What is the mechanism of action (MOA) of Baclofen (GABA receptor agonist)?

Mechanism of Action of Baclofen

Baclofen is a GABA-B receptor agonist that reduces spasticity through both presynaptic inhibition of excitatory neurotransmitter release and postsynaptic activation of potassium channels, resulting in hyperpolarization of neurons at the spinal level. 1

Primary Mechanism

• Baclofen activates GABA-B receptors, which are metabotropic G-protein coupled receptors distinct from the classic GABA-A receptors 2, 3
• The FDA label states that baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals, though actions at supraspinal sites may also contribute to its clinical effect 1

Presynaptic Effects

• Baclofen activation of GABA-B receptors on primary afferent terminals retards calcium ion influx, thereby reducing the evoked release of excitatory amino acids and other neurotransmitters 3
• This presynaptic inhibition is particularly strong, as demonstrated by significant reductions in the frequency of miniature excitatory postsynaptic currents in ventral horn neurons 2
• The drug normalizes altered interneuron activity and decreases alpha motoneuron activity, which are key mechanisms in reducing spasticity 4

Postsynaptic Effects

• Baclofen induces direct postsynaptic depression by activating G-protein-coupled potassium channels on ventral horn neurons 2
• This activation causes outward potassium currents that persist even in the presence of tetrodotoxin and glutamate receptor antagonists, confirming direct postsynaptic action 2
• The postsynaptic hyperpolarization contributes to reduced neuronal excitability 1

Clinical Relevance

• Although baclofen is a structural analog of the inhibitory neurotransmitter GABA, the FDA notes there is no conclusive evidence that actions on GABA-A systems are involved in producing its clinical effects 1
• The combined presynaptic and postsynaptic inhibitory effects on synaptic transmission in ventral horn neurons explain the antispasticity effects of both oral and intrathecal baclofen therapy 2
• Baclofen has general CNS depressant properties, producing sedation, somnolence, ataxia, and respiratory/cardiovascular depression at higher doses 1

Important Caveats

• The precise mechanism of action is not fully known, and supraspinal sites of action may contribute to clinical effects beyond spinal mechanisms 1
• The drug's lipophilic nature allows it to cross the blood-brain barrier, exhibiting strong intrinsic activity and high affinity for GABA-B receptors 2
• All effects are blocked by selective GABA-B receptor antagonists (such as CGP35348), confirming receptor specificity 2