Aaron J. Gissen

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 μg/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 μg/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.

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.

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 methyl-prednisolone 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. There was no evidence of an effect of the acidic pH since neither amplitudes nor conduction velocities were affected by the PEG-free Liley solution at pH 6.45 and the degrees of block were the same at pH 7.4 as at the lower pH. Experiments done on desheathed nerves showed no significant change in amplitude or conduction velocity with 3% PEG. Exposure of de-sheathed nerves to the 20, 30, and 40% PEG showed the same degrees of block as the sheathed nerves. We conclude that PEG, in concentration up to 40%, does not cause neurolysis.

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 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 and greater ionization of bupivacaine, which impedes diffusion across the permeability barriers present in fast-conducting A fiber.

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.