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Nociceptive Threshold (nociceptive + threshold)
Selected AbstractsHypoalgesia in mice lacking GABA transporter subtype 1JOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2008Yin Fang Xu Abstract ,-Aminobutyric acid (GABA) transporters play a key role in the regulation of GABA neurotransmission. We reported previously that overexpression of the GABA transporter subtype 1 (GAT1), the major form of the GABA transporter in the CNS, led to hyperalgesia in mice. In the present study, nociceptive responses of GAT1-knockout mice (GAT1,/,) were compared with those of heterozygous (GAT+/,) and wild-type (GAT+/+) mice by four conventional pain models (tail-immersion test, hot-plate test, acetic acid,induced abdominal constriction test, and formalin test). In addition, the analgesic effects of two GAT1-selective inhibitors, NO-711 and tiagabine, were examined in all three genotypes using the same four models. Our data demonstrated that GAT1 deficiency because of genetic knockout or acute blockade by selective inhibitors leads to hypoalgesia in mice. These results confirmed the crucial role of GAT1 in the regulation of nociceptive threshold and suggested that GAT1 inhibitors have the potential for clinical use in pain therapy. © 2007 Wiley-Liss, Inc. [source] Antinociceptive efficacy of levetiracetam in a mice model for painful diabetic neuropathyACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2008M. OZCAN Background and Objective: Despite important advances in available knowledge, management of neuropathic pain remains incomplete, and results from experimental and clinical studies indicate that some anticonvulsants show promise for treating neuropathic pain. The aim of this study was to assess the antinociceptive efficacy of levetiracetam (LEV, ucb L059) in a mice model for painful diabetic neuropathy using the in vivo nociceptive behavioral ,hot-plate test.' Methods: The hot-plate test consisted of placing individual mice (adult male Balb/C) on the hot plate at 50±0.1 °C and timing the delay for the first hind paw lift (nociceptive threshold). After obtaining control values, diabetes was induced by injection of streptozotocin [200 mg/kg intraperitoneally (i.p.)] and 2 weeks after induction of diabetes (serum glucose ,400 mg/dL) LEV was administered i.p. and hot-plate tests were repeated. Pain threshold values were determined and analyzed by Kruskal,Wallis one-way analysis of variance (ANOVA) followed by a pairwise comparison using a Dunnett's t -test on the ranked data. Results: LEV (60, 300 and 900 mg/kg) had no significant effect on the nociceptive threshold in normal mice (n=8 for each dose, P>0.05). There were significant decreases in pain threshold latency in diabetic mice compared with the normal healthy group and these were significantly and dose-dependently restored by much lower doses of LEV (20, 100 and 200 mg/kg) in a reversible manner. Conclusion: Results obtained from the in vivo behavioral test lend support to the validation of the promising therapeutic potential of the novel antiepileptic agent LEV in the treatment of neuropathic pain. [source] Effects Of Topically Applied Capsaicin Cream On Neurogenic Inflammation And Thermal Sensitivity In RatsJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 2 2000M. Yoshimura The effects of capsaicin cream on neurogenic inflammation and thermal nociceptive threshold were investigated in rats. Firstly, for topical application of capsaicin cream to hind paw, we shaped boots from dental cement to prevent the animals from licking off the drug. Capsaicin cream (1%) led to significant increases in the amounts of Evans blue and substance P (SP) released into the perfusate, and the former response was significantly suppressed by pretreatment with RP67580, an NK1-receptor antagonist, but not by treatment with an NK2-receptor antagonist. Subsequent electrical stimulation of the sciatic nerve resulted in a significant reduction in Evans blue and SP extravasation 24 h after topical application of capsaicin cream. On the other hand, when capsaicin cream was repeatedly applied to both hind paws once a day, withdrawal latency for noxious heat stimulation decreased after 24 h, and this thermal hyperalgesia was reversed 3 days later. These results suggest that capsaicin cream initially affects neurogenic inflammation mechanisms and then blocks the pain transmission mechanism. [source] Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2002A. M. Hughes Aims, The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. Methods, The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg,1 dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg,1 ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDICTM thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. Results, Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (,5.52, 4.24) and 11.75 vs 15.25 (,11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. Conclusions, Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms. [source] Fructose-1,6-bisphosphate reduces inflammatory pain-like behaviour in mice: role of adenosine acting on A1 receptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2009DA Valério Background and purpose:, D-Fructose-1,6-bisphosphate (FBP) is an intermediate in the glycolytic pathway, exerting pharmacological actions on inflammation by inhibiting cytokine production or interfering with adenosine production. Here, the possible antinociceptive effect of FBP and its mechanism of action in the carrageenin paw inflammation model in mice were addressed, focusing on the two mechanisms described above. Experimental approach:, Mechanical hyperalgesia (decrease in the nociceptive threshold) was evaluated by the electronic pressure-metre test; cytokine levels were measured by elisa and adenosine was determined by high performance liquid chromatography. Key results:, Pretreatment of mice with FBP reduced hyperalgesia induced by intraplantar injection of carrageenin (up to 54%), tumour necrosis factor , (40%), interleukin-1 , (46%), CXCL1 (33%), prostaglandin E2 (41%) or dopamine (55%). However, FBP treatment did not alter carrageenin-induced cytokine (tumour necrosis factor , and interleukin-1 ,) or chemokine (CXCL1) production. On the other hand, the antinociceptive effect of FBP was prevented by systemic and intraplantar treatment with an adenosine A1 receptor antagonist (8-cyclopentyl-1,3-dipropylxanthine), suggesting that the FBP effect is mediated by peripheral adenosine acting on A1 receptors. Giving FBP to mice increased adenosine levels in plasma, and adenosine treatment of paw inflammation presented a similar antinociceptive mechanism to that of FBP. Conclusions and implications:, In addition to anti-inflammatory action, FBP also presents an antinociceptive effect upon inflammatory hyperalgesia. Its mechanism of action seems dependent on adenosine production but not on modulation of hyperalgesic cytokine/chemokine production. In turn, adenosine acts peripherally on its A1 receptor inhibiting hyperalgesia. FBP may have possible therapeutic applications in reducing inflammatory pain. [source] Inflammation alters somatostatin mRNA expression in sensory neurons in the ratEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2005Seham A. Abd El-Aleem Abstract Proinflammatory neuropeptides, such as substance P and calcitonin gene-related peptide, are up-regulated in primary afferent neurons in acute and chronic inflammation. While these neuropeptides have been intensively studied, potentially anti-inflammatory and/or anti-nociceptive neuropeptides such as somatostatin (SS) have been less widely investigated. Endogenous somatostatin is thought to exert a tonic antinociceptive effect. Exogenous SS is anti-inflammatory and antinociceptive and is thought to exert these actions through inhibition of proinflammatory neuropeptide release. In this study we have compared the expression of somatostatin in two inflammatory models: arthritis, a condition associated with increased nociception, and periodontitis, in which there is little evidence of altered nociceptive thresholds. In acute arthritis (< 24 h) SS mRNA was down-regulated in ipsilateral dorsal root ganglia (DRG; 52 ± 7% of control, P < 0.05), and up-regulated in contralateral DRG (134 ± 10% of control; P < 0.05). In chronic arthritis (14 days) this pattern of mRNA regulation was reversed, with SS being up-regulated ipsilaterally and down-regulated contralaterally. In chronic mandibular periodontitis (7,10 days), SS mRNA was up-regulated in only the mandibular division of the ipsilateral trigeminal ganglion (TG) (day 7, 219 ± 9% and day 10, 217 ± 12% of control; P < 0.02) but showed no change in other divisions of the trigeminal ganglion or in the mesencephalic nucleus. These data show that antinociceptive and anti-inflammatory neuropeptides are also regulated in inflammation. It is possible that the degree of inflammation and nociception seen may depend on the balance of pro- and anti-inflammatory and nociceptive peptide expression in a particular condition. [source] Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 21JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2003R Bianchi Erythropoietin (EPO) has neurotrophic and neuroprotective effects and its efficacy and safety has been demonstrated in patients with ischemic stroke. We investigated its efficacy in preventing and reversing established nerve disorders in streptozotocin (STZ) diabetes. After STZ injection (60 mg/kg/ip), EPO (5000 units/kg b.w. i.p. three times a week) was started in a group of rats and continued for five weeks (prevention schedule). In another group of diabetic rats, EPO was started six weeks after STZ, continued for five weeks (therapeutic schedule). Groups of non-diabetic control rats were similarly treated. Antidromic nerve conduction velocity (NCV) in the tail was assessed at five weeks for all groups and at 11 weeks for the therapeutic schedule. Compared to non-diabetic rats, NCV was 21% lower (P < 0.001) at five weeks in the STZ group, EPO partially prevented this decrease (14% lower than with non-diabetic controls), with a significant difference from the untreated-diabetic group (P < 0.01). After six weeks of uncontrolled diabetes, at the beginning of therapeutic EPO, NCV was reduced by 23% and after 11 weeks by 40%, EPO efficacy was confirmed. Thermal (hot plate method) and mechanical (Randall-Selitto method) nociceptive thresholds were monitored weekly throughout the study. In addition, in all groups, the density of intra-epidermal nerve fibers, which reflects possible degeneration of somatic unmyelinated fibers, was assessed in the hindpaw using protein-gene-product 9.5 immunostaining. Rats developed mechanical hyperalgesia within two weeks after STZ injection. Both the prevention and therapeutic schedules of EPO reduced diabetic hyperalgesia after two weeks of treatment, reaching statistical significance at fur, and five weeks of treatment, with no such effect in non-diabetic controls. Hindpaw thermal response latencies were significantly (P < 0.001) increased in untreated diabetic rats compared with untreated controls. EPO had no effect on these latencies in control rats but partially prevented the increase in diabetic rats, so the values were still different from controls, but significantly different from untreated diabetics at four and five weeks in both the prevention and therapeutic studies (P < 0.05). These observations extend the therapeutic utility of EPO and highlight its potential for treating established diabetic neuropathies. [source] Stress-Induced Analgesia and Morphine Responses Are Changed in Catechol- O -methyltransferase-Deficient Male MiceBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2008Oleg Kambur It is not clear how the effects of COMT are mediated and only few relevant animal studies have been performed. Here, we used old male Comt gene knock-out mice as an animal model to study the effects of COMT deficiency on nociception that was assessed by the hot plate and tail flick tests. Stress-induced analgesia was achieved by forced swim. Morphine antinociception was measured after 10 mg/kg of morphine subcutaneously. Morphine tolerance was produced with subcutaneous morphine pellets and withdrawal provoked with subcutaneous naloxone. In the hot plate test, morphine-induced antinociception was significantly greater in the COMT knock-out mice, compared to the wild-type mice. This may be due to increased availability of opioid receptors as suggested by previous human studies. In the tail flick test, opioid-mediated stress-induced analgesia was absent and morphine-induced analgesia was decreased in COMT knock-out mice. In the hot plate test, stress-induced analgesia developed to all mice regardless of the COMT genotype. There were no differences between the genotypes in the baseline nociceptive thresholds, morphine tolerance and withdrawal. Our findings show, for the first time, the importance of COMT activity in stress- and morphine-induced analgesia in mice. COMT activity seems to take part in the modulation of nociception not only in the brain, as suggested earlier, but also at the spinal/peripheral level. [source] Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2002A. M. Hughes Aims, The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers. Methods, The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg,1 dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg,1 ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDICTM thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen. Results, Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (,5.52, 4.24) and 11.75 vs 15.25 (,11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively. Conclusions, Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms. [source] | |||||||||||||