Tufan Mert

Comparison of nerve conduction blocks by an opioid and a local anesthetic

The experiments were done on frog sciatic nerves, using a sucrose-gap recording technique. The aim of our study was to investigate and to compare the tonic and phasic conduction blocking potency of tramadol and lidocaine on whole nerve and their interactions with Ca(2+). The concentration of a tramadol solution producing the same amount of tonic and phasic conduction blocks was three and six times higher than that needed for lidocaine, respectively. Increasing the Ca(2+) concentration in the test solution enhanced the conduction blocking potency of tramadol, but decreased that of lidocaine. It is concluded that tramadol blocks nerve conduction like a local anesthetic but with a weaker effect than that of lidocaine. Interactions of Ca(2+) and these drugs suggested that these drugs might have either different binding sites or different action mechanisms.

Macrophage depletion delays progression of neuropathic pain in diabetic animals

Despite the fact that it is a frequent diabetic complication, the mechanisms underlying the manifestation of diabetic neuropathic pain remain poorly understood. In this study, we hypothesized that the depletion of peripheral macrophages with liposome-encapsulated clodronate (LEC) can prevent, at least delay, the progression of diabetes-induced neuropathic pain. Therefore, the aim of this study was to evaluate the effects of macrophage depletion on mechanical allodynia and thermal hyperalgesia in the streptozotocin (STZ)-induced rat model of diabetic neuropathy. LEC was intravenously administrated to rats three times with 5-day intervals. A single intravenous injection of STZ caused an increase in the average blood glucose levels and a decrease in body weight. Although LEC treatment did not affect the body weight gain, the blood glucose level was lower and serum insulin level higher in LEC-treated diabetic rats than in that of diabetic rats. In addition, LEC treatment alleviated the excessive damage in beta cells in diabetic rats. Diabetic animals displayed marked mechanical allodynia and thermal hyperalgesia. While the treatment of diabetic rats with LEC did not significantly change the thermal withdrawal latency, diabetes-induced decrease in mechanical paw withdrawal threshold was significantly corrected by the LEC treatment. The results of this study show that thermal hyperalgesia and mechanical allodynia induced by diabetes may be associated with alterations in blood glucose level. Depletion of macrophages with LEC in diabetic rats may reduce mechanical allodynia without affecting thermal hyperalgesia. Taken together, these results suggested that depletion of macrophages in diabetes may partially postpone the development of diabetic neuropathic pain.

Differential effects of lidocaine and tramadol on modified nerve impulse by 4-aminopyridine in rats

We have used the sucrose gap method to measure the effects of drugs on the electrophysiological properties of rat sciatic nerves. The results showed that 4-aminopyridine produced a slight conduction block, prolonged the duration of action potential, enhanced the hyperpolarizing afterpotential, and elicited a hump that followed the action potential. In the presence of 4-aminopyridine, the impulse-blocking activity of lidocaine and tramadol was enhanced. Both lidocaine and tramadol effectively depressed the delayed depolarization generated by 4-aminopyridine. While tramadol decreased the activity-evoked hyperpolarizing afterpotentials, lidocaine completely removed them. These findings indicate that lidocaine may be more effective in blocking the Na+ channels than tramadol. Tramadol may be more effective on the delayed rectifier K+ channels than lidocaine.

Neurobiological effects of pulsed magnetic field on diabetes‐induced neuropathy

In the clinic, although several pharmacological agents or surgical procedures are used to treat diabetes and diabetes-induced neuropathic pain, their success has been limited. Therefore, development of different alternatives in treatments is very important. The purpose of this study was to determine the efficacy of pulsed magnetic field (PMF) in improving signs and symptoms of diabetic neuropathy. In this study, the effects of PMF treatment were investigated in Streptozotocin (STZ)-induced acute and chronic diabetic rats by measuring the thermal latencies, mechanical thresholds, whole blood glucose levels and body weights. After STZ administration to rats, blood glucose level elevated and body weight decreased. Although PMF treatment did not affect changes in body weight, the blood glucose levels of PMF-treated diabetic rats exhibited a decrease during the treatments. Diabetic animals displayed marked decrease in mechanical thresholds and thermal latencies. While treatment of PMF partially restored the mechanical thresholds and thermal latency in acute diabetic rats, PMF caused a corrective effect on only mechanical threshold of chronic diabetic rats. These results suggested that treatment of PMF can potentially ameliorate the painful symptoms of diabetes, such as hyperalgesia and allodynia, by partially preventing the hyperglycemia.

Changes in electrophysiological properties of regenerating rat peripheral nerves after crush injury

The conduction of action potential in peripheral nerves requires the coordinated opening and closing of Na(+) and K(+) channels. In the present study, we used the sucrose-gap recording technique to determine the electrophysiological changes of the regenerating nerves after sciatic nerve injury by using 4-aminopyridine (4-AP) and tetraethylammonium (TEA), and lidocaine. 4-AP enhanced the amplitude and duration of the compound action potentials (CAPs) of regenerating sciatic nerve 15 days post crush (15 dpc), and elicited delayed depolarizations (Del-dep) in 38 dpc and intact groups. Hyperpolarizing afterpotentials elicited by 4-AP were completely removed by TEA in both 15 and 38 dpc. Lidocaine effectively blocked the CAP amplitude. This blockage was more pronounced in 15 dpc than 38 dpc. This agent also exhibited a partial blockage on the Del-dep amplitude. These results may indicate that the changes in the activities of 4-AP- and TEA-sensitive K(+) channels and slow Na(+) channels may play critical roles in nerve excitability and conduction.

Anti-inflammatory and Anti-nociceptive Actions of Systemically or Locally Treated Adipose-Derived Mesenchymal Stem Cells in Experimental Inflammatory Model

ABSTRACTCell-based therapies using mesenchymal stem cells provide hopeful results. Therefore, in this present study, possible anti-inflammatory and anti-nociceptive actions of locally or systemically treated adipose-derived mesenchymal stem cells (ADMSCs) investigated in experimental inflammation model. ADMSCs were isolated from a male Wistar rat under anesthesia, and then they were cultured and expanded for transplantation in all the experimental animals. Effects of intraperitoneal or intraplantar ADMSC treatments on the hallmarks of the inflammatory nociception, such as hyperalgesia, allodynia, edema, and several biochemical parameters were investigated using a well-established carrageenan (CG)-induced hindpaw inflammation model in male rats. Both local and systemic ADMSC treatment increased the latencies, thresholds, and the development of edema in a time-dependent manner. In addition, administration of ADMSC suppressed the increased level of interleukin (IL)-1β, IL-6, and nitric oxide (NO), but further enhanced that of IL-10. Locally treated ADMSC at inflammatory sites effectively suppressed the CG-induced inflammatory responses when compared to the intraperitoneal route of administration. Findings suggest that therapeutic potential of ADMSC can change depending on its route of administration. Local ADMSC treatments may suppress the development of inflammatory-nociception and edema by decreasing the production of pro-inflammatory cytokines and NO level and increasing the anti-inflammatory cytokine production at inflammatory sites.

Role of Potassium Channels in the Frequency-Dependent Activity of Regenerating Nerves

After a peripheral nerve injury, ion channel organization and the electrical properties of nerve fibers drastically change during the regeneration process. The present study was designed to compare the frequency-dependent characteristics of regenerating nerves in the presence of 4-aminopyridine (4-AP) and tetraethylammonium (TEA). The results showed that increasing the stimulus frequency produced a greater impulse blockade (frequency-dependent block – FDB) and distinct hyperpolarizing afterpotentials (HAPs) in regenerating nerves. In particular, regenerating sciatic nerves 15 days post-crush (dpc) were more sensitive to the frequency-dependent stimulations than 38-dpc and intact nerves in the presence or absence of drugs. The frequency-dependent effects of TEA on the compound action potentials (CAPs) appeared when TEA was applied to 4-AP-treated nerves. This shows that TEA-sensitive channels may not be masked by the myelin. 4-AP was here found to have more pronounced frequency-dependent effects on regenerating nerves than on intact nerves. Delayed depolarization (in 38-dpc: 22.6 ± 1.3 mV and 47.52 ± 3.63 ms, in intact: 12.0 ± 1.9 mV and 88.51 ± 4.72 ms) elicited by 4-AP resulted in an increase in FDBs and HAP amplitudes. These results suggest that 4-AP-sensitive channels may play important roles in frequency-dependent nerve conduction. Consequently, regenerating or myelin damaged nerves are more sensitive to repetitive firing with or without drug. An understanding of the frequency-dependent properties of regenerating nerves may be of value in the treatment of the nerve diseases.

Modulating actions of NMDA receptors on pronociceptive effects of locally injected remifentanil in diabetic rats

BACKGROUND In this study, we investigated the effects of locally (intraplantar) applied remifentanil, a μ opioid receptor agonist, to the paws and tested whether locally N-methyl d-aspartate (NMDA) receptors agonist or antagonist can modify remifentanil-induced effects in diabetic rats. METHODS Effects of locally (intraplantar) remifentanil, NMDA and MK801 or their combinations were investigated by measuring the latencies, thresholds and two biochemical parameters (malondialdehyde (MDA) and nitric oxide (NO)), in streptozotocin induced diabetic rats. RESULTS Diabetic rats exhibited hyperalgesia and allodynia and remifentanil treatment aggravated the hyperalgesia and allodynia. The hyperalgesic and allodynic effects of remifentanil decreased in diabetic rats as compared to healthy rats. MK801 suppressed the hyperalgesic and allodynic actions of remifentanil in diabetic rats. However, hyperalgesic and allodynic actions of NMDA increased in diabetic rats. In contrast to age matched group, the combination of NMDA and remifentanil did not produce synergistic actions in diabetic rats. The levels of MDA and NO in the paw tissues of the diabetic rats significantly increased. MK801 significantly decreased NO levels, but not MDA, in diabetic rats. CONCLUSIONS The hyperalgesic and allodynic actions of locally treated remifentanil may decrease in diabetic conditions. Increases in NMDA receptors activation, reactive oxygen species production and NO release may modify the sensitivity to remifentanil in diabetes induced neuropathic pain states.

Pain-relieving effects of pulsed magnetic fields in a rat model of carrageenan-induced hindpaw inflammation

Abstract Purpose: Many strategies have been investigated to exclude the several side-effects of pharmacological or invasive treatments. Non-invasive pulsed magnetic field (PMF) treatment with no toxicity or side-effects can be an alternative to pharmacologic treatments. The purpose of this study was, therefore, to investigate the pain-relieving effects of PMF treatment in the inflammatory pain conditions. Materials and methods: Effects of PMF treatment on the hallmarks of the inflammatory pain indices such as hyperalgesia, allodynia, edema and several biochemical parameters that evaluate oxidative stress were investigated using a well established carrageenan (CAR)-induced hindpaw inflammation model in rats. Results: CAR injection lowered the paw withdrawal thermal latencies (hyperalgesia) and mechanical thresholds (allodynia). CAR also decreased the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels and increased malondialdehyde (MDA) levels compared with healthy rat paw tissues. PMF treatment produced significant increases in the thermal latencies and mechanical thresholds in CAR-injected paws. In the inflamed paw tissues, PMF increased the activities of SOD, CAT and GPx and decreased MDA level. We also demonstrated that PMF decreased paw mass indicating that it has an anti-edematous potential. Conclusions: The present results reveal that PMF treatment can ameliorate the CAR-induced inflammatory pain indices such as mechanical allodynia, thermal hyperalgesia and edema, and attenuate the oxidative stress. The action mechanisms of PMF in CAR-induced inflammation might be related to the increases in the levels of antioxidant enzymes in inflamed tissues. The findings suggest that PMF treatment might be beneficial in inflammatory pain conditions.

Comparison of actions of systemically and locally administrated local anaesthetics in diabetic rats with painful neuropathy.

Nothing is known about actions of levobupivacaine, a long‐acting local anaesthetic belonging to the amino amide group, in diabetes‐induced neuropathic pain conditions. In this study, we therefore investigated the possible antihyperalgesic and antiallodynic effects of levobupivacaine in diabetic animal model. Actions of systemically (intraperitoneal) or locally (intraplantar) administrated levobupivacaine on streptozotocin‐induced diabetic rats with painful neuropathy were examined using a thermal plantar test and a dynamic plantar aesthesiometer. Effects of levobupivacaine were compared with those of a well‐known amide local anaesthetic lidocaine. Levobupivacaine was more potent than lidocaine in all tests employed on diabetic rats. After intraperitoneal injections to diabetic rats, levobupivacaine, but not lidocaine, produced pronounced antihyperalgesic and antiallodynic effects. However, intraplantar administration of both levobupivacaine and lidocaine produced antihyperalgesic and antiallodynic action in diabetic rats. In contrast to the transient effects of lidocaine (30 min), antihyperalgesic and antiallodynic actions of levobupivacaine gradually disappeared within 120 min after intraplantar injections. Intraperitoneal or intraplantar administrations of levobupivacaine or lidocaine at the effective dose had no effect on any parameters in intact rats. Findings revealed that antiallodynic and antihyperalgesic potency of levobupivacaine was higher in comparison with that of lidocaine after their intraperitoneal or intraplantar administration to diabetic animals. Furthermore, locally administrated levobupivacaine has the greatest antihyperalgesic and antiallodynic actions in diabetic rats.