC50 at 131 μg/ml.Conclusion: EFESC showed reduced in BSL and prevents hyperalgesia in experimental diabetic neuropathy. It also reduced aldose-reductase level that may play an important role in reducing the complication of diabetic neuropathy.

scholarly journals Chronic Treatment With Hydrogen Sulfide Donor GYY4137 Mitigates Microglial and Astrocyte Activation in the Spinal Cord of Streptozotocin-Induced Diabetic Rats

2020 ◽  
Vol 79 (12) ◽  
pp. 1320-1343
Author(s):  
Abdulaziz M F Shayea ◽  
Alyaa M A Mousa ◽  
Waleed M Renno ◽  
Mohammed Shaban Nadar ◽  
Bedoor Qabazard ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Hydrogen Sulfide ◽  
Diabetic Neuropathy ◽  
Proinflammatory Cytokines ◽  
Thermal Hyperalgesia ◽  
Diabetic Rats ◽  
Water Soluble ◽  
Diabetic Patients ◽  
Astrocyte Activation ◽  
Neuroprotective Effects

Abstract Long-term diabetic patients suffer immensely from diabetic neuropathy. This study was designed to investigate the effects of hydrogen sulfide (H2S) on peripheral neuropathy, activation of microglia, astrocytes, and the cascade secretion of proinflammatory cytokines in the streptozotocin (STZ)-induced peripheral diabetic neuropathy rat model. STZ-induced diabetic rats were treated with the water-soluble, slow-releasing H2S donor GYY4137 (50 mg/kg; i.p.) daily for 4 weeks. Antiallodynic/antihyperalgesic activities were evaluated using different tests and histopathological changes and the expression of proinflammatory cytokines in the spinal cord were examined. GYY4137 treatment produced neuroprotective effects in the spinal cord of diabetic animals and modulated their sensory deficits. The treatment decreased allodynia (p < 0.05) and mechanical hyperalgesia (p < 0.01) and restored thermal hyperalgesia (p < 0.001) compared with diabetic rats. The treatment decreased the microglial response and increased astrocyte counts in spinal cord gray and white matter compared with untreated diabetic rats. Proinflammatory cytokines were reduced in the treated group compared with diabetic rats. These results suggest that H2S has a potentially ameliorative effect on the neuropathic pain through the control of astrocyte activation and microglia-mediated inflammation, which may be considered as a possible treatment of peripheral nerve hypersensitivity in diabetic patients.

The CA1 hippocampal serotonin alterations involved in anxiety-like behavior induced by sciatic nerve injury in rats

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Sepideh Saffarpour ◽  
Farinaz Nasirinezhad
Keyword(s):  
Neuropathic Pain ◽  
Sciatic Nerve ◽  
Pain Threshold ◽  
Experimental Studies ◽  
Thermal Hyperalgesia ◽  
Radiant Heat ◽  
Male Rats ◽  
Ca1 Region ◽  
Plus Maze

AbstractObjectivesSeveral clinical and experimental studies reported the anxiety as one of the neuropathic pain comorbidities; however, the mechanisms involved in this comorbidity are incompletely cleared. The current study investigated the consequence of pain induced by peripheral neuropathy on the serotonin (5-HT) level of the CA1 region of the hippocampus, which is known as a potential reason, for anxiety associated with neuropathic pain.MethodsIn this manner, 72 male rats were inconstantly subdivided into three experimental groups as follows: control, sham, and chronic constriction injury (CCI). Neuropathic pain was initiated by the CCI of the sciatic nerve, and then, mechanical allodynia, thermal hyperalgesia, and anxiety-like behavior were evaluated using the von Frey filaments, radiant heat, open field test (OFT), and elevated plus maze (EPM) respectively. To investigate the probable mechanisms, the in vivo extracellular levels of 5-HT were assessed by microdialysis and using reverse-phase high-pressure liquid chromatography (HPLC) in the CA1 region of hippocampus on days 16 and 30 post-CCI.ResultsOur data suggested that CCI caused anxiety-like behavior in OFT and EPM test. 5-HT concentration in the CA1 region of the hippocampus significantly (F=43.8, p=0.000) reduced in CCI rats, when the pain threshold was minimum. Nevertheless, these alterations reversed while the pain threshold innate increased.ConclusionsNeuropathic pain, initiated by constriction of the sciatic nerve can induce anxiety-like behavior in rats. This effect accompanies the reduction in 5-HT concentration in the CA1 region of the hippocampus. When the pain spontaneously alleviated, 5-HT level increased and anxiety-like behavior relieved.

scholarly journals Effect of Flavone Derivatives on Vincristine and Oxaliplatin Induced Peripheral Neuropathy in Mice

2021 ◽  
Author(s):  
Parimala Kathirvelu ◽  
Jagan Nadipelly ◽  
Vijaykumar Sayeli ◽  
Viswanathan Subramanian ◽  
Jaikumar Shanmugasundaram ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Mechanical Allodynia ◽  
Antinociceptive Effect ◽  
Thermal Hyperalgesia ◽  
Chemotherapeutic Agents ◽  
Hot Water ◽  
Cold Allodynia ◽  
Hydroxy Flavone ◽  
Flavone Derivatives ◽  
Anti Inflammatory

Introduction: Therapy with anticancer drugs like paclitaxel, platinum complexes and vincristine result in severe peripheral neuropathy. Very few treatment options are available to overcome this debilitating side effect. Flavone and its monohydroxy derivatives have been proved to possess anti-nociceptive and anti-inflammatory effects in animal models. Aim: To investigate flavone, 5-hydroxy flavone, 6-hydroxy flavone and 7-hydroxy flavone for their effect on neuropathy induced by vincristine and oxaliplatin in mice. Materials and Methods: In this experimental animal study, neuropathy was induced in mice by multiple doses of vincristine or a single dose of oxaliplatin. The manifestations of mechanical allodynia, cold allodynia and thermal hyperalgesia were measured by von Frey’s hair aesthesiometer, acetone spray test and hot water tail immersion test. The data was subjected to ANOVA followed by Dunnett’s test for multiple comparison and paired t-test at appropriate places. Results: Flavone and monohydroxy flavones significantly reduced the paw withdrawal response scores due to mechanical allodynia and cold allodynia resulting from vincristine or oxaliplatin administration (p<0.05). The tail withdrawal latency due to thermal hyperalgesia was also significantly increased by different flavone derivatives (p<0.05). However, 7-hydroxy flavone was ineffective in oxaliplatin-induced mechanical allodynia and vincristine induced thermal hyperalgesia. Analysis of the results indicated that the manifestations of neuropathy induced by vincristine or oxaliplatin were amenable to treatment with flavone derivatives in the following order; cold allodynia>thermal hyperalgesia>mechanical allodynia. Opioid mediated antinociceptive effect, interaction with cation channels and anti-inflammatory effect of the investigated flavones may be suggested as possible mechanisms for their beneficial effects in neuropathy due to chemotherapeutic agents. Conclusion: Various neuropathic manifestations induced by vincristine and oxaliplatin were effectively attenuated by flavone and monohydroxy flavones.

scholarly journals Pre-emptive PPAR-γ Activation Abolishes Development of Nerve Injury-induced Behavioral Hypersensitivity: Elucidating Underlying Mechanisms

2021 ◽  
pp. 23-37
Author(s):  
Seema Thakur ◽  
Haritha Pasupulati ◽  
Saurabh Sharma ◽  
Satyanarayana S. V. Padi
Keyword(s):  
Oxidative Stress ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Chronic Constriction Injury ◽  
Thermal Hyperalgesia ◽  
Plasma Extravasation ◽  
Painful Condition ◽  
Cold Allodynia ◽  
Ppar Γ ◽  
Underlying Mechanisms

Background: Neuropathic pain is a chronic incapacitating painful condition for which there is no effective treatment. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play key roles in modulating immune and inflammatory responses. The antinociceptive properties of PPAR-γ activation on development of neuropathic pain are not fully known. Objective: To determine the role of PPAR-γ activation on the development of neuropathic pain following chronic constriction injury and to elucidate underlying mechanisms. Methodology: Neuropathy was induced by chronic constriction injury of sciatic nerve in rats. Cold allodynia and thermal hyperalgesia were assessed and the markers of inflammation and nitroso-oxidative stress were estimated. Results: Pre-emptive administration of pioglitazone, a PPAR-γ agonist (3, 10 or 30 mg/kg, i.p. 1 hr before surgery and continued once daily for 2 weeks) dose-dependently attenuated paw withdrawal latency to cold (allodynia) and thermal (hyperalgesia) stimuli. Pioglitazone significantly reduced elevated TBARS, protein carbonylation, nitrite levels and markedly restored depleted GSH, and reduction in activities of SOD and catalase in injured nerves. Further, pioglitazone markedly reduced plasma extravasation and levels of pro-inflammatory cytokines TNF-α and IL-1β following nerve injury. Moreover, pioglitazone did not alter the locomotor activity. Pretreatment with PPAR-γ antagonist BADGE (30 mg/kg, i.p.) blocked the beneficial effects of pioglitazone. Essentially, pioglitazone promoted the long-lasing recovery and also prevented the development of neuropathic pain even after treatment termination. Conclusion: Pioglitazone, a PPAR-γ agonist receptor-dependently abolished the development of traumatic neuropathic pain and exerted long-lasting antinociceptive effects through reducing nitroso-oxidative stress and inflammation. Our findings strongly suggest that pre-emptive activation of PPAR-γ prevented or at least delayed the development of nerve injury-induced pain hypersensitivity.

scholarly journals Hydrogen sulfide attenuates diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor

2020 ◽  
Vol 245 (9) ◽  
pp. 823-834
Author(s):  
Hao Li ◽  
Shulin Liu ◽  
Zheng Wang ◽  
Yonglai Zhang ◽  
Kaiguo Wang
Keyword(s):  
Neuropathic Pain ◽  
Hydrogen Sulfide ◽  
Diabetic Neuropathy ◽  
Opioid Receptor ◽  
Pain Modulation ◽  
Diabetic Patients ◽  
Spontaneous Pain ◽  
Therapeutic Effects ◽  
Diabetic Neuropathic Pain ◽  
Μ Opioid Receptor

Diabetic neuropathic pain is a frequent complication of diabetic neuropathy. The specific manifestations of diabetic neuropathic pain include spontaneous pain and hyperalgesia, which seriously affect the quality of life of patients. Previous publications have shown that H2S has both pro-nociceptive and anti-nociceptive effects. This present investigation aimed to examine the anti-nociceptive effect of H2S on diabetic neuropathic pain. We established a diabetic neuropathic pain animal model with high-glucose, high-fat diet, and STZ, then treated rats with different concentrations of H2S and inhibitors of NOS, sGC, PKG, and opioid receptors. The mechanical allodynia and thermal hyperalgesia of rats were measured to assess the anti-nociceptive effects of H2S. The mRNA and protein expression of NOS and PKG1 were measured to explore their roles in the anti-nociceptive action of H2S. The results revealed that inhalation of H2S gas had anti-nociceptive effect in diabetic neuropathic pain model rats without affecting the blood glucose level and body mass. It increased the mRNA and protein level of nNOS, and the inhibitor of nNOS, 7-NI, abolished the anti-nociceptive effect of H2S. Furthermore, inhibitors of sGC and PKG could also abolish the anti-nociceptive effect of H2S. The expression of PKG1 was found to be increased by H2S, which was reversed by the inhibitors of nNOS, sGC, and PKG. Finally, CTOP, a μ-opioid receptor antagonist, abolished the anti-nociceptive effect of H2S, indicating that the μ-opioid receptor plays a role in the anti-nociceptive effect of H2S. In conclusion, the findings of this investigation suggest that hydrogen sulfide may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor. Impact statement There are currently approximately 425 million diabetic patients worldwide, of which approximately 90% of patients with diabetes suffer from neuropathy. Diabetic neuropathic pain (DNP) is a common complication of diabetic neuropathy. Nearly half of the patients hospitalized with diabetes have pain symptoms or symptoms related to neurological injury, and the incidence increases with age and diabetic duration. Anti-DNP analgesics have either limited therapeutic effects or serious side effects or lack of clinical trials, which has limited their application. Physiopathological mechanisms and treatment of DNP remain a significant challenge. The present confirmed that inhalation of H2S may attenuate the diabetic neuropathic pain through NO/cGMP/PKG pathway and μ-opioid receptor. It provides us the animal study foundation for the application of H2S on the treatment of DNP and clarifies some target molecules in the pain modulation of DNP.

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