Developmental neurophysiology of mammalian peripheral nerves and age-related differential sensitivity to local anaesthetic.

Using an in vitro nerve preparation, we have studied the relative electrophysiological properties of myelinated and unmyelinated nerve fibres in the vagus nerve of 1-, 9- and 36-month-old rabbits and their sensitivity to local anaesthetic. The baseline (values before infusion of local anaesthetic) mean amplitude and conduction velocity (CV) of the compound action potential (APc) were recorded and the nerve was exposed to a range of concentrations (0.5-4.0 mmol litre-1) of lignocaine for periods sufficient to attain equilibrium block. There was an increase in the amplitude of the A fibre elevation from the 1-month to the 9- and 36-month-old rabbits. The CV of the A and B fibres increased significantly with age, while the CV of the C fibres did not change. The ED50 values of lignocaine for reduction of the A fibre elevation in the 1-, 9- and 36-month-old rabbits were 0.66, 0.94 and 0.85 mmol litre-1, respectively. The respective values for the B fibres were 0.74, 1.21 and 0.82 mmol litre-1, while those of the C fibres were 1.50, 2.44 and 2.07 mmol litre-1. In general, nerves from young and old rabbits were more sensitive to local anaesthetic-induced conduction blockade, suggesting that smaller doses of local anaesthetic are required clinically for anaesthesia in paediatric and older age groups.

Effects of fentanyl and sufentanil on peripheral mammalian nerves.

The effects of fentanyl and sufentanil on peripheral nerves were evaluated in isolated sheathed and desheathed rabbit vagus nerves. The action potential amplitudes of A and C fibers were recorded before and after a 30-min exposure to 50 and 100 micrograms/ml of fentanyl and sufentanil. A reversible decrease in the action potential amplitude of A fibers in desheathed nerves was observed after exposure to 100 micrograms/ml of each drug. The action potential amplitude of C fibers was also decreased but not to the same degree as was the A fiber action potential. Pretreatment with naloxone failed to block the reduction in action potential amplitude produced by the two opiates. No evidence of irreversible conduction blockade indicative of local neural toxicity was seen in these studies. The results suggest that high concentrations of fentanyl and sufentanil may exert a weak local anesthetic-type action on peripheral nerves.

The effect of polyethylene glycol on mammalian nerve impulses.

Polyethylene glycol (PEG) is a polymeric compound used as a vehicle for depot steroid preparations such as methylprednisolone acetate and triamcinolone diacetate injected into the epidural or intrathecal space to relieve low back pain. There have been reports of neurodysfunction associated with these injections, and it has been postulated that the PEG vehicle is the offending agent. Studies supporting such a possibility have, however, relied upon concentrations of PEG higher than those used clinically (3%) or have used PEG in combination with other drugs. Using an in vitro rabbit sheathed-nerve preparation, we investigated the effects of a 1-hr exposure to different concentrations (3-40%) of PEG in Liley solution on the transmission of impulses of the A, B, and C nerve fibers. The 3% and 10% PEG had no effect on mean amplitudes of the compound action potentials (CAPs) nor did they significantly decrease conduction velocity. Twenty percent PEG slightly depressed and 30% markedly decreased CAPs. Both 20% and 30% PEG significantly slowed the conduction velocities of A, B, and C nerve fibers. Forty percent PEG abolished CAPs. With washout CAPs recovered to at least 80% of their baseline levels, and conduction velocities returned toward baseline levels. The pH of the Liley solution decreased with an increasing concentration of PEG, from 7.4 in the control Liley solution to 6.45 in the solution of 40% PEG.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential nerve blockade: esters v. amides and the influence of pKa.

The in vitro sensitivities to local anaesthetic blockade of A, B and C fibres in rabbit vagus nerves were examined using a series of structurally similar amide agents, which varied in lipid solubility and anaesthetic potency. The actions of these drugs were compared with one another, and with those of a series of amino-ester local anaesthetics studied previously. The results demonstrated that A fibres are the most, and C fibres the least, sensitive to blockade by local anaesthetic agents. As with the ester drugs, equipotent concentrations of the amides blocked C fibres at approximately the same rate, but the absolute and relative rates of development of A fibre blockade were related to lipid solubility. As the latter increased, so did the rate of A fibre blockade. Combining the results of the two studies suggests that an agent of low lipid solubility and high pKa might be used to produce differential C fibre blockade. Comparison of the results obtained with the two different classes of drug indicates that the ester structure may have an inherently more potent action than the amide.

Effect of pregnancy on bupivacaine-induced conduction blockade in the isolated rabbit vagus nerve.

Bupivacaine-induced conduction blockade of A, B, and C fibers of the isolated vagus nerve was compared in fourteen pregnant and fourteen nonpregnant rabbits. After a control period in HEPES-Liley solution, the isolated nerves were exposed to bupivacaine concentrations of 0.1 mM to 1.0 mM. After 30 min exposure, the nerves were stimulated supramaximally and the percent reduction in amplitude of A, B, and C fiber compound action potentials was recorded. Linear regressions were fitted by the least squares method. The A fiber conduction blockade was consistently greater in the nerves from pregnant rabbits (P less than 0.001). The slope of the C fiber dose-response curves was also significantly greater in nerves from pregnant rabbits (P less than 0.01). The results indicate that the response of isolated nerves from pregnant animals to local anesthetic-induced conduction blockade differs from that of nerves from nonpregnant animals. However, it is not certain whether the difference is related simply to a more rapid diffusion and shorter onset of block or an enhanced sensitivity of the nerve membrane during pregnancy.

Differential nerve blocking activity of amino-ester local anaesthetics.

The in vitro sensitivities to local anaesthetic blockade of A, B and C nerve fibres in rabbit vagus nerves were examined using a series of structurally similar amino-ester agents which varied in lipid solubility and anaesthetic potency. A fibres were found to be the most sensitive and C fibres the least sensitive to conduction blockade with all the agents, provided that equilibrium blockade was allowed to develop. A correlation existed between the intrinsic anaesthetic potency of the various agents and their lipid solubilities. Equipotent concentrations of the drugs blocked C fibres at approximately the same rate, but there were marked variations in the rate at which A fibres were blocked. Amethocaine, an agent of high lipid solubility, blocked A fibres more quickly than C. As lipid solubility decreased through the series studied, so the onset of conduction blockade of A fibres was prolonged. It is suggested that this related to decreasing ability to penetrate the lipid diffusion barriers around A fibres. The traditional view that C fibres were more sensitive to block may have arisen because of confusion between absolute sensitivity and rate of development of conduction blockade.

Differential sensitivities of mammalian nerve fibers during pregnancy.

The onset of conduction blockade in the vagus nerve of pregnant and nonpregnant rabbits was studied utilizing an in vitro sheath nerve preparation. The time required for 50% depression of the action potential (AP) of A, B, and C vagal fibers from five pregnant and six nonpregnant animals was determined after the application of bupivacaine (0.35 mM). The onset of conduction block occurred in 6.7-12.1 min in the A, B, and C fibers from pregnant animals compared to onset times of 17.9-31.6 min in nerves taken from nonpregnant rabbits. The difference in onset time for each type of nerve fiber from pregnant and nonpregnant animals was highly significant. The results suggest either an increased sensitivity of nerve fibers from pregnant animals to bupivacaine or an enhanced diffusion of the bupivacaine to the membrane receptor site. Mechanical factors are clearly not responsible for the observed results. Hormonal factors may play a role in the decreased anesthetic latency, because progesterone levels were significantly higher in the pregnant animals.

Differential sensitivity of fast and slow fibers in mammalian nerve. II. Margin of safety for nerve transmission.

In a previous study it was found that concentrations of local anesthetics required to block large, fast-conducting nerve fibers were lower than those required to block small, slow-conducting fibers. The present study was instituted to evaluate the margin of safety for transmission in large versus small nerve fibers, the margin of safety being defined as the ratio between the magnitude of the action potential and the magnitude of the critical membrane potential. The effect of reducing the sodium-activating current, which reduces the magnitude of the action potential by sodium deficient solutions and tetrodotoxin application to the desheathed rabbit vagus nerve trunk (in vitro), was examined. Anode block (another method of reducing sodium current) is also discussed. In all instances, the margin of safety for transmission was greater in small, slow fibers than in large, fast fibers. The variations seen in nerve response to tetrodotoxin application are explained by the presence of nerve fiber diffusion barriers; the large fibers show more diffusion protection than the small fibers. Onset, duration, and intensity of differential nerve blockade by drugs reflect a balance between diffusion barriers and axon membrane sensitivity.

Differential sensitivity of fast and slow fibers in mammalian nerve. III. Effect of etidocaine and bupivacaine on fast/slow fibers.

Etidocaine and bupivacaine are long acting local anesthetics with contrasting effects on motor and sensory function. The effect of these drugs on fast-conducting (large, motor) and slow-conducting nerve fibers (small, pain) in the isolated rabbit vagus nerve was examined. Both drugs had an equivalent effect on slow fibers. Etidocaine had a short latency and bupivacaine a prolonged latency of effect on fast fibers. During this long latency of effect by bupivacaine on fast fibers, only the slow fibers were blocked. This period of differential effect on fast and slow fibers is believed to be the explanation for the early effect of bupivacaine on pain fibers followed by a later block of motor function. This difference is believed to be due to the lower lipid solubility solubility and greater ionization of bupivacaine, which impedes diffusion across the permeability barriers present in fast-conducting A fiber.

Differential sensitivities of mammalian nerve fibers to local anesthetic agents.

The differential sensitivities of mammalian nerve fibers to various local anesthetic agents were investigated. Lidocaine, tetracaine, etidocaine, and bupivacaine demonstrated a consistent pattern of conduction blockade in which the large fast-conducting A fibers were blocked at the lowest drug concentration, the intermediate B fibers were blocked at a higher drug concentration, and the smallest, slowest-conducting C fibers required the highest drug concentration for conduction blockade. A comparison of procaine, chloroprocaine, cocaine, tetrodotoxin and saxitoxin on B and C fibers showed similar effects. These findings indicate that local anesthetic agents are similar to other biological stress modalities in terms of their differential effects on nerve fibers of various sizes and conduction velocities, i.e., the large fast-conducting fibers are more susceptible to conduction blockade than are the smaller, slower-conducting fibers. Discrepancies between results of this study and previous reports in the literature are discussed.

Decamethonium and serum potassium in man.

Decamethonium and succinylcholine were used to study the effects of depolarizing muscle relaxants on serum potassium in 60 patinets, free of neuromuscular disease, during major orthopedic surgery. Significant increases in serum K+ were found after administration of decamethonium or succinylcholine in the usual clinical doses. The abnormal elevations of serum K+ found in patients with burns, massive trauma, or muscle denervation are thus accentuations of the process that occurs in normal man following use of these depolarizing drugs. The administration of any depolarizing agent to these abnormal patient groups would, therefore, appear contraindicated.