Review of Medical Physiology - William F. Ganong 2002

Physiology of Nerve and Muscle Cells
Synaptic and Junctional Transmission
Neuromuscular Transmission - Denervation Supersensitivity

When a skeletal motor nerve is severed and subsequently degenerates, the Muscle gradually develops an extremely high sensitivity to acetylcholine. This denervation supersensitivity is also characteristic of smooth Muscles. Unlike skeletal muscles, smooth muscles do not atrophy in this case, but they become overly sensitive to the chemical transmitter that normally excites them. Denervated exocrine glands, with the exception of Sweat Glands, also exhibit increased sensitivity. A classic example of denervation supersensitivity is the response of a denervated iris. If the postganglionic sympathetic fibers innervating the iris are cut on one side in an experimental animal, and norepinephrine is administered intravenously a few weeks later, the pupil of the denervated iris will dilate markedly. On the other, intact side, the pupil will dilate only slightly, and this response is much less sustained. The responses resulting from axon transection are shown in Fig. 4-37. The increased sensitivity of postsynaptic structures to the transmitter produced at the axon terminals is a common phenomenon, largely caused by the synthesis of a greater number of receptors or their activation. In addition, orthograde (Wallerian degeneration; see Chapter 2) and retrograde degeneration of the proximal axon stump occur back to the nearest collateral (supporting collateral). A number of changes occur in The Cell body, notably a decrease in Nissl substance (chromatolysis). Subsequently, the nerve begins to sprout, forming many small branches that follow the path where the axon previously ran (sprouting/regeneration branching). Sometimes axons grow in the reverse direction—toward their original point of origin, particularly when injured near the Neuromuscular Junction. Nerve regeneration, however, is frequently hindered because the severed portion of the axon is often located within an area of general tissue damage. Interesting new experimental data indicate that this complication can be partially overcome by administering neurotrophins. For example, sensory Neurons lose their integrity if dorsal nerve roots are torn from the Spinal Cord, but they are capable of regenerating and establishing functional connections within the spinal cord if experimental animals are treated with the neurotrophins neurotrophin-3 or GDNF (see Chapter 2).

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Fig. 4-36. Terminals of postganglionic autonomic nerve fibers on smooth muscle (reprinted with permission from Kandel ER, Schwartz JH [editors]: Principles of Neural Science, 2nd ed. Elsevier, 1985).

When higher neural centers are damaged, The activity of lower centers under their control typically increases (release phenomenon). This elevated activity may be partly due to denervation supersensitivity of the lower centers. However, one theory suggests that many signs and symptoms of neurological disorders stem from degenerative supersensitivity of various neuronal groups within the Brain.

Hypersensitivity is confined strictly to the structures directly innervated by the damaged neuron and does not develop in neurons and muscles located downstream. Suprasegmental spinal cord injury does not cause increased acetylcholine sensitivity in paralyzed skeletal muscles, nor does destruction of preganglionic autonomic nerves induce supersensitivity in denervated Internal Organs. This fact has practical significance for treating disorders caused by vasospasm in the extremities. For example, upper extremity sympathectomy, performed by removing the upper Sympathetic trunk ganglia and the stellate ganglion, leads to hypersensitivity of vascular smooth muscles to circulating norepinephrine and occasional vasospasm. However, if a preganglionic upper extremity sympathectomy is performed by cutting the sympathetic trunk below the third ganglion (to interrupt ascending preganglionic fibers) and the white rami communicantes of the first three Thoracic nerves, no supersensitivity is observed. Denervation supersensitivity can have various causes. As noted in Chapter 1, a shortage of a specific chemical messenger typically leads to an upregulation in the number of its receptors. In terminals that normally produce norepinephrine, a specific mechanism involved in catecholamine reuptake is lost; nerve terminals in normal Tissues take up large amounts of norepinephrine, but following their degeneration, circulating norepinephrine reaching the receptors produces a much greater effect than would otherwise be expected.

Fig. 4-37. Changes occurring in a neuron and its innervated structures after axon compression or transection at the point marked X.

Denervation of skeletal muscles enhances the sensitivity of muscle fiber membranes to acetylcholine. Normally, nicotinic acetylcholine receptors are restricted to the end-plate regions, and in adults, they contain ε-subunits (see above). Following denervation, the sensitivity of the end plates themselves does not increase, but acetylcholine receptors of the fetal type (containing γ-subunits) appear in many other large areas of the muscle fiber membrane. After nerve regeneration, these receptors disappear, and sensitivity returns to normal. A similar distribution pattern of acetylcholine receptors is observed during development. They begin to cluster at neuromuscular junctions only when the motor nerve reaches the muscle and produces a protein called agrin, which binds to a muscle-specific kinase (MuSK). Agrin apparently plays a similar role during nerve regeneration following injury.