Persistent Depolarization Inhibition

Role in Classification of Inhibitory Processes

Inhibition is a temporary active process that regulates the level of excitation. In the central nervous system and internal organs, excitation and inhibition constantly replace one another. Historically, inhibition is divided into peripheral inhibition (discovered by the Weber brothers in 1847 regarding the effect of the vagus nerve, n. vagus, on the heart) and central inhibition (first investigated by I.M. Sechenov in 1862).

Based on electrophysiological mechanisms, three types of inhibition are distinguished:

• Hyperpolarization inhibition — a decrease in tissue excitability caused by inhibitory neurotransmitters acting on postsynaptic membranes.
• Persistent depolarization inhibition — failure of the membrane to return to its resting state.
• Stabilization inhibition — inability to generate an action potential due to the blockade of membrane sodium permeability without a change in the resting membrane potential (induced by biologically active substances).

Mechanism of Persistent Depolarization Inhibition

This process can occur independently as a functional mechanism or as a result of the interaction of two excitatory events. Key characteristics of the mechanism:

• Conditions for occurrence — high frequency of excitation.
• Neurotransmitter accumulation — accumulation of the excitatory neurotransmitter prevents the postsynaptic membrane potential from returning to the resting state.
• Charge alteration — physiologically, the difference between the current membrane potential and the threshold potential (critical level of depolarization) increases.
• Membrane specificity — this type of inhibition can also occur under the influence of inhibitory neurotransmitters due to specific cellular membrane properties.

By nature, this type of inhibition is similar to parabiosis or accommodation.

Clinical Significance: Depolarization Block

When the dose of agents acting on cholinergic synapses is increased, an excess of acetylcholine causes persistent depolarization of the postsynaptic membrane.

This results in a depolarization block of neuromuscular transmission and a cholinergic crisis, which manifests as:

• Exaggerated M-cholinoceptor stimulation symptoms (parasympathetic effects).
• Paradoxical worsening of muscle weakness (myasthenic symptoms).

Notably, released endogenous acetylcholine does not relieve this block. Instead, it further enhances postsynaptic membrane depolarization, thereby deepening the neuromuscular block.

Diagnosis and the Dual Block Phenomenon

Edrophonium is used for the differential diagnosis of a cholinergic crisis (anticholinesterase overdose) versus a myasthenic crisis (disease exacerbation or medication shortage). It is a short-acting peripheral quaternary amine administered intravenously. Its effect begins in 30–60 seconds and lasts 5–15 minutes. In a cholinergic crisis, administering edrophonium does not improve skeletal muscle tone and may temporarily worsen muscle weakness, which quickly resolves due to the drug's short duration of action.

With repeated frequent administrations of succinylcholine, a desensitization phenomenon may occur:

• Desensitization (N_m-cholinoceptors) — alteration of endplate sensitivity.
• Switch in block type — the initial depolarization block transitions into a non-depolarization (antidepolarization) block.
• Clinical significance: anticholinesterase agents can alleviate the myoparalytic effect only during the phase of the antidepolarization block.