Baclofen

[Enzymes]

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Does anyone understand why baclofen's action (GABA agonist) on muscle spindle afferents helps spasticity? I encountered this question in a NBME 12, but I was thrown off by the "afferent" part of it. Anyone understand this mechanism?

 

[Handinhand]

Baclofen is a GABA-B agonist and it's important to make that distinction because besides sharing the same endogenous ligand, GABA-A and GABA-B are completely different receptors.

In respect to the muscle spindle afferents, the only thing I can think of is that Baclofen inhibits the gamma-motor neurons that increase/decrease intrafusal fiber length, which increases/decreases the responsiveness of the muscle spindles.

 

[surgok]

Baclofen activates GABA-b which increases K+ efflux. So the effect is same as GABA-a which is inhibitory.
Normally, CNS modulates the muscle spindle afferent input by appropriately inhibiting the gamma-motor neurons. In UMN damage, this modulation is removed, so you get exaggerated response to stimuli. Clasp knife rigidity is one example (that is until golgi tendon kicks in).
By inhibiting afferent input, firing frequency of alpha-motor neurons decrease, thereby alleviating spasticity.

 

[Enzymes]

So basically the muscle spindle afferents are doing their thing by sending afferents via the normal reflex pathway. But the damaged UMN cannot inhibit these reflexes appropriately, so the reflex is hyperexcitable? You lost me with gamma motor neurons though. I thought alpha motor neurons and Renshaw Cells were the one's involved in the muscle stretch reflex.

Thanks for the help!

 

[surgok]

So basically the muscle spindle afferents are doing their thing by sending afferents via the normal reflex pathway. But the damaged UMN cannot inhibit these reflexes appropriately, so the reflex is hyperexcitable? You lost me with gamma motor neurons though. I thought alpha motor neurons and Renshaw Cells were the one's involved in the muscle stretch reflex.

Thanks for the help!

I meant to say alpha motor neurons.

Because gamma motor neurons are overactive, the muscle spindle becomes very sensitive to stretch. The afferent signal is exaggerated, leading to exaggerated response from alpha motor neuron and increased resistance to stretch.

 

[thehundredthone]

The muscle spindle has afferent innervation through Ia fibres and efferent innervation through the gamma motor neuron. The alpha motor neuron supplies the muscles themselves, not the spindle. Normally, both alpha and gamma fire together and the intrafusal fibres contract with the extrafusal fibres, thereby maintaining a certain degree of tautness in the spindle no matter how much the extrafusal fibres shorten. This allows the spindle to detect stretching at all degrees of contraction. This is coordinated by the Ia fibres of the spindle which detect the tautness of the spindle. These fibres are the ones inhibited by the UMN, preventing them from overly activating the gamma motor neuron.

Damaged UMNs affect both alpha and gamma, but gamma more than alpha (gamma bias). This decreases the inhibitory effect of the UMN on the gamma motor neuron, causing the spindle to be more taut than usual for a given length of muscle. The end result is that the spindle senses excessive stretching and the reflex fires causing the alpha motor neuron to activate and contract the muscle. This is what causes spastic hypertonia. Baclofen agonises GABAergic mechanisms directly thereby allowing the inhibitory pathways to work and let the muscle relax as it is stretched.

Alpha motor neurons, gamma motor neurons, and Renshaw cells are all part of the reflex pathway. Basically the muscle spindles are overdoing their thing without UMN inhibition and sending excessive signals to the reflex pathway causing the muscle to contract even when it should not be.

 

[surgok]

The muscle spindle has afferent innervation through Ia fibres and efferent innervation through the gamma motor neuron. The alpha motor neuron supplies the muscles themselves, not the spindle. Normally, both alpha and gamma fire together and the intrafusal fibres contract with the extrafusal fibres, thereby maintaining a certain degree of tautness in the spindle no matter how much the extrafusal fibres shorten. This allows the spindle to detect stretching at all degrees of contraction. This is coordinated by the Ia fibres of the spindle which detect the tautness of the spindle. These fibres are the ones inhibited by the UMN, preventing them from overly activating the gamma motor neuron.

Damaged UMNs affect both alpha and gamma, but gamma more than alpha (gamma bias). This decreases the inhibitory effect of the UMN on the gamma motor neuron, causing the spindle to be more taut than usual for a given length of muscle. The end result is that the spindle senses excessive stretching and the reflex fires causing the alpha motor neuron to activate and contract the muscle. This is what causes spastic hypertonia. Baclofen agonises GABAergic mechanisms directly thereby allowing the inhibitory pathways to work and let the muscle relax as it is stretched.

Alpha motor neurons, gamma motor neurons, and Renshaw cells are all part of the reflex pathway. Basically the muscle spindles are overdoing their thing without UMN inhibition and sending excessive signals to the reflex pathway causing the muscle to contract even when it should not be.

Great explanation. But I thought Ia afferent didn't receive UMN input nor has any direct input to gamma motor neurons. My understanding was that UMN modulates alpha motor neurons and gamma motor neurons.

 

[thehundredthone]

It is now established that la interneurons receive the same diverse excitatory and inhibitory inputs from segmental afferents (e.g., flexor afferents) and supraspinal descending tracts as are received by alpha motoneurons (Hultborn et al., 1976).

Of course, both alpha motor neurons and these interneurons are involved in the regulation of the stretch reflex and the developemnt of spasticity. I was only trying to explain that the gamma motor neurons themselves are not directly inhibited by the UMN.

From the same article:

Of the orally active agents, Baclofen is a centrally acting GABA analog. It binds to GABA receptor at the presynaptic terminal and inhibits muscle stretch reflex. Baclofen can also be used intrathecally.

It's a good article, if you have the time to read it all.