Efficacy of mandibular topical anesthesia varies with the site of administration.
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This study compared the threshold of pain sensitivity in the anterior mandibular mucobuccal fold with the posterior. This was followed by a comparison of the reduction of needle insertion pain in the anterior mucobuccal fold and the pterygo-temporal depression by either topical anesthesia or nitrous oxide inhalation. The pain threshold was determined by an analgometer, a pain-measuring device that depends on pressure readings; additionally, pain caused by a needle inserted by a normal technique was assessed using a visual analog scale (VAS). The threshold of pain was significantly lower in the incisor and canine regions than in the premolar and the molar regions (P < 0.001). Compared to a placebo, topical anesthesia significantly reduced the pain from needle insertion in the mucobuccal fold adjacent to the mandibular canine (P < 0.001), but did not significantly reduce pain in the pterygotemporal depression. The addition of 30% nitrous oxide did not significantly alter pain reduction compared to a control of 100% oxygen. These results suggest that topical anesthesia application may be effective in reducing the pain of needle insertion in the anterior mandibular mucobuccal fold, but may not be as effective for a standard inferior alveolar nerve block. The addition of 30% nitrous oxide did not lead to a significant improvement. (+info)
Local anesthetic anchoring to cardiac sodium channels. Implications into tissue-selective drug targeting.
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Local anesthetics inhibit Na+ channels in a variety of tissues, leading to potentially serious side effects when used clinically. We have created a series of novel local anesthetics by connecting benzocaine (BZ) to the sulfhydryl-reactive group methanethiosulfonate (MTS) via variable-length polyethylether linkers (L) (MTS-LX-BZ [X represents 0, 3, 6, or 9]). The application of MTS-LX-BZ agents modified native rat cardiac as well as heterologously expressed human heart (hH1) and rat skeletal muscle (rSkM1) Na+ channels in a manner resembling that of free BZ. Like BZ, the effects of MTS-LX-BZ on rSkM1 channels were completely reversible. In contrast, MTS-LX-BZ modification of heart and mutant rSkM1 channels, containing a pore cysteine at the equivalent location as cardiac Na+ channels (ie, Y401C), persisted after drug washout unless treated with DTT, which suggests anchoring to the pore via a disulfide bond. Anchored MTS-LX-BZ competitively reduced the affinity of cardiac Na+ channels for lidocaine but had minimal effects on mutant channels with disrupted local anesthetic modification properties. These results establish that anchored MTS-LX-BZ compounds interact with the local anesthetic binding site (LABS). Variation in the linker length altered the potency of channel modification by the anchored drugs, thus providing information on the spatial relationship between the anchoring site and the LABS. Our observations demonstrate that local anesthetics can be anchored to the extracellular pore cysteine in cardiac Na+ channels and dynamically interact with the intracellular LABS. These results suggest that nonselective agents, such as local anesthetics, might be made more selective by linking these agents to target-specific anchors. (+info)
Benzocaine enhances and inhibits the K+ current through a human cardiac cloned channel (Kv1.5).
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OBJECTIVE: The aim of this study was to analyze the effects of a neutral local anaesthetic, benzocaine, on a cardiac K+ channel cloned from human ventricle. METHODS: Experiments were performed on hKv1.5 channels stably expressed on mouse cells using the whole-cell configuration of the patch clamp technique. RESULTS: At 10 nM, benzocaine increased the current amplitude ("agonist effect") by shifting the activation curve 8.4 +/- 2.7 mV in the negative direction, and slowed the time course of tail current decline. In contrast, benzocaine (100-700 microM) inhibited hKv1.5 currents (KD = 901 +/- 81 microM), modified the voltage-dependence of channel activation, which became biphasic, and accelerated the channel deactivation. Extracellular K+ concentration ([K+]o) also affected the channel gating. At 140 mM [K+]o, the time course of tail currents deactivation was significantly accelerated, whereas at 0 mM [K+]o, it was slowed. At both [K+]o the activation curve became biphasic. Benzocaine accelerated the tail current decay at 0 mM but not at 140 mM [K+]o. The reduction in the permeation of K+ through the pore did not modify the blocking effects of micromolar concentrations of benzocaine, but suppressed the agonist effect observed at nanomolar concentrations. CONCLUSIONS: All these results suggest that benzocaine blocks and modifies the voltage- and time-dependent properties of hKv1.5 channels, binding to an extracellular and to an intracellular site at the channel level. Moreover, both sites are related to each other and can also interact with K+. (+info)
Selective block of late Na(+) current by local anaesthetics in rat large sensory neurones.
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The actions of lignocaine and benzocaine on transient and late Na(+) current generated by large diameter (> or =50 microm) adult rat dorsal root ganglion neurones, were studied using patch-clamp techniques. Both drugs blocked whole-cell late Na(+) current in a concentration-dependent manner. At 200 ms following the onset of a clamp step from -110 to -40 mV, the apparent K for block of late Na(+) current by lignocaine was 57.8+/-15 microM (mean+/-s.e.mean, n = 4). The value for benzocaine was 24.9+/-3.3 microM, (mean+/-s.e. mean, n = 3). The effect of lignocaine on transient current, in randomly selected neurones, appeared variable (n = 8, half-block from approximately 50 to 400 microM). Half-block by benzocaine was not attained, but both whole-cell (n = 11) and patch data suggested a high apparent K,>250 microM. Transient current always remained after late current was blocked. The voltage-dependence of residual late current steady-state inactivation was not shifted by 20 microM benzocaine (n = 3), whereas 200 microM benzocaine shifted the voltage-dependence of transient current steady-state inactivation by -18.7+/-5.9 mV (mean+/-s.e.mean, n = 4). In current-clamp, benzocaine (250 microM) could block subthreshold, voltage-dependent inward current, increasing the threshold for eliciting action potentials, without preventing their generation (n = 2). Block of late Na(+) current by systemic local anaesthetic may play a part in preventing ectopic impulse generation in sensory neurones. (+info)
Local anesthetic inhibition of m1 muscarinic acetylcholine signaling.
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BACKGROUND: Local anesthetics inhibit lipid mediator signaling (lysophosphatidate, thromboxane) by acting on intracellular domains of the receptor or on the G protein. On receptors for polar agonists, the ligand-binding pocket could form an additional site of interaction, possibly resulting in superadditive inhibition. The authors therefore investigated the effects of local anesthetics on m1 muscarinic receptor functioning. METHODS: The authors expressed receptors in isolation using Xenopus oocytes. Using a two-electrode voltage clamp, the authors measured the effects of lidocaine, QX314 (permanently charged), and benzocaine (permanently uncharged) on Ca2+-activated Cl- currents elicited by methylcholine. The authors also characterized the interaction of lidocaine with [3H] quinuclydinyl benzylate ([3H]QNB) binding to m1 receptors. RESULTS: Lidocaine inhibited muscarinic signaling with a half-maximal inhibitory concentration (IC50 18 nm) 140-fold less than that of extracellularly administered QX314 (IC50 2.4 microm). Intracellularly injected QX314 (IC50 0.96 mm) and extracellularly applied benzocaine (IC50 1.2 mm) inhibited at high concentrations only. Inhibition of muscarinic signaling by extracellularly applied QX314 and lidocaine was the result of noncompetitive antagonism. Intracellularly injected QX314 and benzocaine inhibited muscarinic and lysophosphatidate signaling at similar concentrations, suggesting an action on the common G-protein pathway. Combined administration of intracellularly injected (IC50 19 microm) and extracellularly applied QX314 (IC50 49 nm) exerted superadditive inhibition. Lidocaine did not displace specific [3H]QNB binding to m1 receptors. CONCLUSIONS: m1 Muscarinic signaling is inhibited by clinically relevant concentrations of lidocaine and by extracellularly administered QX314, suggesting that the major site of action is a extracellular domain of the muscarinic receptor. An additional less potent but superadditive inhibitory effect on the G-protein is suggested. (+info)
Modulation of gastric distension-induced sensations by small intestinal receptors.
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Duodenal lipid exacerbates gastrointestinal sensations during gastric distension. Using luminal application of the local anesthetic benzocaine, we investigated the role of intestinal receptors in the induction of these sensations. Nine healthy subjects were studied on five occasions, during which isotonic saline or 20% lipid (2 kcal/min), combined with (duodenal or jejunal) 0.75% benzocaine or vehicle at 2.5 ml/min, was infused intraduodenally before and during gastric distension. Intragastric pressures and volumes, gastrointestinal sensations, and plasma CCK levels were determined. Duodenal lipid combined with vehicle increased gastric volume (in ml: saline, -10 +/- 18; lipid/vehicle, 237 +/- 30) and plasma CCK [mean levels (pmol/l): saline, 2.0 +/- 0. 2; lipid/vehicle, 8.0 +/- 1.6] and, during distensions, induced nausea (scores: saline, 3 +/- 2: lipid/vehicle, 58 +/- 19) and decreased pressures at which fullness and discomfort occurred. Duodenal but not jejunal benzocaine attenuated the effect of lipid on gastric volume, plasma CCK, and nausea during distension (135 +/- 38 and 216 +/- 40 ml, 4.6 +/- 0.6 pmol/l and not assessed, and 37 +/- 12 and 64 +/- 21 for lipid + duodenal benzocaine and lipid + jejunal benzocaine, respectively) and on pressures for sensations. In conclusion, intestinal receptors modulate gastrointestinal sensations associated with duodenal lipid and gastric distension. There is also the potential for local neural mechanisms to regulate CCK release and thereby reduce afferent activation indirectly. (+info)
Inhibition of m3 muscarinic acetylcholine receptors by local anaesthetics.
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1. Muscarinic m1 receptors are inhibited by local anaesthetics (LA) at nM concentrations. To elucidate in more detail the site(s) of LA interaction, we compared these findings with LA effects on m3 muscarinic receptors. 2. We expressed receptors in Xenopus oocytes. Using two-electrode voltage clamp, we measured the effects of lidocaine, QX314 (permanently charged) and benzocaine (permanently uncharged) on Ca(2+)-activated Cl(-)-currents (I(Cl(Ca))), elicited by acetyl-beta-methylcholine bromide (MCh). We also characterized the interaction of lidocaine with [(3)H]-quinuclydinyl benzylate ([(3)H]-QNB) binding to m3 receptors. Antisense-injection was used to determine the role of specific G-protein alpha subunits in mediating the inhibitory effects of LA. Using chimeric receptor constructs we investigated which domains of the muscarinic receptors contribute to the binding site for LA. 3. Lidocaine inhibited m3-signalling in a concentration-dependent, reversible, non-competitive manner with an IC(50) of 370 nM, approximately 21 fold higher than the IC(50) (18 nM) reported for m1 receptors. Intracellular inhibition of both signalling pathways by LA was similar, and dependent on the G(q)- protein alpha subunit. In contrast to results reported for the m1 receptor, the m3 receptor lacks the major extracellular binding site for charged LA. The N-terminus and third extracellular loop of the m1 muscarinic receptor molecule were identified as requirements to obtain extracellular inhibition by charged LA. (+info)
Clinical effectiveness of lidocaine and benzocaine for topical anesthesia.
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The effectiveness of lidocaine and benzocaine in reducing pain produced by needle insertion into the palate was evaluated in a double-blind and placebo-controlled study using a more suitable method. Twenty subjects, 10 men and 10 women, submitted to 4 sessions in which they were randomly treated with 5% lidocaine, a placebo that tasted like lidocaine, 20% benzocaine, and a placebo that tasted like benzocaine. At each session, a 27-gauge needle was inserted into the palate twice, once before (baseline) and once after drug application for 1 minute. Immediately after each insertion, subjects indicated on a visual analog scale the pain intensity perceived. Lidocaine and benzocaine were equally efficient, and both were better than placebo in reducing pain caused by insertion of needles into the palate. (+info)