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    The effect of combined systemic administration of morphine and L-name, a nitric oxide synthase inhibitor, on behavioral signs of neuropathic pain in rats
    (John Wiley & Sons Ltd, 2002) Ulugol, A; Aslantas, A; Karadag, HC; Bulbul, ED; Tuncer, A; Dokmeci, I
    The controversy over using opioids for managing chronic neuropathic pain is widely acknowledged, and nitric oxide (NO) is suggested to play an important role in the maintenance of the behavioral signs of neuropathic pain. We evaluated the effect of combined systemic administration of morphine and N-G-nitro-L-arginine-methyl ester (L-NAME), a NO synthase (NOS) inhibitor, on allodynia in the spinal nerve ligation model of pain in rats. Nerve injury was produced by tight ligation of the left L5 and L6 spinal nerves and this procedure resulted in neuropathic pain behaviors in the ipsilateral hindlimb. Mechanical and cold allodynia were detected, respectively, by application of von Frey filaments or acetone to the plantar surface of the foot. Morphine (0.1-10 mg/kg, i.p.) and L-NAME (3-30 mg/kg, i.p.) reduced mechanical and cold allodynia with their higher doses. Combining subthreshold dose of L-NAME (3 mg/kg, i.p.) with morphine, an appreciable increase in the antiallodynic effect of morphine was observed. This effect was prevented by L-arginine (500 mg/kg, i.p.) and naloxone (I mg/kg, i.p.). These results suggest that combining morphine with a NOS inhibitor may be a promising approach in the treatment of neuropathic pain.
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    The effect of WIN 55,212-2, a cannabinoid agonist, on tactile allodynia in diabetic rats
    (Elsevier Sci Ireland Ltd, 2004) Ulugol, A; Karadag, HC; Ipci, Y; Tamer, M; Dokmeci, I
    The antinociceptive action of cannabinoids in acute and inflammatory pain states have been well-documented. There is also accumulating evidence suggesting that cannabinoids are effective analgesics in chronic pain conditions. WIN 55,212-2, a mixed CB1 and CB2 cannabinoid receptor agonist, has been shown to be effective against hyperalgesia and allodynia in painful peripheral mononeuropathy. Recently, in addition to their spinal and supraspinal antinociceptive action, cannabinoids have also reported to exert local analgesic effects. The aim of this study is to observe the effect of a high affinity cannabinoid, WIN 55,212-2, on tactile allodynia and thermal hyperalgesia in diabetic rats. Diabetes was produced with the injection of a single dose of streptozocin (50 mg/kg, i.p.) and this procedure resulted in neuropathic pain behaviors in the hindlimbs. Mechanical allodynia was detected by application of von Frey filaments to the plantar surface of the foot, and thermal hyperalgesia was studied using the Hargreaves' method; however, thermal hyperalgesia did not develop in diabetic rats. With its higher doses, both systemic (3 and 10 mg/kg, i.p.) and peripheral (30 mug, i.p.l.) injections of WIN 55,212-2 reduced mechanical allodynia. These results suggest that WIN 55,212-2 has an antiallodynic effect in streptozocin-induced diabetic rats and may be a promising approach in the treatment of diabetic neuropathy. (C) 2004 Elsevier Ireland Ltd. All rights reserved.
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    Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats
    (Elsevier Sci Ireland Ltd, 2002) Ulugol, A; Karadag, HC; Tamer, M; Firat, Z; Aslantas, A; Dokmeci, I
    Recent observations suggest the involvement of adenosine in the peripheral antinociceptive effect of amitriptyline in nerve-injury-induced neuropathic pain. The aim of the present investigation was to evaluate, firstly, the peripheral and systemic effects of amitriptyline on tactile allodynia in the streptozotocin (STZ)-induced diabetic rat model of neuropathic pain and, secondly, whether caffeine coadministration affects the actions of amitriptyline. Diabetes was induced by a single intraperitoneal (i.p.) injection of STZ (50 mg/kg), and tactile allodynia was detected by application of von Frey filaments to the ventral surface of the hindpaw. Both systemic (0.5-2.0 mg/kg, i.p.) and peripheral (10-100 nmol, subcutaneously (s.c.)) administration of amitriptyline were found to produce increases in paw withdrawal thresholds, at higher doses. Coadministration of caffeine (5 mg/kg, i.p.; 1500 nmol, s.c.), at doses which produced no effect on its own, partially reversed systemic and local anti-allodynic effects of amitriptyline. These results indicate an anti-allodynic effect of both peripheral and systemic amitriptyline, and suggest the involvement of endogenous adenosine in the action of amitriptyline in this rat model of painful diabetic neuropathy. These data also suggest that topical application of tricyclic antidepressants may be useful in treating neuropathic pain in diabetics. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.
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    The role of histamine H-1 receptors in the thermoregulatory effect of morphine in mice
    (Elsevier Science Bv, 1996) Ulugol, A; Karadag, HC; Dokmeci, D; Baldik, Y; Dokmeci, I
    Morphine is known to release histamine from mast cells and increase the turnover of neuronal histamine. It is also known that histamine receptors mediate some of the morphine effects. The contribution of histamine H-1 and H-2 receptors to the thermoregulatory effect of morphine in mice was investigated in the present experiments. Morphine produced a hypothermic effect, especially at the dose of 10 mg/kg. Although the histamine H-1 receptor antagonist, dimethindene (0.1 mg/kg, i.p.), attenuated the hypothermic effect of morphine (10 mg/kg), a histamine H-2 receptor antagonist, ranitidine (100 mg/kg, i.p.), had no effect. These results suggest that the hypothermic effect of morphine in mice is mediated, at least partly, through histamine H-1 receptors.
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    The role of nitric oxide in the protective effect of insulin against pentylenetetrazole-induced seizures in mice
    (John Wiley & Sons Ltd, 2000) Ulugol, A; Arikan, E; Dost, T; Dokmeci, D; Karadag, HC; Dokmeci, I
    Both insulin, depending on the glycemic state, and nitric oxide (NO), depending on the experimental conditions, have been suggested to have either proconvulsant or anticonvulsant effects. It is also known that NO plays an important role in some of the peripheral effects of insulin. The aim of the present study was to investigate the effects of NO and insulin against convulsions produced by pentylenetetrazole (PTZ, 60 mg/kg, i.p.) in mice and whether NO plays a role in the effect of insulin. Nitric oxide synthase (NOS) inhibitor, N-G-nitro-L-arginine-methyl ester (L-NAME, 1-100 mg/kg, i.p.) shortened the onset of PTZ-induced convulsions and increased the incidence and mortality rate, at the higher doses. Insulin (1 U/kg, i.p.), when given with dextrose (3 g/kg, i.p.) to counteract the hypoglycemic effect of the hormone, prolonged the onset of convulsions and decreased the incidence and mortality rate. L-NAME pretreatment (3 mg/kg, i.p.), at the dose which it produced no effect on PTZ-induced convulsions, attenuated the protective effect of 1 U/kg insulin + 3 g/kg dextrose combination significantly. Concomitant administration of the NO synthesis precursor, L-arginine (500 mg/kg), completely reversed this facilitatory effect of L-NAME. Our results indicate that NO has a protective effect against PTZ-induced convulsions in mice; insulin has a similar effect when given with dextrose; and, NO production may play an important role in the anticonvulsant effect of insulin.
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    Systemic agmatine attenuates tactile allodynia in two experimental neuropathic pain models in rats
    (Elsevier Ireland Ltd, 2003) Karadag, HC; Ulugol, A; Tamer, M; Ipci, Y; Dokmeci, I
    Recent evidence suggests that agmatine, an endogenous polyamine metabolite, might be an important neurotransmitter in central nervous system and has potential as a treatment of pain. The aim of our study was to evaluate the effect of agmatine on allodynia in two experimental neuropathic pain models, the spinal nerve ligation (SNL) model and the streptozocin (STZ)-induced diabetic neuropathy in rats, and to determine if the N-methyl-D-aspartate (NMDA) receptor antagonists and the nitric oxide synthase (NOS) inhibitors influence this effect of agmatine. Nerve injury was produced by tight ligation of the left L5 and L6 spinal nerves, and diabetic neuropathy is induced with the injection of a single dose of STZ; these procedures resulted in tactile allodynia in the hindpaw. Tactile allodynia was detected by application of von Frey filaments to the plantar surface of the foot. Agmatine reduced mechanical allodynia with its higher doses. Dizocilpine maleate (MK-801), a NMDA receptor antagonist, and the NOS inhibitors, N-G-nitro-L-arginine methyl ester and 7-nitroindazole, did not influence the antiallodynic effect of agmatine. These results suggest that agmatine has an antiallodynic effect in both spinal nerve ligation and diabetic models and may be a promising drug in the treatment of neuropathic pain. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.