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Quercetin Attenuates Thermal Hyperalgesia and Cold Allodynia in STZ-Induced Diabetic Rats

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Quercetin Attenuates Thermal Hyperalgesia and Cold Allodynia in STZ-Induced Diabetic Rats Indian Journal of Experimental Biology Vol. 42, August 2004, pp. 766-769 Quercetin attenuates thermal hyperalgesia and cold allodynia in STZ-induced diabetic rats Muragundla Anjaneyulu & Kanwaljit Chopra* Pharmacology Division, Universit y In stitute of Pharmaceutical Sciences, Panjab University, Chandigarh , I 60 014, India Received 21 January 2004; revised 5 May 2004 Neuropathic pain is one of the important mi crovascular complications of diabetes. Oxidative stress and superoxide play a criti cal role in th e development of neurovascular complications in diabetes. Aim of th e present study was to eva lu ate the effec t of qu ercetin, a bi onavo noid on thermal nocicepti ve responses in streptozotoci n (STZ)-induced diabetic rats assessed by tail-immersion and hot plate meth ods. After 4-weeks of a single intra venous STZ injecti on (45 mg/kg body wei ght), diabetic rat s exhibited a significant th ermal hyperal gesia and cold all odynia along with in creased plasma glucose and decreased body weights as compared with control rat s. Chronic treatment with quercetin (I 0 mg/kg body wei ght; p.o) for 4- weeks starting from the 4' 11 week of STZ-injection significantly attenuated th e cold all odyni a as well as hypera lges ia. Results indicate th at qu ercetin, a natural anti ox idant, may be helpful in diabetic neuropathy. Keywords: Diabeti c neuropathy, Hyperalgesia, Quercetin, Cold all odyni a, Tail-immersion, Hot plate. Neuropathic pain is one of the most common Based on analgesic and antioxidant properties of complications in diabetes mellitus. Jt is mostly quercetin, the present study has been aimed to characteri zed by hyperalgesia and allodynia. Clinical evaluate the effect of quercetm on thermal and experimental studies have revealed that reactive hyperalgesia and cold allodynia, the indices of oxygen species (ROS) play a significant role in diabetic neuropathic pain in rats. pathophysiology of neuropathic pain in diabetes. Materials and Methods Quercetin (3, 5, 7, 3', 4'-pentahydroxyflavone) is a Animals-Male Sprague-Dawley rats (200-250 g) phenolic compound widely distributed in the plant bred in Central Animal House facilities of Panjab kingdom. [t is found in many frequently consumed University were housed under optimal laboratory foods, including apples, onion, tea, berries and conditions. Animals were acclimatized to laboratory brassica vegetables. Renewed interest has been conditions before the experiments th at were carried observed in recent years on multipk activities of out between 0900 and 1700 hr. Approval of novel bioflavonoids. They are reported t•) have many Institutional Animal Ethics Committee was obtained. beneficial effects on human health, including Treatment schedule-After a basal reading at 4'h cardiovascular protection, anticancer activity, anti­ week of STZ injection, control and diabetic rats were ulcer effects, anti-allergic activity, cataract randomly selected and divided in three groups of 6-7 prevention, antiviral activity and anti-inflammatory 2 animals each. i.e. control, diabetic control and effects I. There are sporadic reports on the analgesic diabetic group treated with quercetin. Starting from activity of certain flavonoids such as hydroxy ethyl 3 4 the 4'" week till 8'" week, the control and diabetic rutoside and gossypin . Recently it has been reported 5 control groups received vehicle of quercetin and that quercetin has analgesic activity in naive animals 6 another diabetic treated group received suspension of tested in few test systems . Moreover, quercetin has quercetin (10 mg/kg body weight/day) orally. been reported to inhibit oxidative damage in various 7 Quercetin (Sigma Chemical, St.Lo ... is , MO, USA) tissues of STZ-induced diabetic rats . suspension was prepared in 0.5 % carboxy methyl cell ulose solution. All the drugs were administered in *Corresponden t author a constant volume of 0.5 mil I OOg body weight of rat. Ph one: 0172-2534105 Fax: +91 -172-2541 142 Induction and assessmellt of diabetes-A single E- mail : · ·r [email protected] dose of 45-mg/kg body weight STZ (Sigma Chemical, ANJANEYULU & CHOPRA: DIABETIC PAIN & QUERCETIN 767 St.Louis, MO, USA) prepared in citrate buffer (pH tests-At the end of 4th week, diabetic animals 8 4.4, 0.1 M) was injected through tail vein . The age exhibited significant decrease in pain threshold from matched control rats received citrate buffer and used noxious stimuli as compared to control rats along with diabetic animals. Diabetes was confirmed (P<O.OO 1). Quercetin administration from the 4th after 48 hr of STZ injection, the blood samples were week to gth week significantly increased the tail collected through tail vein and plasma glucose levels withdrawal latencies from 4th to gth week compared to were estimated by enzymatic GOD-PAP (glucose control diabetic rats (P<O.OO 1, Fig. 1A). oxidage peroxidase) diagnostic kit method (Span Effect of chronic quercetin treatment on diabetic Diagnostic Chemicals, lndiaf The rats having plasma pain threshold in tail-immersion (cold water) 10 glucose levels more than 250 mg/dl were selected tests-At the end of 4th week, diabetic animals and used for the present study. Body weight and exhibited significant decrease in pain threshold from plasma glucose level were also measured before and non-noxious stimuli as compared to control rats at the end of experiment to see the effect of quercetin (?<0.001). Quercetin administration from the 4th on these parameters. week to gth week significantly increased the tail Assess111ent of thermal hyperalgesia and cold withdrawal latencies from 4th to gth week compared to allodynia-Tail-immersion (warm water) test: Tail of control diabetic rats (P<O.OOI, Fig. 1B). rat was immersed in a warm water (47° ± 1°C) bath Effect of chronic quercetin treatment Oil diabetic until tail withdrawal (flicking response) or signs of pain threshold in. hot plate tests-At the end of 4th struggle were observed (cut-off 15 sec). Shortening of week, diabetic animals exhibited significant decrease the tail-withdrawal time indicates hyperalgesia. in pain threshold as compared to control rats Tail-immersion (cold water) test-The procedure (?<0.05). Quercetin administration from the 4th week was same as warm water test but the temperature of to gth week significantly increased the tail withdrawal water was set at I 0° ± 0.5°C, a temperature that is latencies from 4th to gth week compared to control normally innocuous". The shortened duration of tail diabetic rats (P<O.OO 1, Fig. 1C). immersion indicates allodynia. The cut-off time was 15 sec. Discussion Hot plate test--Jn this test, animals were The markedly decreased nociceptive thresholds in individually placed on a hot plate (Eddy's Hot Plate) STZ-injected diabetic rats as compared with control with the temperature adjusted to 55° ± 1° C. The rats indicated development of significant thermal latency to the first sign of paw licking or jump hyperalgesia and cold-allodynia. Mechanical response to avoid heat pain was taken as an index of hyperalgesia, thermal allodynia and formalin-evoked pain threshold and the cut-off time was kept 10 sec in flinching in STZ-rats have been demonstrated order to avoid damage to the paw. 12 13 previously ' • The hyperalgesic response in the tail­ Statistical analysis-The nociceptive threshold withdrawal test is generally attributed to central (latency in seconds) to thermal noxious and non­ 4 15 mechanisms ' • , whereas the hyperalgesic response noxious stimuli was measured and expressed as mean on the hot plate is considered to result from a ± S.E. The hyperalgesic and allodynia responses were combination of both central and peripheral analysed by ANOVA followed by Tukey's t test. P < mechanisms 15 0.05 was considered as significant. Student's t test Generation of superoxide due to oxidative stress in was used to compare the values from two groups. diabetes may be responsible for vascular and neuronal 16 complications of painful neuropathy . Present study Results on the tail-immersion and hot plate methods indicates Blood glucose and body weights-Diabetic rats that quercetin prevents the both spinal and supraspinal exhibited significantly increased plasma glucose neuropathy in diabetic mice. This is in agreement with levels compared to control rats (?<0.001). There was the reports where glutathione (GSH) and alpha-lipoic a marked decrease in the body weight of STZ-injected acid, well known, antioxidants significantly prevented 17 18 rats as compared to control rats (?<0.001). These thermal and mechanical hyperalgesia · • It is also parameters were unaffected by quercetin treatment. reported that dimethylthiourea, a hydroxyl scavenger, Effect of chronic quercetin treatment on diabetic also prevented the development of mechanical 19 pain threshold in tail-immersion (warm water) hyperalgesia in the diabetic rats . The mechanism by 768 INDIAN J EXP I3IOL, AUGUST 2004 Ill Control DDiabetes 0 Diabetes+Quercetin 14 b b 12 ® 10 8 6 4 2 0 u 15 II) ..!!!.. II) 10 E ; c: 0 ; 5 0 Ill II) 0:: 0 5 4 3 2 1 0 0 1 2 3 4 Treabnent (week) Fig. !-Effect of chronic treatment of quercetin on pain threshold values in STZ-injected diabetic rats subjected to the tail immersion test in (A) hot water (47° ± I °C), (B) cold water (10° ± 0.5 °C) and (C) the hot plate test (55° ± I °C). [Values are in mean± S.E. P values; •<0.00 I as compared with control rats at before and respective week; b<O.OO I as compared with control diabetic rats at before and respective week; c<O.OO l as compared with controls at first week and d<0.05 as compared with control diabetic rats at respective week] which quercetin, a natural antioxidant, inhibits lipid treatment has been demonstrated to reduce allodynia 26 peroxidation by blocking the enzyme xanthine in diabetic rats .
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