Rhythm transformation in nerve fibers by local anesthetics: From biophysics of sodium channels to physiology of anesthesia

The review considers the basic stages in the study of rhythm transformation in the nerve fibers by local anesthetics and underlying use-dependent block of sodium channels. A potency of use-dependent local anesthetics to produce the rhythm transformation in nociceptive nerve fibers sufficient to attain local anesthesia without complete block of conduction was examined. A hypothesis was tested on attaining the conditions of local anesthesia by a decrease in discharge frequency of C-fiber nociceptors below the critical level separating the firing frequency in these sensors corresponding to their excitation with subnociceptive and nociceptive chemical stimuli. This critical level (about 2 Hz) was determined by comparison of the discharges in feline cutaneous C-fiber nociceptors during injection of chemical nociceptive and non-nociceptive stimuli. The discharge frequency in C-fiber nociceptors can be decreased in a use-dependent manner below the critical level by subcutaneous injection of lidocaine or N-propyl-ajmaline. The importance of use-dependent local anesthesia for preservation of trophic influences of the nervous system in the damaged tissue is discussed.     

Permeability of axon membranes to local anesthetics

The permeability of the neutral form of tertiary amine local anesthetics across squid axon membranes was studied by utilizing three different experimental methods: (1) narcotic action of axon excitability was measured by monitoring the time derivative of action potential and the results were analyzed in terms of a diffusion reaction equation of local anesthetics to obtain their permeabilities; (2) the influx of local anesthetic into the axon was measured by use of the radioisotope tracer technique; and (3) the desorption rates of the neutral form of local anesthetics from lipid monolayers were measured and the desorption rate was correlated with permeability.The relative permeabilities obtained for procaine, lidocaine and tetracaine by the above three methods were comparable. The order of relative permeabilities was $\text{procaine}\text{>}\text{lidocaine}\text{>}\text{tetracaine}$, and had an inverse correlation with the partition coefficients of anesthetics at oil/water phases. Some discussion concerning the concept of permeability is made when the partition coefficient of a permeant molecule is high.     

Binding of spin-labeled local anesthetics to lobster nerves

Summary The hyperfine coupling constant of spin-labeled local anesthetics, 2-(N-methyl N-(2,2,6,6-tetramethylpiperidinooxyl)) ethyl 4-alkoxybenzoates, showed these compounds to partition betwen the aqueous exterior and the hydrocarbon phase of the membrane. Increased partitioning into the hydrocarbon phase of the membrane was in the order: hexyloxy>butoxy>ethoxy. Since these compounds are known to have different durations of anesthesia in the same order, this suggests that durations of activity and ability to partition into the hydrocarbon region of the membrane are related.     

Renal impairment and analgesia: From effectiveness to adverse effects

Kidney pain is one of the clinically significant features of renal dysfunction. Mild to severe pain is seen in the lower back area. Painkillers are mostly recommended in these cases to relieve the symptom. Yet, several analgesics are associated with side effects that can worsen the state of the disease. This review is based on the studies conducted in these aspects analgesics used to treat kidney pain and their effectiveness, renal consequences of postoperative analgesia, and pharmacogenetics of these palliatives are briefly summarized in this paper.     

Biochemical aspects of the action of local anesthetics

Notions on the molecular mechanisms of anesthesia are presented. The chemical characteristics are given for main representatives of certain groups of local anesthetics with peculiarities of their membrane-tropic action mentioned. The effect of local anesthetics on the synaptic transmission, membrane enzymes, ion transport through the cell membranes is considered simultaneously with the anesthesia phenomenon on the basis of the data available in literature and results of the authors' investigations.     

Therapeutic peptides: Targeting the mitochondrion to modulate apoptosis

For many years, medical drug discovery has extensively exploited peptides as lead compounds. Currently, novel structures of therapeutic peptides are derived from active pre-existing peptides or from high-throughput screening, and optimized following a rational drug design approach. Molecules of interest may prove their ability to influence the disease outcome in animal models and must respond to a set of criteria based on toxicity studies, ease of administration, the cost of their synthesis, and logistic for clinical use to validate it as a good candidate in a therapeutic perspective. This applies to the potential use of peptides to target one central intracellular organelle, the mitochondrion, to modulate (i.e. activate or prevent) apoptosis. Putative mitochondrial protein targets and the strategies already elaborated to correct the defects linked to these proteins (overexpression, inactivation, mutation..., etc.) are described, and recent advances that led or may lead to the conception of therapeutic peptides via a specific action on these mitochondrial targets in the future are discussed.     

Binding of spin-labeled local anesthetics to phosphatidylcholine and phosphatidylserine liposomes

A homologous series of spin-labeled local anesthetics, 2-[N-methyl N-(2,2,6,6-tetramethylpiperidinooxyl)] ethyl-p-alkoxybenzoates were shown to bind to phosphatidylcholine and phosphatidylserine liposomes. Under similar conditions, 70% of the ethoxy homolog (R2C) of these spin-labeled local anesthetics bound to synthetic dipalmitoyl lecithin while 98% bound to phosphatidylserine liposomes. Five percent of R2C's bound signal could be released by 4 mm calcium from phosphatidylserine liposomes, but calcium had no effect on R2C bound to synthetic lecithin. The butoxy (R4C) and hexyloxy (R6C) homologs bound to phosphatidylcholine in the order R6C > R4C. All of R6C and all of R4C were bound to phosphatidylserine liposomes, while only 90% of R6C bound to synthetic dipalmitoyl lecithin. Calcium was incapable of displacing bound R4C or R6C from either phosphatidylcholine or phosphatidylserine liposomes. The results are discussed in light of anesthetic binding by electrostatic and Van der Waal's forces to phospholipids.     

Effects of local anesthetics on the Chara plasmalemma.

The effects of lidocaine, tetracaine, procaine and bupivacaine (less than 1000 microM) on the Chara corallina internodal cell were studied. These local anesthetics depolarized the membrane at rest, while they affected the rising phase and the peak level of action potential not appreciably. Instead, they prolonged the time course of the falling phase of action potential as slowly as the repolarization was imperfect, even after enough lapse beyond the refractory period. Consequently, an action potential appeared to enhance the degree of depolarization at rest. Such a depolarization with stimulus/excitation was named use-dependent depolarization, while the depolarization without excitation, the resting one. The order of the potency of the use-dependent depolarization almost coincided with that of the nerve-blocking potency. During depolarization the change in membrane conductance was not simple. However, the conductance-voltage (Gm-Vm) relationship curve in the presence of local anesthetic suggested that depolarization was due to, not only the decrease in the electrogenic H(+)-pump, but also the increase in the diffusion conductance.     

Invited review: the mitochondrion in osteoarthritis

In a variety of tissues, cumulative oxidative stress, disrupted mitochondrial respiration, and mitochondrial damage promote aging, cell death, and ultimately, functional failure and degeneration. Because articular cartilage chondroyctes are highly glycolytic, mitochondrially mediated pathogenesis has not been previously applied in models for pathogenesis of osteoarthritis (OA), a cartilage degenerative disease that increases markedly in aging. However, chondrocyte mitochondria respire in vitro and they demonstrate swelling and changes in number in situ in the course of OA. Normal chondrocyte mitochondrial function is hypothesized to critically support adenosine triphosphate (ATP) reserves in functional stressed chondrocytes during OA evolution. In this model, disruption of chondrocyte respiration by nitric oxide, a mediator markedly up-regulated in OA cartilage, is centrally involved in chondrocyte functional compromise. Furthermore, mitochondrial dysfunction can mediate several specific pathogenic pathways implicated in OA. These include oxidative stress, inadequacy of chondrocyte biosynthetic and growth responses, up-regulated chondrocyte cytokine-induced inflammation and matrix catabolism, increased chondrocyte apoptosis, and pathologic cartilage matrix calcification. In addition, the direct, sublethal impairment of chondrocyte mitochondrial ATP synthesis in vitro decreases matrix synthesis and increases matrix calcification ('disease in a dish'). The weight of evidence reviewed herein strongly supports chondrocyte mitochondrial impairment as a mediator of the establishment and progression of OA.