What is alpha-Bungarotoxin?
- Highly toxic peptide
- Comes from a potent snake toxin from the Southeast Asian banded krait Bungarus multicinctus
- Inhibits the binding of ACh to AChR by binding irreversibly and competitively to the NMJ nAChR
- Causes paralysis and respiratory failure
What is the schematic overview of the neuromuscular junction?
- Action potentials in the motor neuron cause exocytosis of ACh-containing synaptic vesicles
- ACh binds to receptors in the plasma membrane of the junctional folds of the skeletal muscle cell
- Initiation of Na+ entry and subsequent action potential in the muscle cell
- Excess ACh is removed by the enzyme acetylcholinesterase
Where does action potential come down from?
The motor neuron
What are the critical ion channels and ion pumps involved in the maintenance of membrane potential and triggering of action potential?
Ion channels: Na+,Na+, K+, K+, Cl-, 2K+, 3Na+
Ion pumps: nAChR, NaCh, KCh, KCh, ClCh, NKA
(look at slide 8)
What is the critical zone of interaction of toxins or drugs?
The nerve
What is an action potential?
The electrical gradient across the plasma membrane of an axon first depolarizes and then repolarizes the cell.
What are the changes in the membrane potential caused by?
The opening and closing of voltage- gated Na+ and K+ channels.
What are the types of drugs acting on the neuromuscular junction?
- Anticholinesterases
- Neuromuscular blocking drugs
Examples of Anticholinesterases
- Edrophonium
- Neostigmine
- Pyridostigmine
Examples of Neuromuscular blocking drugs
- Tubocurarine
- Pancuronium
- Vecuronium
- Atracurium
- Mivacurium
- Suxamethonium
What are neuromuscular blocking drugs subdivided into?
Presynaptic agents that:
- inhibit ACh synthesis
- inhibit ACh release
Postsynaptic agents that are used to cause clinical paralysis during anaesthesia:
- Non-depolarizing Competitive antagonists which block N-AChR
- Persistent depolarizing ACh receptor agonists
Examples of Presynaptic neuromuscular blocker
- Inhibition of ACh synthesis: Hemicholine inhibits choline transport. (It is not used anymore due to adverse side effects)
- Inhibition of ACh release: Botulinum toxin inhibits exocytosis of synaptic vesicle
Examples of Postsynaptic neuromuscular blocker
Competitive antagonists which block nAChR:
- Tubocurarine
- Pancuronium
- Atracurium
ACh receptor agonists
- Depolarizing neuromuscular blocking drugs
- Depolarizing block is NOT reversible by anti-AChE drugs
- Suxamethonium (succinylcholine)
What is clinical spasticity?
The molecular mechanisms underlying clinical spasticity (flexor muscle spasms) do not directly involve the monosynaptic stretch reflex arch.
- excruciating muscle spasms due to underlying disease
What are proprioceptors?
The body is equipped with proprioceptors to provide information about the orientation of the body in space and the relative position of the various body parts. They measure the position of joints and the length of the muscle.
What is an important class of proprioceptors?
Muscle spindles
- Spindles contain intrafusal muscle fibres positioned parallel between the main extrafusal, contractile fibres.
- The efferent innervation of the ends of the intrafusal fibres comes from the gamma motoneurons.
- The middle of the intrafusal muscle fibres is surrounded by a spiral of nerve endings, the anulospiral ending.
- Anulospiral endings report the state of a stretch of the intrafusal muscle fibres to the spinal cord via Ia fibres.
Monosynaptic and polysynaptic reflexes
Although the messages from the proprioceptors may also reach the cerebellum and cerebral cortex, subconscious reflexes to these messages are mediated at the level of the spinal cord.
What is a monosynaptic stretch reflex?
If a blow suddenly stretches a skeletal muscle on its tendon, the muscle spindles are also stretched, which stimulates Ia fibres.
Where do la fibres fun through?
La fibres run via the dorsal root to the anterior horn of the spinal cord, where they directly stimulate the motoneurons of the same muscle, causing its contraction.
- Reflex time: about 20 ms.
What is the stretch reflex of the quadriceps muscle?
- The afferent neuron from the quadriceps
(extensor) muscle makes an excitatory connection with the motor neuron innervating this same muscle group. - The afferent neuron also makes an excitatory connection with an interneuron. This interneuron makes an inhibitory connection with the motor neuron innervating the agonist muscle group, the biceps (flexor).
What are polysynaptic reflexes?
They are complex and may involve motor, sensory, and autonomic neurons. Since many more synapses are involved, the reflex time is longer than in the monosynaptic reflex.
Reflex time is also dependent on the intensity of the stimulus.
Example: Flexor withdrawal reflex of leg muscle groups
What are spasmolytic drugs?
To modify a simple stretch reflex (originating and terminating in the same muscle), the activity of the respective excitatory and inhibitory synapses has to be modulated
How do you reduce the activity of a hyperactivity stretch reflex?
- Ia fibres (which excite the motoneuron of the extensor muscle have to be reduced in their activity.
or - Interneuron fibres (which make an inhibitory connection with the motor neuron innervating the agonist muscle group) must be enhanced in their activity.
Examples of spasmolytic drugs?
- Diazepam: facilitates GABA (g-aminobutyric acid)-mediated presynaptic inhibition
- Baclofen: interferes with the release of excitatory transmitters
They both act more on central processes.
