Structure. The cell bodies of motor neurons supplying skeletal muscle lie in the spinal cord. Information is carried by an elongated axon that ends in a specialized structure that is designed for the production and release of acetylcholine (ACh) (Fig. 20-1: Schematic representation of the neuromuscular junction). The main site of action of neuromuscular blocking agents (muscle relaxants) is on the nicotinic cholinergic receptor at the end plate of the muscle. They also have effects at presynaptic receptors located on the nerve terminal.
Nerve Stimulation. Under resting conditions, the electrical potential of the inside of a nerve cell is negative with respect to the outside (typically –90 mV).
Activation of the postsynaptic nicotinic receptor requires simultaneous occupation of the receptor's two αsubunits by ACh. Skeletal muscle contraction occurs when ACh-induced changes in the muscle cell's transmembrane permeability result in inward movement of sodium sufficient to decrease intracellular negativity (depolarization) and cause an action potential.
Propagation of the action potential initiates release of calcium from the sarcoplasmic reticulum, where activation of myosin adenosine triphosphate leads to excitation–contraction coupling of the myofilaments.
ACh is hydrolyzed (within milliseconds to prevent prolonged depolarization) by acetylcholinesterase (true cholinesterase) to choline, which is reused for synthesis of new ACh, and acetate.
Presynaptic Events
The release of ACh normally decreases during high-frequency stimulation under physiologic conditions because the pool of readily releasable ACh becomes depleted faster than it can be replenished. In the presence of nondepolarizing NMBDs, this decreased release of ACh produces a progressive decrease in skeletal muscle response and a characteristic TOF and tetanic fade.
Succinylcholine (SCh) has virtually no effect on presynaptic receptors, explaining the lack of fade observed with this drug.