7.8:
Directly Acting Muscle Relaxants: Dantrolene and Botulinum Toxin
Most skeletal muscle relaxants act on the central nervous system to relieve pain from muscle stiffness or weakness.
However, some muscle relaxants, such as dantrolene and botulinum toxin, act directly on the skeletal muscle cells.
Dantrolene binds the ryanodine receptor, RYR1, on the sarcoplasmic reticulum membrane of skeletal muscle cells and blocks the release of calcium ions. Lack of calcium reduces the tension-generating actin-myosin interaction, which relaxes the muscle tone and prevents unnecessary heat generation.
Due to such a cooling effect, dantrolene is also used to treat malignant hyperthermia, a life-threatening heritable condition triggered as a reaction to certain general anesthetics or neuromuscular blockers.
On the other hand, botulinum toxin is used to treat spastic disorders like cerebral palsy, and multiple sclerosis.
At the neuromuscular junction, the active toxin acts on vesicle fusion proteins such as SNAP-25 or synaptobrevin-2 and induces their proteolytic cleavage.
This interferes with vesicle fusion and inhibits the exocytosis of acetylcholine from the presynaptic nerve terminal, partially paralyzing muscle fibers.
7.8:
Directly Acting Muscle Relaxants: Dantrolene and Botulinum Toxin
Directly acting muscle relaxants like dantrolene and botulinum toxin (BoNT) have distinct mechanisms and applications. Dantrolene, a hydantoin derivative, acts on the ryanodine receptor (RYR1) in skeletal muscle cells. RYR1 are calcium channels present at the sarcoplasmic reticulum membrane. In response to excitation, they release calcium ions from the sarcoplasmic reticulum to the cytosol. Calcium promotes actin-myosin-mediated contraction of muscles.
The binding of dantrolene to the RYR1 inhibits the opening of the channel and blocks the release of calcium. However, dantrolene does not affect RYR2 receptors in cardiac or smooth muscle, so these organs remain minimally affected.
Dantrolene also treats malignant hyperthermia, a life-threatening heritable condition often triggered by general anesthetics or neuromuscular blockers. In some cases, individuals cannot sequester excess calcium via calcium transporters, while other affected patients have altered calcium-induced calcium release. A small calcium influx triggers a more significant calcium release from intracellular stores. The calcium release persists, muscle contraction continues, generating lactic acid and increasing the body temperature. Prompt treatment of patients with dantrolene helps reduce lactic acidosis and body temperature by inhibiting calcium release.
BoNT is a neurotoxin that acts on the presynaptic neuron's vesicle fusion proteins and inhibits acetylcholine release at the neuromuscular junction. They temporarily impede the function of specific muscles or nerves, interfering with neurotransmission, which helps paralyze muscles and relieve pain. BoNT has two subunits, a heavy chain of 100 kDa and a light chain of 50 kDa. The light chain is the active part of the neurotoxin. It proteolytically cleaves vesicle fusion proteins like SNAP-25 and synaptobrevin-2 and inhibits the exocytosis of acetylcholine-filled vesicles. BoNT is helpful in the treatment of cerebral palsy, multiple sclerosis, or cervical dystonia.