Some studies suggest that 5-lipoxygenase (5-LOX) inhibition or leukotriene receptor antagonism may effectively attenuate different kinds of pain. In the present study, we investigated whether esculetin (which, among other actions, potently inhibits 5-LOX) possesses analgesic activity in acute non-inflammatory pain and acute inflammatory pain models in rats. We also examined the effects of zileuton, a selective 5-LOX inhibitor, on esculetin activity. Plasma concentrations of leukotriene B4 (LTB4 ) after administration of esculetin were also determined. Esculetin (1.25-20 mg/kg, i.p.) dose-dependently alleviated hyperalgesia and exhibited antinociceptive effects in both experimental models. The greatest effect of esculetin was observed with a dose of 20 mg/kg. In carrageenan-induced inflammatory pain in rats, 20 mg/kg esculetin reversed or mitigated hyperalgesia, increasing the threshold to mechanical stimuli from a control value of -23.8 ± 1.8% to 15.2 ± 2.2% (P < 0.01) and that to thermal stimuli from -52.5 ± 6.1% to -9.5 ± 3.9% (P < 0.01). In non-inflammatory pain, after esculetin (20 mg/kg) administration the threshold values to mechanical and thermal stimuli increased to 75.9 ± 4.2% and 59.2 ± 4.3%, respectively (P < 0.01 for both). Zileuton (30 mg/kg, p.o.) alone slightly but significantly increased the pain threshold in the non-inflammatory and inflammatory acute pain models. Pretreatment with 30 mg/kg, p.o., zileuton significantly enhanced the analgesic activity of 5 mg/kg, i.p., esculetin in both pain models. Moreover, esculetin (10 mg/kg, i.p.) decreased LTB4 concentrations in the blood from 244 ± 29 pg/mL in the control group to 185 ± 11 pg/mL (P < 0.005). The results of the present study suggest the involvement of the 5-LOX pathway in esculetin analgesia.
The possible mechanisms involved in the antinociceptive effect of venlafaxine (VFX), a selective serotonin and noradrenaline reuptake inhibitor, after a single administration and chronic treatment were investigated in a diabetic neuropathic pain (DNP) model. VFX produced a significant antihyperalgesic effect after a single and repeated administration. This effect was reversed by pretreatment with yohimbine (a relatively selective α2-adrenergic antagonist) and p-chloroamphetamine (a neurotoxin which destroys serotonergic neurons). Conversely, naloxone (a nonselective opioid antagonist) did not reverse the effect of VFX in a DNP model. It is concluded that both noradrenergic and serotonergic mechanisms participate in the antinociceptive effect of VFX in the DNP model. However, the noradrenergic mechanism probably plays a more important role.
Combination therapy, such as classical antidepressants (amitriptyline, moclobemide) with opioids, or agents with noradrenaline reuptake inhibition and μ-opioid receptor activation could be a new target for research into treatment of painful diabetic neuropathy.
Purpose Optimal glycemic control is crucial for proper wound healing in patients with diabetes. However, it is not clear whether other antidiabetic drugs support wound healing in mechanisms different from the normalization of blood glucose control. We assessed the effect of insulin and metformin administration on the wound healing process in rats with streptozotocin-induced diabetes. Methods The study was conducted on 200 male Wistar rats with streptozotocin-induced diabetes. In the last phase of the study, 45 rats, with the most stable glucose levels in the range of 350–500 mg/dL, were divided into three groups: group I received human non-protamine insulin subcutaneously (5 IU/kg body mass) once a day, group II received metformin intragastrically (500 mg/kg b.m.), and group III (control) was given saline subcutaneously. After 14 days of antidiabetic treatment, a 2 cm × 2 cm thin layer of skin was cut from each rat’s dorsum and a 4 cm disk with a hole in its center was sewn in to stabilize the skin and standardize the healing process. The wound healing process was followed up for 9 days, with assessment every 3 days. Biopsy samples were subjected to hematoxylin and eosin staining and immunohistochemical assays. Results Analysis of variance revealed significant influence of treatment type (insulin, control, or metformin) on the relative change in wound surface area. The wound healing process in rats treated with insulin was more effective than in the metformin and control groups. Wound tissue samples taken from the insulin-treated animals presented significantly lower levels of inflammatory infiltration. Immunohistochemical assessment showed the greatest density of centers of proliferation Ki-67 in insulin-treated animals. Conclusion These results suggest that an insulin-based treatment is more beneficial than metformin, in terms of accelerating the wound healing process in an animal model of streptozocin-induced diabetes.
ObjectivesEsculetin (6,7-dihydroxycoumarin) is a natural coumarin with anti-oxidant, anti-inflammatory and anti-nociceptive activity. It acts as a potent inhibitor of lipoxygenases (5-LOX and 12-LOX) and decreases the production of matrix metalloproteinases (MMP-1, MMP-3 and MMP-9). Because both inhibition of lipoxygenases and inhibition of matrix metalloproteinases are effective strategies in the treatment of rheumatoid arthritis, we investigated whether esculetin may be effective in adjuvant-induced arthritis in rats.Material and methodsThe study was performed on male Lewis rats, in the adjuvant-induced arthritis model. Rats were divided into two groups: control (treated with 1% methylcellulose) and experimental (treated with esculetin – 10 mg/kg ip.). The tested compound was administered for 5 consecutive days starting on the 21st day after induction of arthritis. Each group consisted of 7 animals. After 5 days of treatment, rats were anesthetized. The concentration of leukotriene B4 (LTB4) in plasma was determined by a competitive enzyme immunoassay.ResultsThe LTB4 level in plasma of rats with adjuvant-induced arthritis is increased in comparison to rats without inflammation (362 ±34 vs. 274 ±15 pg/ml, p < 0.01, respectively). Five-day treatment with esculetin in adjuvant-induced arthritis rats decreases the LTB4 level to a level comparable with rats without inflammation (284 ±23 pg/ml, p < 0.01).ConclusionsLTB4 is the most potent chemotactic agent influencing neutrophil migration into the joint. It is known that its level in serum of patients with active rheumatoid arthritis is increased and correlates with disease severity. Some other lipoxygenase inhibitors have already been tested as potential drug candidates in clinical and preclinical trials for rheumatoid arthritis (Zileuton, PF-4191834). Because esculetin decreases the LTB4 level in plasma of rats in adjuvant-induced arthritis, it may also be considered as an attractive drug candidate for patients with rheumatoid arthritis.
Depending on the dose used, BK produces pro- or anti-nociceptive action. Both B1 and B2 receptors are involved in the action of icv applied BK.
The results suggest that DHEA could be indicated as a drug to improve treatment of chronic pain disorders.
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