Sodium Channel Blocker Lidocaine Research Articles

Intravenous Lidocaine Relieves Spinal Cord Injury Pain

Neuropathic pain in spinal cord injury is a common challenging therapeutic condition. The current study examines the analgesic effect of the sodium channel blocker lidocaine on neuropathic pain in patients with spinal cord injury and the predictive role of concomitant evoked pain on pain relief with lidocaine. Twenty-four spinal cord injury patients with neuropathic pain at or below the level of injury were randomized and completed a double-blind crossover trial of 5 mg/kg lidocaine and placebo infused over 30 min. Twelve patients reported evoked pain, and 12 patients had no evoked pain. Spontaneous and evoked pains were assessed using a visual analog scale and quantitative sensory testing. Lidocaine significantly reduced spontaneous pain in all patients (P < 0.01) and in each of the two groups with (P < 0.01) and without (P = 0.048) evoked pain, with no difference in number of responders (pain reduction > or = 33%) between the patients with (n = 6) and without (n = 5) evoked pain. Lidocaine significantly relieved both at-level and below-level neuropathic pain and decreased brush-evoked dysesthesia but not cold allodynia, pinprick hyperalgesia, or pain evoked by repetitive pinprick. Lidocaine reduced neuropathic pain at and below the level of injury irrespective of the presence or absence of evoked pain. Results are consistent with a central-acting effect of sodium channel blockers acting on neuronal hyperexcitability. Agents (such as anticonvulsants or antiarrhythmics) with sodium channel-blocking properties may be a treatment option for spinal cord injury pain.

Pharmacological characterisation of the rat brachial plexus avulsion model of neuropathic pain

Recently, our laboratory has proposed the avulsion of rat brachial plexus as a new and reliable model for the study of neuropathic pain. In this model, the neuropathy can be detected even at distant sites from the injury, both in ipsilateral and contralateral hindpaws. The purpose of this study was to pharmacologically characterise this behavioural model of persistent peripheral neuropathic pain by assessing the effects of several analgesic drugs currently used in clinical practice. For this purpose, the effects of these drugs on the mechanical and cold allodynia were analysed 20–40 days after rat brachial plexus avulsion. Injection of saline, administered by the same route as the other drugs, did not significantly affect the nociceptive threshold either in sham-operated or in neuropathic rats. However, administration of the opioid analgesic morphine (5 mg/kg, s.c.), the α 2 adrenoceptor agonist clonidine (300 μg/kg, i.p.), the NMDA receptor antagonist ketamine (25 mg/kg, i.p.) or the anticonvulsant drug gabapentin (70 mg/kg, p.o.) consistently reduced both mechanical and cold allodynia following avulsion of rat brachial plexus. The administration of the selective COX-2 inhibitor celecoxib (10 mg/kg, p.o.) blocked mechanical allodynia, but not cold allodynia, whereas the sodium channel blocker lidocaine (40 mg/kg, i.p.) attenuated only cold allodynia. The non-steroidal anti-inflammatory drug diclofenac (100 mg/kg, i.p.), the steroidal anti-inflammatory dexamethasone (1.5 mg/kg, i.p.) and the antidepressant imipramine (10 mg/kg, i.p.) all failed to significantly attenuate both mechanical and cold allodynia in the rats following avulsion of brachial plexus. These findings suggest that avulsion-associated mechanical and cold allodynia, two classic signs of persistent neuropathic pain, were consistently prevented by several analgesics currently available in clinical practice, namely morphine, clonidine, ketamine and gabapentin, and to a lesser extent by celecoxib and lidocaine. Therefore, this new proposed model of persistent nociception seems to be suitable for the study of the underlying mechanisms involved in neuropathic pain and for the identification of potential clinically relevant drugs to treat this aspect of peripheral neuropathy.

Interaction between perirhinal and medial prefrontal cortex is required for temporal order but not recognition memory for objects in rats.

The present study investigated the roles of the perirhinal cortex, medial prefrontal cortex, and intrahemispheric interactions between them in recognition and temporal order memory for objects. Experiment 1 assessed the effects of bilateral microinfusions of the sodium channel blocker lidocaine into either the anterior perirhinal or medial prefrontal cortex immediately before memory testing in a familiarity discrimination task and a recency discrimination task, both of which involved spontaneous exploration of objects. Inactivation of the perirhinal cortex disrupted performance in both tasks, whereas inactivation of the medial prefrontal cortex disrupted performance in the recency, but not the familiarity, discrimination task. In a second experiment, the importance of intrahemispheric interactions between these structures in temporal order memory were assessed by comparing the effects of unilateral inactivation of either structure alone with those of crossed unilateral inactivation of both structures on the recency discrimination task. Crossed unilateral inactivation of both structures produced a significant impairment, whereas inactivation of either structure alone produced little or no impairment. Collectively, these findings suggest that the perirhinal cortex, but not the medial prefrontal cortex, contributes to retrieval of information necessary for long-term object recognition, whereas both structures, via intrahemispheric interactions between them, contribute to retrieval of information necessary for long-term object temporal order memory. These data are consistent with models in which attributed information is stored in posterior cortical sites and supports lower-order mnemonic functions (e.g., recognition memory) but can also be retrieved and further processed via interactions with the prefrontal cortex to support higher-order mnemonic functions (e.g., temporal order memory).

Tedisamil and lidocaine enhance each other's antiarrhythmic activity against ischaemia-induced arrhythmias in rats.

1. Combinations of the action potential-widening drug tedisamil (Class III antiarrhythmic activity), and the inactivated state sodium channel blocker lidocaine (Class Ib antiarrhythmic activity) were assessed for antiarrhythmic actions in a rat model of ischaemia-induced arrhythmias and for electrophysiological actions in normal rat myocardial tissue. 2. Both tedisamil and lidocaine dose-dependently suppressed ischaemia-induced arrhythmias. The ED(50) values were 3.0+/-1.3 and 4.9+/-0.6 micro mol kg(-1) min(-1), respectively. 3. Combinations of the two drugs acted synergistically such that the ED(50) for tedisamil was reduced to 0.8+/-0.2 micro mol kg(-1) min(-1) in the presence of 2 micro mol kg(-1) min(-1) lidocaine. Similarly, the ED(50) for lidocaine was reduced to 0.7+/-0.2 micro mol kg(-1) min(-1) in the presence of 2 micro mol kg(-1) min(-1) tedisamil (both P<0.05). 4. In a separate series of experiments in which normal ventricular tissue was electrically stimulated, 2 micro mol kg(-1) min(-1) lidocaine produced a leftward shift in the dose-response curve for tedisamil's effect on effective refractory period (P<0.05). This dose of lidocaine had no effect on its own. These data indicate that the synergistic actions of combinations of tedisamil and lidocaine were mediated, at least in part, by extension of effective refractory period in normal myocardial tissue. 5. In contrast to the strategy of developing drugs that are selective for a single electrophysiological mechanism, the results of the present study suggest that effective antiarrhythmic drugs might be developed by optimising the combination of two complimentary electrophysiological mechanisms (i.e., action potential-prolonging activity and inactivated state sodium channel blockade).

Independent modulation of basal and feeding-evoked dopamine efflux in the nucleus accumbens and medial prefrontal cortex by the central and basolateral amygdalar nuclei in the rat

Interactions of the central and basolateral nuclei of the amygdala with the mesocorticolimbic dopamine system are implicated in the acquisition and performance of conditioned responses for food reward. This study investigated whether dopamine transmission in the nucleus accumbens and the medial prefrontal cortex of the rat is influenced by the amygdala and if so, to assess the significance of the interaction in free feeding of a palatable food. To this end, we examined the effects of reverse-dialysis of the sodium channel blocker lidocaine into either the central or basolateral on dopamine efflux in the nucleus accumbens and the medial prefrontal cortex as determined by microdialysis and high-pressure liquid chromatography with electrochemical detection. The present results revealed for the first time that inactivation of the central decreased basal levels of dopamine efflux in the nucleus accumbens, but not in the medial prefrontal cortex. Furthermore, administration of lidocaine into the central significantly attenuated feeding-evoked increases in dopamine efflux in both terminal regions. These neurochemical effects were accompanied by feeding-related behaviours akin to the Klüver-Bucy syndrome. In contrast, inactivation of the basolateral affected neither food intake nor dopamine efflux in the nucleus accumbens, but triggered dramatic long-lasting oscillations in dopamine efflux in the medial prefrontal cortex, irrespective of whether food was presented or not. Overall, these findings indicate that the central and basolateral independently modulate dopamine transmission in both terminal regions of the mesocorticolimbic dopamine system. The central, in particular, and its influence on the dopamine system, may be involved in the regulation of food intake.

Additive stimulatory effect of extracellular calcium and potassium on non-transferrin ferric iron uptake by HeLa and K562 cells

We studied the effects of Ca 2+ and K + on non-transferrin iron uptake from ferric citrate complex by HeLa and K562 cells. Uptake experiments in Na-HEPES buffer (137 mM NaCl, 4 mM KCl) showed that extracellular Ca 2+ stimulated the iron uptake. The rate of iron uptake in 4 mM Ca 2+ was about 3–5 times higher than without Ca 2+. The iron uptake in K-HEPES buffer (68 mM NaCl, 75 mM KCl) with a high K + level was transiently stimulated during the first 10 min. The rate of iron uptake for 0.4 mM Ca 2+ was approximately 3 times higher in K-HEPES buffer than in Na-HEPES buffer. The calcium channel blockers verapamil (50 μM) and nifedipine (5 μM) had no effect on the uptake either in control Na-HEPES buffer or after K + stimulation in K-HEPES buffer. The sodium channel blocker lidocaine (50 μM) also had no effect on the uptake of iron in Na-HEPES buffer as well as after K + stimulation. Furthermore, the iron uptake was not significantly affected when Na + in the Na-HEPES and K-HEPES buffers was replaced by isotonic saccharose. We conclude that extracellular calcium per se, and not intracellular calcium or Ca 2+ transport, stimulates ferric iron uptake by both HeLa and K562 cells. A high level of extracellular K + also stimulates the uptake, probably via cell membrane depolarization. Na + is not involved in these stimulations of iron uptake. The transient K + effect and continuous Ca 2+ effect seem to be additive.

Pharmacological involvement of the calcium channel blocker flunarizine in dopamine transmission at the striatum

Single intrastriatal microinjections of 25, 50 and 100 nmol/μl of flunarizine in normal rats produced a dose-dependent turning behavior toward the injected side when they were challenged with apomorphine (1 mg/kg, s.c). This effect was seen at 1, 3 and 7 days following administration of the high dose of flunarizine, but had subsided by 24 h after administration of the intermediate dose; the low dose was ineffective. However, intrastriatal injection of the high dose of flunarizine resulted in a local lesion and thereafter this dose was not used. A similar dose-response relationship was determined for nifedipine, an L-type calcium channel antagonist. Injection of this antagonist did not result in apomorphine-elicited rotational behavior, reflecting its lack of antidopaminergic action. Intrastriatal injections of haloperidol (5 μg/μl), an antagonist of dopamine D 2 receptors, or the sodium channel blocker lidocaine (40 μg/μl), were given in order to compare their effects to those observed with flunarizine. Intracerebral injection of haloperidol produced ipsilateral turning in response to systemic administration of apomorphine given 60 min after. The same response was obtained with the injection of apomorphine 10 min after the injection of intracerebral lidocaine. This effect was no longer apparent 24 h after the microinjection of haloperidol and 60 min after the injection of lidocaine. In rats rendered hemiparkinsionian by lesioning the nigrostriatal pathway with 6OHDA, intrastriatal microinjection of flunarizine (50 nmol/μl) significantly reduced apomorphine (0.2 mg/kg, s.c.)-elicited turning behavior towards the non-lesioned side. These results suggest an antidopaminergic effect of flunarizine mediated by antagonistic action of post-synaptic striatal dopamine receptors. However, an action of the drug on sodium channels may not be ruled out. These studies offer additional supporting evidence for the induction or aggravation of extrapyramidal side-effects in patients receiving flunarizine.

Response to intravenous lidocaine infusion predicts subsequent response to oral mexiletine: A prospective study

The local anesthetic sodium-channel blockers lidocaine and mexiletine reduce spontaneous and evoked activity in experimental neuroma models and have been reported to relieve a variety of clinical neuropathic pain conditions. The predictive value of relief from an intravenous lidocaine infusion (IVL) for subsequent relief from a 4-week trial of oral mexiletine was assessed in a prospective study of nine subjects with chronic neuropathic pain of peripheral origin. Subjects received IVL, 2 mg/kg and 5 mg/kg, over 45 min during separate sessions in random order under double-blind conditions. One week later, a 4-week titrating trial of oral mexiletine was initiated. Both doses of IVL significantly reduced pain visual analogue scores (VAS) scores. Although IVL 5mg/kg produced significantly higher pain relief scores than IVL 2 mg/kg, subjects responded in a highly consistent manner to the two IVL. Subsequent response to oral mexiletine was significantly correlated with the average response to the two IVL. Mexiletine dose and blood levels were not correlated with pain relief. The results suggest that IVL may be a valuable tool in selecting patients for oral therapy with analogous drugs.

Dose-dependent alteration of rat cardiac sodium current by isoproterenol: Results from direct measurements on multicellular preparations

Conflicting results have been reported in literature about the influence of beta-adrenergic stimulation on the fast cardiac sodium current (INa+). To elucidate these mechanisms in multicellular preparations we used the loose-patch-clamp technique to evaluate the effect of the beta-adrenergic agonist isoproterenol 1-1000 nmol/l. Isoproterenol enhanced INa+ at all membrane potentials by elevation of the maximal available INa+ . Only at the high concentration of 1 micromol/l was INa+ slightly depressed after depolarizing conditioning clamps. The most marked increase of the maximal available INa+ was 30+/-9% after application of 100 nmol/l isoproterenol. To learn about the mechanisms in view of sodium channel modulation we combined isoproterenol with the sodium channel blocker lidocaine (47 micromol/l). Under these circumstances the effects of both drugs were completely independent. This investigation shows clearly that low concentrations of isoproterenol increase INa+ in multicellular preparations by a gating-independent mechanism.