The 1963 Nobel Prize for Physiology or Medicine was awarded to Eccles, Huxley and Hodgkin for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane.
In most neurones the resting potential has a negative value of ~-70 mV. The resting potential is mostly determined by the concentrations of the ions in the fluids on both sides of the cell membrane and the ion transport proteins that are in the cell membrane. How the concentrations of ions and the membrane transport proteins influence the value of the resting potential is outlined below.
Video 1: A video which summarises the membrane potential and the ion channels involved.
The evolutionary need for the fast and efficient transduction of electrical signals in the nervous system resulted in the appearance of myelin sheaths around neuronal axons. Myelin is a multilamellar membrane which enwraps the axon in segments separated by intervals known as nodes of Ranvier. It is produced by specialised cells, Schwann cells, exclusively in the peripheral nervous system, and by oligodendrocytes exclusively in the central nervous system. The myelin sheath reduces membrane capacitance and increases membrane resistance in the inter-node intervals, thus allowing a fast, saltatory movement of action potentials from node to node.
A local anaesthetic is a drug that causes reversible local anaesthesia and a loss of nociception. Local anaesthetics are formulated as the hydrochloride salt to render them water soluble. They often contain preservatives, but only the single-dose ampoules without additives (apart from glucose at 80 mg/ml used in ‘heavy’ bupivacaine) are suitable for subarachnoid administration, as the preservatives carry the risk of producing arachnoiditis. Adrenaline or felypressin (a synthetic derivative of vasopressin with no antidiuretic effect) are added to some local anaesthetic solutions in an attempt to slow down absorption from the site of injection and to prolong the duration of action. Local anaesthetics are usually racemic mixtures, with the exception of levobupivacaine (which is S(-) -bupivacaine) and ropivacaine (S(-)-ropivacaine).
Read more about isomerism here.
Mechanism of action
Local anaesthetic action is dependent on blockade of the Na+ channel. Unionised lipid-soluble drug passes through the phospholipid membrane where, in the axoplasm, it is protonated. In this ionised form it binds to the internal surface of a Na+ channel, preventing it from leaving the inactive state. The degree of blockade in vitro is proportional to the rate of stimulation due to the attraction of local anaesthetic to ‘open’ Na+ channels.
Alternatively, ‘membrane expansion’ may offer an additional mechanism of action. Unionised drug dissolves into the phospholipid membrane and may cause swelling of the Na+ channel/lipoprotein matrix, resulting in its inactivation.