Denervation supersensitivity refers to an increased sensitivity of nerve cells that occurs as a result of trauma or disease processes (such as diabetes, sickle cell, or viruses) or exposure to toxic chemicals. This supersensitivity (or hypersensitivity) is the dramatic increase in sensitivity of postsynaptic muscles, glands, or neurons to chemical neurotransmitters (like acetylcholine) after their nerve supply is cut or damaged. This compensatory mechanism occurs as cells become “starved” of neural signals, typically peaking 48–72 hours after injury, with receptors spreading across the entire membrane.

Cannon’s Law of Denervation (1939) states that when an efferent nerve is destroyed, the isolated structure (muscle, gland, or neuron) develops an increased irritability to chemical agents. This “supersensitivity” means denervated tissue reacts excessively to substances like acetylcholine or norepinephrine. It is a fundamental concept in neurology and pain medicine.

Mechanism

When nerves are damaged or cut (denervated), the target cells (e.g., muscles) lose their trophic, regulatory input and become more sensitive to chemical signals as a compensatory mechanism. Following denervation, muscles increase synthesis and expression of extrajunctional acetylcholine receptors across the entire muscle fiber membrane, rather than just at the synapse. As a result, skeletal and smooth muscle become highly sensitive to cholinergic agonists.

This serves as a compensatory reaction to the loss of nerve impulses and trophic factors, making the structure more responsive to any neurotransmitter present. Structures become supersensitive or hyperreactive to neurotransmitters or chemical excitants. Increased sensitivity can start within 1–2 days and can persist until innervation is restored. In striated muscle, sensitivity to acetylcholine can increase 10- to 100,000-fold.

It often leads to pain syndromes, including myofascial pain, causalgia, and neuropathies resulting from trauma or nerve compression (e.g., in spondylosis). In chronic pain syndromes, the “current of injury” (referring to the abnormal electrical potential produced by damaged nerve tissue) causes this hypersensitivity, leading to chronic pain and sensitivity to stimuli.

Reversibility

Evidence suggests this supersensitivity can be reversed by providing new stimulation to the denervated tissue, such as through electric impulses. Directly stimulating denervated muscle electrically to cause contraction can prevent or reduce this supersensitivity.