European journal of pharmacology
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Chronic constriction injury of the sciatic nerve is an animal model for neuropathic pain. In this model, the analgesic potency of systemic morphine was significantly diminished in nerve-injured mice (ED(50) 19.4 mg/kg) compared with sham-operated mice (ED(50) 3.3 mg/kg) using a unilateral hot plate withdrawal test, with a similar reduction in sensitivity of intrathecal morphine. The sciatic nerve injury resulted in a reorganization of the dorsal root ganglion (DRG) neurons. ⋯ To explore the functional significance of these dermal changes, we examined the topical morphine and lidocaine analgesia following chronic sciatic nerve constriction. Both morphine and lidocaine retained topical activity following chronic sciatic nerve injury, but their analgesic dose-response curves were shifted to the right when compared to sham-operated mice. Thus, the chronic nerve constriction injury model is associated with pathological changes in distribution of the central and peripheral axons of the dorsal root ganglion neurons that correspond to a decreased pharmacological sensitivity to topical analgesic agents.
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Oxidative stress is implicated as a final common pathway in the development of diabetic neuropathy and pharmacological interventions targeted at inhibiting free radical production have shown beneficial effects. In the present study, we have investigated the effects of edaravone (3 mg/kg; 3-Methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger (relatively selective to hydroxyl radicals) in streptozotocin (50 mg/kg i.p.) induced diabetic neuropathy in male Sprague-Dawley rats. Significant reduction (18%) in motor nerve conduction velocity, nerve blood flow (55%) and tail flick latency in cold (53%) and hot (50%) immersion test was observed in diabetic rats compared to age matched non-diabetic rats. ⋯ Increase in blood pressure and vascular resistance was also significantly attenuated by edaravone treatment. This study provides experimental evidence to preventive and curative effect of edaravone on nerve function and oxidative stress in animal model of diabetic neuropathy. Hence edaravone may be tried clinically for the treatment of diabetic neuropathy since it is clinically used in stroke patients.
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The antinociceptive effects of WIN55,212-2, a synthetic cannabinoid, were evaluated in the model of partial sciatic nerve ligation after daily subcutaneous administration of 0.1 mg/kg a week before and two weeks after surgery. Mechanical allodynia and thermal hyperalgesia were evaluated in 46 rats allocated to receive: (1) Vehicle (before surgery)-Vehicle (after surgery); (2) Vehicle-WIN55,212-2; (3) WIN55,212-2-Vehicle; (4) WIN55,212-2-WIN55,212-2; (5) AM251+vehicle; (6) AM251+WIN55,212-2; (7) AM630+vehicle; (8) AM630+WIN55,212-2; (9) Sham receiving vehicle; and (10) Sham receiving WIN55,212-2. The decreased in mechanical allodynia and thermal hyperalgesia by WIN55,212-2 was significantly greater when it was administered during one week before surgery. In conclusion, pre-emptive use of cannabinoids produced greater antinociceptive effects in a model of neuropathic pain and this effect is mediated by cannabinoid CB(1) and CB(2) receptors.
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High-efficacy activation of central 5-HT(1A) receptors by means of the recently discovered, selective 5-HT(1A) receptor ligand, F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]methyl}piperidin-1-yl]methanone, fumaric acid salt] causes an unprecedented, broad-spectrum analgesia in rat models of acute and chronic pain of nociceptive and neuropathic origin; it also is effective in conditions where opioids either are ineffective, induce analgesic tolerance, or elicit persistent hyperalgesia/allodynia. Inversely mirroring morphine's actions, F 13640's ("curative-like") analgesic effects persist after the discontinuation of treatment. Here, we examined the relationships, if any, between the dose and the duration of F 13640 treatment on the one hand, and the duration of persistent analgesia on the other. ⋯ These 250- and 56-fold variations of the dose and duration of treatment caused post-treatment, persistent analgesia for about 10 and 40 days, respectively. At least as much as dose, the duration of F 13640 treatment determines F 13640-induced persistent analgesia. Neuroadaptive modulations at pre- and postsynaptic, brain and spinal cord 5-HT(1A) receptors may be involved in the dynamical, dose- and time-dependent, pre-treatment rise and post-treatment decay of the analgesia induced by high-efficacy 5-HT(1A) receptor activation.
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The present study was undertaken to elucidate the alterations in various behavioral and neurochemical basis of antidepressant action of bupropion [(+/-)-alpha-t-butylamino-3-chloropropiophenone], a dopamine reuptake inhibitor and to elucidate the possible mechanism of its action. The involvement of L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway in the antidepressant action of bupropion was investigated besides its actions on various brain transmitters like norepinephrine, dopamine and homovanillic acid. Bupropion (10, 15, 20 and 40 mg/kg., i.p.) dose dependently inhibited the immobility period in mice in both forced swim test and tail suspension test. ⋯ In addition, treatment of mice with methylene blue (10 mg/kg., i.p.) [direct inhibitor of both nitric oxide synthase (NOS) and soluble guanylate cyclase (sGC)] potentiated the effect of bupropion (10 mg/kg., i.p.) in the forced swim test. Furthermore, the reduction in the immobility period elicited by bupropion (20 mg/kg., i.p.) was also inhibited by pretreatment with sildenafil (5 mg/kg., i.p.) [phosphodiesterase 5 inhibitor]. The study indicated that bupropion possesses antidepressant activities in different animal models of depression through its dopaminergic and/or by modulating the L-arginine-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway.