Spinal Cord Transmission, Reflexes, Muscle Flashcards
Exam 3
Spinal Cord Transmission
Ascending & Descending Tracts (Gen. Overview)
What information ascends, descends the spinal cord? What is a tract?
-Sensory information ascends the spinal cord, beginning in the periphery of the body and traveling up through the spinal cord, brain stem, cerebellum, and brain.
-There are more sensory pathways than motor pathways, and that’s because we have temperature, vibration, and pain sensors
-Motor information descends the spinal cord and travels to our skeletal muscles
-Tract refers to a bundle of axons within the CNS. A bundle of axons outside the CNS are called nerves.
Motor and Descending Pathways
Pyramidal Tracts: Primary voluntary movement
-Lateral corticospinal tract
-Anterior corticospinal tract
Extrapyramidal Tracts (Accessory tracts): Movement that we do not usually have a knowledge of. Ex: fine-tuning our motor commands
-Rubrospinal tract
-Reticulospinal tract
-Olivospinal tract
-Vestibulospinal tract
Sensory and Ascending Pathways
What are they? (Names)
Dorsal Column Medial Lemniscus: Located in the dorsal part of the cord. These transmit information from pressure sensors in our skin (if we’re holding onto something, or our hands are in the air). Touch sensors
Anterolateral System: Pain signals. Typically follow one of two pathways
-Lateral spinothalamic tract
-Anterior spinothalamic tract
Spinothalamic tract terminology corresponds to the fact that the pain is going into the cord, relayed through the thalamus, and then out to the parietal cortex where it can be sorted out (where is it coming from?)
Rexed’s Laminae- Lamina I
What type of fibers synapse here?
-Numbered starting at the most dorsal portion of the dorsal horn
-Lamina I (Lamina Marginalis): Transmits fast, sharp pain via myelinated nociceptors that fall into the category of A-delta fibers.
Fast pain comes in through the dorsal rootlet, into the dorsal horn, where it has synapses in Lamina I. From there, the sensory information crosses over to the other side of the cord and then ascends the anterolateral pathway
Rexed’s Laminae- Lamina II, III, ~V
-Substantia Gelatinosa
-Synapses for slow pain conduction are located here. Sometimes slow pain signals will also synapse at lamina V
-Slow pain is typically routed through nociceptors that are non-myelinated (C fibers).
Once information is received in the substantia gelatinosa (and sometimes lamina V) it jumps over to the other side of the cord and ascends via the anterolateral pathway
Lamina 1-VI
Mechanoreceptors
-Also have mechanoreceptors that relay information to these areas of the grey matter in the cord.
-Mechanoreceptors are pressure sensors
Rexed’s Laminae-Lamina VII, VIII, IX
-These laminae make up the anterior horn.
-This is where our large motor neuron cell bodies sit, and they can be elicited to send an action potential if the stimulus is strong enough
Lamina X, Anterior White Commisure
Lamina X- An area of the grey matter where signals are relayed to the other side of the cord
AWC- The area of white matter in the spinal cord where information is relayed to the other side
Names & function of the 5 main spinal tracts
Typically the name tells us where the pathway is located or what function it performs
Spinocerebellar Tract: Sensory information that goes up the spinal cord to the cerebellum
Dorsal-Column Medial Lemniscal System (DCML): Major pressure sensory pathway that sits in the dorsal column of the cord. The medial lemniscal portion of the name refers to an area of the brainstem that the information passes through
Spinothalamic Tract/Anterolateral: Pain
Corticospinal Tracts/ Pyramidal tracts: Signal originates in the cerebral cortex (motor cortex) and passes through the spine on the way to the skeletal muscles
Extrapyramidal Tracts: Primarily accessory motor pathways
Dorsal Column Medial Lemniscus
Fibers? Sensory Information? Two routes this info can take
-Major sensory pathway for everything other than pain
-Capable of very fast sigal propagation
-Variety of a-fibers: alpha, beta, delta, gamma
- Fine vibration, fine pressure
- Crosses over at the medulla in the medial lemniscus
The path to getting to the medula follows one of two routes:
Touch sensation coming into the cord-> enters through the posterior rootlets of the doral horn and enters the grey matter of the cord. The information that enters the grey matter of the cord often stays there. This usually involves lateral inhibition or modulation of the activity in the cord
The other route that the sensory information takes is up to the brain through a pathway in the dorsal column (if the information needs to ascend all the way to the brain)
Dorsal Column Pathways: Fasciculus Gracilis
The further up the cord you get, the larger the dorsal column becomes.
-Lower extremity sensory information is fed into the fasciculus gracilis. As we ascend the cord, more bundles are added to the lateral side of the dorsal column
A tickle on the foot –> information is passed through the dorsal root –> dorsal root ganglia –> into the dorsal column–> ascends the same side of the cord that it entered on–> crosses over at the lower medulla–> medial lemniscus –>relayed to the ventrobasal complex of the thalamus –> internal capsule; a route that the information takes on the way to the parietal lobe
Dorsal Column Pathways: Fasciculus Cuneatus
-Higher up the cord. This is where the sensory information from the upper extremities is fed into the cord
A tickle on the arm –> information is passed through the dorsal root –> dorsal root ganglia –> into the dorsal column–> ascends the same side of the cord that it entered on–> crosses over at the lower medulla (lemniscal decussation)–> medial lemniscus –>relayed to the ventrobasal complex of the thalamus –> internal capsule; a route that the information takes on the way to the parietal lobe
Parietal Lobe layout
Which areas of the parietal lobe receive what information?
-Topographical layout
-Most anterior portion of the parietal lobe receives sensory information from lower extremities
-Immediately posterior (more midline) to that is the trunk sensory area
-Posterior to the trunk sensory area is the upper extremities
-The inferior, lateral borders of the parietal lobe receive sensory information for the face
Creepy Homunculus
The amount of area that you have processing sensory information in the brain is proportional to the number of sensory receptors
We have tons of receptors in our hands. These very sensitive sensors allow us to read braile.
We have a lot of receptors in the face
We have a low density of pressure sensors in trunk
Descending Motor Pathway
Pyramidal Tracts-Primary Pathway
Why are these called pyramidal tracts?
-Two separate tracts, primary and secondary. 80% of motor signals travel through the primary route
-Pass through the pyramids of the medulla
-Primary descending pathway begins in the primary motor cortex –> internal capsule (right outside thalamus) –> upper medulla –> medullary pyramids (anterior brainstem) –> lower medulla –> crosses over at pyramidal decussation –> lateral corticospinal tracts down the cord until at the appropriate level –> activation of motor neurons in anterior horn
Midbrain? Pons? Medulla? Pyramids? Pyramidal Decussation?
-The ridges are the pyramids
-The “cross-hatch” pattern is where the pyramidal decussation lies. These are strands of neurons crossing over, or bridging the gap, between the left and right pyramids
Pyramids? Decussation? Pons?
Anterior Corticospinal Tract
Pyramidal Tracts- Secondary Pathway
What is different about this pathway? How much information gets lost?
-Significantly smalled than the lateral corticospinal tracts.
-Responsible for ~17% of our motor function
2-3% of information does not crossover at all
Crossover happens at the level of the cord where the tract needs to activate a motor neuron
Begins in the primary motor cortex –> internal capsule (right outside thalamus) –> upper medulla –> medullary pyramids (anterior brainstem) –> lower medulla –> pyramidal decussation (information passes through the decussation, does not cross over here)–> continues down the anterior corticospinal tract on the same side of the body in which the signal originated –> crosses over at the level of the motor neuron where the message needs to be communicated
Fast Pain- Gen overview
Which portion of pathway? Runs parallel to? NE? Alt. Name?
-Lateral pathway of the anterolateral pathway
-A delta fibers, heavily mylenated
-Glutamate is always neurotransmitter, acts very quickly
-Runs parallel to the DCML, reaches the parietal lobe allowing for detailed localization of pain
-Also called neospinothalamic tract
Slow Pain- Gen Overview
-Anterior portion of the anterolateral pathway
-Slow, non-myelinated fibers (C fibers)
-Primary NE is substance P, can also use CGRP (Calcitonin G-related peptide) or glutamate (but not fast here)
-“Everything else” other than fast pain. Heat & vibration
-Stimulus travels up to the brainstem, but does not make it past that. Poor localization of pain because it does not reach the parietal lobe. Body has a difficult time pinpointing where the pain is occuring
-Paleospinothalamic Tract
Pain Transmission Pathway
Fast Pain: Anterolateral/Spinothalamic Tracts
Pathway?
Enters the cord at the level of the painful stimulus (primary ascending) –> synapses in lamina I –> crosses over at the anterior white commisure via the secondary ascending neuron
–> ascends the lateral portion of the anterolateral pathway, passing through the brainstem, ventrobasal complex of thalamus, internal capsule, and finally arriving in the parietal lobe
Pain Transmission Pathway
Slow Pain: Anterolateral/Spinothalamic Pathway
Pathway? Emotional centers? Reticular Formation?
-Enters cord at level of the stimulus (primary ascending)–> synapses in laminas II, III, sometimes V–> crosses over at the AWC (secondary ascending) –> ascends the cord in the anterior portion of this pathway.
The majority of this information terminates in the brainstem at the reticular formation (swaft of tissue) or immediately after leaving the brainstem
-Chronic, slow pain typically affects the emotional centers in the brain. The emotional centers in the brain are located very close to the middle of the brain, or right around where the brainstem connects with the diencephalon
Descending Motor Accessory Pathways
Extrapyramidal Tracts
- Vestibulospinal tract: Maintain balance, focus our eyes
- Olivospinal: Don’t really have anything to say
- Reticulospinal tract: Maintaning a certain level of muscle tone. Muscles aren’t entirely relaxed, all of the time. Underlying activity
- Rubrospinal: Monitoring and adjusting voluntary movements
Descending Pain Suppression System (DIC)
-Inhibitory in nature
-Operates in the background and helps the body deal with pain after the ascending signal has arrived at the brain
-Three neurons in the DIC
-The first order descending neuron originates from either the periaqueductal grey (around the midbrain) or the periventricular nuclei (located in front of 3rd ventricle)
-When excited, the first order descending neuron will release Enkephalins right in the middle of the pons (Raphe magnus nucleus)
-Enkephalins excite the second order descending neuron inside of the RMN. Second order descending neuron releases serotonin (5-HT) in the dorsal horn of the spinal cord. 5-HT is inhibitory in the spinal cord
-5-HT can excite a third order descending neuron (very small) that also excretes enkephalins, but in the cord enkephalins are an inhibitory neurotransmitter
-The enkephalin receptors in the cord are located ON the pain nociceptors of the pain sensing neuron. The pain sensing neuron has dendrites out in the periphery
-Pain signal travels into the dorsal root–> dorsal rootlets –> dorsal part of the cord –> enkephalin is being released and binding to the nociceptors –> inhibits that receptor causing pain to be diminished
-Another neuron that contains enkephalin receptors is the second order neuron in the ascending pathway
-Depending on the type of pain, the synapse will be in laminate I, II, III
Enkephalins, Enkephalin Receptors, and DBS
What is it? Where are they located? Where are they E, I
Endogenous Morphine analog
Opiate receptors = enkephalin receptors
Enkephalin is released in the raphe magnus nucleus (the first synapse in the DIC)- Stimulatory at this point
Enkephalin is also released in the dorsal horn (inhibitory here)
If we were to implant an electrode into the periaquaductal gray or the periventricular nuclei, that would generate an inhibitor pain signal that could reduce the amount of pain we perceive. Why? DIC. If activated strongly enough, it can surpass pain within the body. The presence of this system gives anesthesia a target for their drugs (dulls pain perception)
Enkephalin Receptors
Where are they located? GPCR? Interacts with what kind of channel?
-Enkephalin receptors are within the cord ON nociceptors and 2nd order ascending neurons
These receptors are GPCRs that typically interact with a K+ channel
When opiates hit these receptors–> open our K+ channels –> outward K+ current = hyperpolarization
Other receptor types/drugs that modulate pain response
-Pain synapses usually express A2 receptors, so an A2 agonist can bind and will also interact with a K+ channel (unsure if the same K+ channel as enkephalin receptors or not)
A2 Agonists: Xylazine, Clonidine, Precedex (most specific). Pain suppression, relaxation, without euphoria
-Volatile anesthetics: Increased K+ conductance, suppressing the CNS. Can also interact with inhibitory neurotransmitters
-Cox-2; Expressed in 1st order & 2nd order ascending pain neurons –> produce prostaglandins –> prostanglandinds interact with PGT receptors–> increases sensitivity to painful stimuli because they increase the likelihood of an action potential firing or repetitive action potentials
-INOS:
Odd enzyme. Induceable nitric oxide synthase –> increases sensitivity to painful stimuli
Ascending Pain Pathway & DIC
Overview of both, and how they interact, what gets shut down here?
1st order ascending nociceptor senses pain –> pain travels up the spinal nerve, through the dorsal root, through the dorsal rootlets–> synapses in the dorsal horn–> 2nd order ascending neuron hops over to the other side of the cord via the AWC–> travels up the anterolateral pathway
-Slow pain will terminate in brain stem
-Fast pain will travel through the brain, thalamus, internal capsule, to the parietal lobe
Our descending pain suppression system starts in either the periaquaductal grey or periventricular nuclei –> 1st order descending neuron (enkephalin neuron) –>synapses in the RMN of the pons, releases enkephalins which are excitatory–> 2nd order descending (serotonergic neuron) travels down toward the dorsal horn, releases 5-HT–> stimulates 3rd order descending neuron–> 3rd order descending releases enkephalins in the synapse in the dorsal horn.
Shuts down the presynaptic and post synaptic side of the synapse
Things that cause a nociceptor to depolarize
What causes pain?
Is pain a survival mechanism? Meditation can do what?
Pain is a survival mechanism that tells us when we’re doing something stupid.
Meditation and massive self-control over the mind can do things like deaden our pain completely, or allow us to lift a car off of a kid
-Damage (crush injury, cuts)
-H+ ions (acid)
-Lactic acid build up in the muscle
-Hyperkalemia (causes cells to depolarize) (Dialysis patient example)
-Histamine (inflammation)
-5-HT in the periphery
-Prostaglandins (cannot generate an action potential, but causes more sensitivity to pain)
-Bradykinins
Chronic Pain
What are some drug classes that can help? SSRI, TCA, Wind up
-Serotonin is recycled and reused by the neuron (serotonin reuptake system)
-If serotonin is what stimulates the 3rd order descending neuron to release enkephalins, then inhibiting the serotonin reuptake process should help reduce pain
-Some tricyclic antidepressants (have been around 50-60yrs) also inhibit serotonin reuptake. One main side effect of this class are drugs is drowsiness, which can actually be beneficial in chronic pain management. Because pain is stimulating the brain, it is harder for these people to sleep
Process of windup:
With chronic pain, more AMPA and NMDA receptors are inserted at the synpase. The more these receptors are stimulated, the more that our body places. If you remove the source of pain, the amount of these receptors will decrease over time (months)
Lateral Inhibition
Pressure sensor in the periphery takes the DCML pathway (this is the portion of the information that stays in the grey matter of the cord)–> this runs paralell to the 1st order ascending nociceptor
When neurons are close to together, they are able to talk to each other (mechanism unknown at the moment, probably uses a neurotransmitter & receptor). Neighboring neurons have the ability to shut down neurons nearby.
When there is a pressure sensor running parallel to a nociceptor, the pressure sensor has the ability to shut down some of the pain response.
This is how acupuncture works
Receptors in the pain system- AMPA
- Primary glutamate receptor is the AMPA receptor –> they open in response to glutamate–> causes ion channel next to the glutamate receptor to open and allow Na+ through the cell wall. (This occurs due to an increase in Na+ permeability in the target cell)
Glutamate release & binding process
-Glutamate is the primary fast pain neurotransmitter and is almost always excitatory
-1st order nociceptor releases glutamate in response to Ca++ fluxing into the cell. Ca++ interacts with glutamate storage vesicles, vesicles fuse with the cell wall and dump their contents into the synapse
-The 2nd order ascending neuron will need to have receptors on it in order to receive messages from the nociceptor
Growth and development?
Receptors in pain system- NMDA
Ions that flow through? Slower or Faster? How do these work?
NMDA-r; glutamate receptor that is attached to an ion channel. This receptor is large, so allows Na & Ca++ through the cell wall (Ca++ is primary). This receptor is a little slower than the AMPA receptor
-The NMDA-r needs two things in order to open:
1. Glutamate and
2. Prior depolarization. NMDA-r are typically blocked by extracellular Mg++. The negative charge on the inside of the cell draws Mg++ to the NMDA-r. When the cell depolarizes, the Mg++ leaves the area
These are placed in the CNS as a result of development; super important in the growth and development of the CNS
Things that block NMDA-r
5 total in this list
ETOH
Lead
Ketamine- Removes the Ca++ mediated portion of this pathway. Pain signals are still being sent via AMPA, but the CNS does not perceive it. Ketamine typically works on the brain in kids rather than in the cord (because of decreased NMDA-r)
Nitrous
Tramadol (but its terrible): Decent SSRI, but does not do much through the enkephalin receptors. Should not be used as primary pain control after surgery
Basic Overview- Spinal Reflex Pathways
Names, Function
- Stretch Reflex
- Tendon Reflex
-Stretch or tension reflexes; embedded in the muscles in our extremities - Withdrawal Reflex
- Crossed Extensor Reflex
-Responses to pain
Basic Spinal Wiring Schematic- General overview
What types of sensors? Where are they located?
-All of these reflex pathways are going to consists of some sensory component and then a way to elicit the reflex
-Reflexes that are dependent on skeletal muscle contraction or relaxation will need to have a way for the sensory reflex arc to influence motor function
-We have pain sensors out in the periphery. These pain sensors can elicit a reflex
-Tension receptors are located in the skeletal muscle or found within the tendons of skeletal muscle. Can sense the amount of tension within a muscle.
Consider the sensor a “spring,” if you pull apart the muscle, the spring will have increased tension
This gives our CNS a picture of what’s happening in the skeletal muscle
Interneurons
What are they? Function? Bridge between what?
-Sensory information can travel into the dorsal horn via it’s regular pathway. Sometimes sensory information projects directly into the anterior horn to elicit a reflex, other times we need the help of an intermediary neuron referred to as an interneuron
-Considered a bridge between the sensor itself and the motor neuron that needs to be communicated with
-Can be excitatory or inhibitory
-Reflexes can be bilateral and interneurons are utilized for crossover of the sensory information
Stretch Reflex
Goal? Reflex 1, 2. Interneurons? How to test for this clinically?
-Goal: Keep your muscles at a constant length. This reflex is engaged to keep our posture constant
Applicable to weight bearing muscle. Usually involve the leg muscle
Ex: Pushing in your forehead; this causes you quadricep muscles to stretch out. Without this reflex, your body will allow itself to be pushed backward
Reflex 1: With this reflex engaged, the quadricep muscles stretch, contract, then shorten back to their original length, allowing us to keep our posture constant.
Typically one sensory neuron is needed to achieve this reflex. The sensory neuron can synapse directly onto the motor neuron in the anterior horn of the cord without the help of an interneuron
**Reflex 2: **Involves an antagonistic muscle and an inhibitory interneuron. Antagonistic muscle in this case is the hamstring muscle. This muscle relaxes via an inhibitory connection, allowing the leg to straighten
How to test for this clinically?
Goal of this test is to determine if the sensors have a complete circuit with the other portions of the pathway.
To elicit this reflex, tap lightly on the ligament inferior to the patella. Striking that ligament causes contraction (shortening) of the quadricep muscle, and relaxation of the hamstring muscle. Striking the ligament does not directly engage the muscle spindle. Foot will also twitch
Quadriceps= extensor muscle
Stretch Reflex- Complete Circuit
- Stretching stimulates the muscle spindle (stretch receptor)
- Sensory neuron is excited
- Sensory information travels to spinal cord. Some information travels to the brain, some passes over to the anterior horn to activate a motor neuron
- Motor neuron is excited
- Effector muscle (where the original muscle spindle is located) contracts to relieve the stretching, antagonistic muscle relaxes
Tendon Reflex
Goal? Where are the sensors? Reflex 1, 2, bicep example, interneurons?
-Protective in nature. Consists of stretch receptors that are embedded in the tendons of our skeletal muscle capable of sensing large amounts of tension within the tendon
-Golgi tendon sensors detect heavy loads on the muscle by measuring tension.
Usually involves both reflexes and an inhibitory and excitatory interneuron
Reflex 1: Ceases contraction (relaxation) under a heavy load in order to prevent tendon tears or ripping the muscle out of their insertion point in the bone
Reflex 2: Contracts antagonistic muscles in order to speed up retraction from the heavy load.
There are ways to get around this reflex, but not totally sure of the mechanism. Ex: lifting a 5000lb car off of a child
Biceps/triceps Ex:
Reflex 1: Inhibits bicep with inhibitory neuron
Reflex 2: Excite triceps with excitatory neuron
Tendon Reflex- Complete Circuit
- Increased tension stimulates the golgi tendon sensor
- Sensory neuron is excited, travels through the dorsal horn
- Interacts with both and inhibitory and excitatory interneuron.
-Inhibtory interneuron is responsible for inhibiting the motor neuron that attaches to the muscle under the heavy load
- The excitatory interneuron causes reflex activation of the antagonistic muscle group
Flexor/Withdrawal Reflex
Goal? Muscle type used? Interneurons? Where are the cell bodies?
Goal: Withdraw from painful stimuli to avoid injury. This is usually done with the flexor muscles
-This reflex involves only one side of the cord. We have ascending and descending interneurons, and an interneuron that facilitates communication with the dorsal and anterior side of the horn
-Involves multiple levels of the cord, ~ two levels above and two levels below, via ascending and descending interneurons. The cell bodies of these interneurons reside in the lateral dorsal area of the white matter “ Tract of Lissaur”
Ex; Stub your toe–> reflex is to pull your limb away from whats doing the injury–> this activates the flexor muscle (hamstring in this case) and also relaxes the antagonistic muscle/extensors (quadriceps) to speed up the process of withdrawing
Flexor Reflex- Complete Circuit
- Painful stimuli
- Sensory neuron excited–> info travels to the cord
- Ascending and descending interneuron transmit information two levels above and two levels below stimuli
- Motor neuron excited–> flexor muscles contract to pull away from painful stimuli
- Antagonistic muscle relaxes
Crossed Extensor Reflex
-Involves withdrawing from pain, but also stabilizing with the other side of the body if there our weight is shifting. Allows us to withdraw from pain, but not fall over
-We have ascending and descending interneurons that run through the tract of lissaur, and interneurons that allow communication to the other side of the cord
Ex: Stub right toe or run into furniture –> we will need to plant our left leg to stabilize –> extensor muscles in the left leg contract, flexor muscles in this leg relax, straightening the leg, and giving us a stable base.
The affected limb will contract the flexor muscle group, and we will see relaxation in the antagonistic muscle group (extensor muscles)
Crossed Extensor Reflex- Complete Circuit
- Painful stimuli on one side of the body
- Sensory information sent to multiple levels of the cord via ascending and descending interneurons
- Motor information leaves the spinal cord
4a. Extensor muscles contract, flexor muscles relax allowing for us to stabilize
4b. Flexor muscles of affected limb contract, extensor muscles relax allowing us to withdraw the limb
nACh-r Variants
Low conductance, Fetal, how does succhinylcholine effect?
-Young/fetal, low conductance channels
-These are not restricted to the NMJ. These can be placed on the periphery of the muscle
-Have five domains;
Alpha & Alpha 1
Beta, Delta, and Gamma in place of Epsilon
-While open, the ion conductance is much slower than the mature version. The channels also stay open longer because their response to ACh is extended
When succhinylcholine is given, these nACh-r channels stay open for much longer. This can obvi
nACh-r Variants
High conductance, Adult
-Mature/Adult, High-Conductance channels are the version of nACh-r found at the NMJ in healthy adults.
-Restricted to the NMJ
-Have five domains;
Alpha & Alpha 1: two neurotransmitter binding domains
Beta, Delta, and Epsilon
Called high conductance because when the channel is open, the speed at which ions move through the channel is incredibly fast. These channels are only open for a very brief period of time
nACh-r Variants
Neuronal
Alpha 7 Neuronal nACh-r
Located in the CNS and ANS
Have five domains, all alpha 7
2nd order ascending neuron is usually…
Myelinated, even if it is a slow pain neuron
Kainate Receptor
3rd type of glutamate receptor in the pain pathway
This receptor mediates GABA activity in the brain
We don’t deal with this much in our class
Neuromuscular Junction Terminology
Junctional Area: In the NMJ
Perijunctional area: Lateral, out at the borders of the NMJ
Postjunctional: Further down the length of the muscle (not usually affected by paralytics)
What happens if our muscles are not working?
The body places what? What do those receptors allow?
The body places more immature/fetal nACh-r into the muscle cell, in the perijunctional or even postjunctional areas.
These fetal nACh-r allow more Ca++ into the cell when bound to Succs, as well as allow more K+ to leave the cell. If there is a terrible motor defecit and the body has place a ton of fetal nACh-r everywhere, the Ca++ being allowed in can actually cause the muscle to contract
Which muscle does the ulnar nerve innervate?
Neuromuscular Monitoring: Ulnar Nerve
What do we see when a stimulus is applied to the ulnar nerve?
-Usually two electrodes; one cathode, one anode, applied over the ulnar nerve and apply electrical current.
-The ulnar nerve innervates the adductor pollicis muscle in the forehand
-When stimulated, the thumb will move forward slightly and then the pinky should twitch as well
How does the electrical current through electrodes cause muscle contraction?
What does full twitch, some twich, no twich mean?
This generates an action potential in our motor neuron. When activated, the electrodes run electrons down the length of the nerve, causing the inside & outside of the cell to be negative. When there is no charge difference, the cell depolarizes because there is no polarity
-If we run a current through and get movement, our block is not very deep
-If we run a sizeable current through the ulnar nerve and get no movement, that would suggest that the neuromuscular block is pretty deep.
-If we’re somewhere inbetween the two, that indicates that we’re probably transitioning to a deeper block or the block is wearing off
Supramaximal Stimuli
Supramaximal stimuli: Voltage used to generate an action potential. Means it is strong enough to recruit all of the motor neurons in hte underlying nerve
If the neuromuscular junction is working correctly, we should see the muscle twitch
We want to use the supramaximal stimulus to ensure we are recruiting all of the motor neurons. Baseline to compare things against
Types of Twitch
Single, TOF, tetanic, PTC, DBS
-Single twitch: A single twitch in response to the voltage
Repetitive stimulation:
-TOF: Two hertz over two seconds.
One hertz = “something” happening over one second; therefore, two hertz (two “somethings”) over one second, x 2 = four twitches
-Tetanic: High frequency stimulation for a short period of time. More than four impulses
-Post tetanic count: Looking at the impulses that the muscle generates after a period of tetanic impulses are sent. Is the muscle still able to generate an action potential after we have generated 100 action potentials via high frequency stimulation? or is the muscle now out of neurotransmitter?
Double burst stimulation (DBS): High frequency stimulation for a couple of seconds, take a break for a couple of seconds, and do it again
Alternative Nerves We Can Monitor
-Ophthalmic branch of facial nerve: Lateral portion of the face. Innervates the orbicularis oculi muscle just around the eye socket
-Peroneal nerve: Butt area. Easy to get to
-Posterior tibial nerve: Behind the ankle
Methods of Monitoring Neuromuscular Activity
-Velocity meters/EMG: Can measure the activity of the underlying muscle
-Visual assessment: What am I seeing?
Single Twitch Stimulation: NDMR vs Succinylcholine
How long does it take for each to take effect? And wear off?
Single twitch stimulation: 0.1-1.0 Hz
NDMR: Takes a few minutes to take affect. Depending on the drug, different half-lives. Some of them have very long half-lives
Depolarizing: Fast onset, less than a minute. Short-acting and cheap. Can give IM. ~3 minutes, we can see a lot of motor function coming back
TOF Stimulation: NDMR vs Succinylcholine
TOF Ratio
Prior to any drugs onboard, need to get a baseline of all four twitches
NDMR: As the drug wears off, we will see one twitch come back (A). As the drug wears off, all twitches will begin to come back. Twitch A will remain the strongest. Twitch B is the fourth twitch.
If we can quantify the strength of the twitches, we can determine the TOF ratio. B/A = TOF ratio
Early in the blockade, the B/A ratio will be very small. As recovery progresses, B/A ratio increases until the TOF ratio reaches 1.
We need four twitches in order to determine TOF ratio
Sucs: As the block wears off, the twitches recover at the same rate. TOF ratio will always be ~1
What is an autoreceptor? It’s function? Role of ACh?
Autoreceptors & ACh
-There is a neuronal ACh autoreceptor located on the motorneuron that contains three alpha subunits and two beta subunits
-Primary action of ACh is to dump into the NMJ.
-Secondary action is to bind to the autoreceptor on the motorneuron, the autoreceptor opens and allows Na+ and Ca+ through. The current of the ions is what allows the VP-1 vesicles to move into the ready state and replace the depleted VP-2 vesicles.
That would imply that this receptor in useful in converting some of the VP-1 into VP-2 vesicles and replace whats been used during an action potential
NDMR vs Succinylcholine; How do they work?
NDMR only, TOF monitoring
**NDMR: ** nACh-r antagonists. Do not allow ACh to bind to the nACh-r on the skeletal muscle in the NMJ, preventing end plate potential.
The second effect that the NDMRs have is that they inhibit the ACh autoreceptor on the motor neuron.
If we don’t have the process of the VP-1 vesicles replacing the VP-2 vesicles, we will see weaker subsequent contractions when applying a repetitive stimulation.
When looking at the TOF stimulation graph, this is why twitch A becomes the strongest twitch. It has had time to figure out how to replace those VP-2 storage vesicles. But after that initial ACh release, we would have fewer and fewer storage vesicles ready to go at the synapse, thus resulting in weaker and weaker contractions
NDMR vs Succinylcholine; How do they work?
Succinylcholine. Ca++??
Primarily affects the post-synaptic skeletal muscle cell.
Binds to the nACh-r, depolarizes the cell, but causes a depolarizing blockade where the skeletal muscle end plate cannot repolarize or contract again
There is no effect here on the VP-1 and VP-2 storage vesicles. ACh can be readily released once the depolarizing blockade wears off
Not broken down well by AChe, but is broken down by plasma cholinesterases that are made in the liver
When succinylcholine binds to the nACh-r, a small amount of Ca++ sneaks in. Not enough to fully make the muscle contract
Adductor Pollicis vs Diaphragm; Paralytic dose comparison
Dose needed to paralyze, and how does recovery happen?
In the graph we reviewed in lecture, it takes about 40mcg/kg to completely wipe out skeletal muscle function of the adductor pollicis.
It took about 100mcg/kg to do the same for the diapgragm. The more important a muscle is, the more difficult it is to paralyze. The neuromuscular transmission system of an important muscle will typically have extra receptors and neurotransmitter to ensure things are functioning properly
When the paralytic is wearing off, the diaphragm will recover before the adductor pollicis muscle. So if testing the level of blockade with the TOF, if the adductor pollicis muscle has four strong twitches, the diaphragm should be working again
Innervation to the Diaphragm
The diaphragm separates which 2 cavities?
The diaphragm separates the abdominal cavity from the thoracic cavity. The body is set up in a way to protect the diaphragm from harm
The diaphragm is a skeletal muscle with motor neurons innervating it. The nerves that originate above C3, C4, C5 are referred to as the phrenic nerve and control the diaphragm. We need to know this forever
Having the phrenic nerve originate high in the neck helps to protect our body’s ability to ventilate
NM Blockade- TOF & Twitches
Percentage of receptors blocked per twitch. Stimulator settings
4th twitch disappears: ~75-80% nACh-r blocked
3rd twitch disappears: ~ 85% nACh-r blocked
2nd twitch disappears: ~85-90% nACh-r blocked
1st twitch disappears: ~90-95% nACh-r blocked
Easy to eyeball; if the patient can lift their head (reasonably healthy patient), they probably have ~70% of nACh-r’s blocked
Applies mostly to NDMR
Stimulator settings are probably 50-80mA
Voltage is the force with which we push the electrons, mA is the current. If we have a high voltage battery, we can push the electrons with a lot of force
Ocular muscles and succinylcholine
What are we worried about?
Each skeletal muscle is typically controlled by one motor neuron with the exception of a few:
Ocular muscles in the eye socket- controlled by several motor neurons, meaning there are several NMJs, allowing for more Ca++ to leak in and cause contraction.
Sometimes the eye will contract just enough to increase intraocular pressure. The worry here is people can lose their vision, especially if they are in a head/face-down position while paralyzed with succs
This causes pressure on the optic nerve
Neurotransmitters in the CNS
GABA & Glycine
Two most important inhibitory neurotransmitters in spinal cord
-Inhibitory in nature. Mediates the inhibitory action via increased Cl- conductance
-The CNS has tons and tons and tons of GABA activity. Without it, we will have uncontrolled neuro activity (seizures)
Glycine: Inhibitory in nature, very important in the spinal cord
Neurotransmitters in the CNS
ACh
What does it do? Benadryl? ACh-e inhibitors?
In the CNS, ACh increases awareness. If we have something that blocks ACh in the CNS, that produces side effects such as drowsiness. This is done via mACh-r in the CNS
Ex: Benadryl (antihistamine; but has a lot of cross-reactivity with mACh-r making it antimuscarinic) Because of it’s antimuscarinic properties, we can see an increase in HR
If we inhibit ACh-e in the CNS, this should increase awareness. Drugs that cross the BBB have these effects.
If trying to reverse a paralytic, but not wanting to wake someone up, need to use an ACh-e that does not cross the BBB
These drugs can be helpful w/ alzheimers disease. -stigmines that cross the BBB
S/E of ACh-e: Augmented ACh activity at any cholinergic receptor. ACh binds to mACh-r in the heart, causing a decrease in heart rate. If we cause more ACh to be available in the body, we would expect to see a large decrease in the HR
Most of our glands use ACh to activate. If we have a lot of extra ACh, we can expect a lot of secretions (lungs)
Neurotransmitters in the CNS
Histamine & Glutamate
Not related to pain pathway
-Histamine works similarly to ACh. Increases awareness
-Drugs that block central histamine receptors cause drowsiness
-Glutamate is a stimulatory neurotransmitter that increases neuronal activity.
Ex: Methamphetamine increases glutamate in the CNS. The problem here is that if you have too much glutamate, it can burnout your brain cells, and those brain cells cannot be replaced
Neurotransmitters in the CNS
Dopamine & Norepi
Dopamine is associated with pleasure/reward. Dopamine can also be a potent motor inhibitor. If we have a difficult time producing enough dopamine, we will see there is not enough inhibition of the motor system.
Ex: Parkinson’s Disease
Norepi increases awareness in the CNS. Many antidepressants are norepinephrine re-uptake inhibitors TCA’s, MAOI’s
pH balance & CNS activity
pH equation, how does it shift. How does Ca++ affect this?
Reduction in pH –> CNS activity is reduced
Increase in pH –> CNS activity is increased
This is largely dependent on Ca++
H+ + HCO3- —– H2CO3 —– CO2 & H20
The body typically buffers acid with bicarbonate. When bicarb combines with acid, carbonic acid is produced. Carbonic acid then dissociates into CO2 and water.
In the blood, we have plasma proteins (albumin) that are negatively charged. These negative charges can buffer protons (H+). Ca++ and H+ ions are both usually hanging out near albumin, and the amount of free Ca++ that we have is directly related to how many protons we have floating around
Increase in H+ –> Ca++ will not have room to occupy albumin, more free Ca++ in the ECF will decrease CNS activity
Decrease in H+ –> Ca++ will occupy albumin, less free Ca++ in the ECF will increase CNS activity (can cause seizures)
Spinal Cord; Arterial Blood Circulation
-Autoregulates in the same manner that the brain does
-Assume that where there are arteries, there is usually a similar vein
-Two posterior spinal arteries; vertebral arteries, anterior inferior cerebellar artery, and the posterior inferior cerebellar artey feed into
-One anterior spinal artery; lies in the anterior spinal sulcus
-Posterior and anterior radicular arteries; branches of the intercostal arteries that feed into either the posterior or anterior portion of the cord
-12 pairs of intercostal arteries. These run fairly deep and connect with spinal arterial circulation
-Coronal arteries; outer surface of the cord. Not continuous
-Does not have circle of willis type flow- do not have as good of collateral flow
Branching Pattern of Spinal Arteries
-Different for every person, very irregular. Not symmetrical
-Typically what will happen is that we an intercostal artery branching to form one radicular artery, and that radicular artery will connect to either the anterior or posterior portion of the spinal cord
-the radicular arteries very seldom divide into two and provide circulation to both the front and the back at the same level of the cord
-Typically every 5-6 levels of the cord we will have a radicular feed artery coming from the left or the right, feeding the front or the back
What branches off the aorta? Which structures do we have at every lvl?
-Intercostal arteries branching from the aorta
- The intercostal arteries connect to the dorsal branch –> connects to the spinal branch which sits on top of the doral root ganglia (We will have this setup at every level of the cord). Whether or not this branch will continue all the way to supply the cord at the posterior or anterior portion will vary at each level.
- This image shows us all of the possible paths these arteries can take. We will not have all four feeding into the spinal cord at one level
-The majority of the blood flow branches around the rib cage, but there are smaller vessels that work their way in to support the underlying tissues
Pattern of intercostal arteries, renal & mesenteric aorta
-Notice the pattern of the intercostal arteries; primarily responsible for keeping the rib cage perfused
-Where do the renal aorta arteries branch off?
-Abdominal aorta?
-The mesenteric artery?
Aneurysm repair & clamping the aorta
-Clamping the aorta can cause ischemia downstream from the clamp
-Renal artery ischemia, spinal artery ischemia are major concerns
-The anterior spinal artery is perfusing the grey matter in the anterior horn. Cell death there would mean paralysis. Can have sensory function issues, but we’re more worried about motor function
-Cross-clamping the aorta below the level of the great radicular artery would be most ideal, not likely though
-Imaging ahead of an aneurysm repair is ideal. The higher the GRA, the safer the repair will be
C-Spine
Anterior spinal artery
Posterior spinal artery
Anterior radicular artery
Posterior radicular artery
Vertebral arteries
GRA, range & absolute range. GRA provides the spinl cord with what?
What % of blood does the anterior spinal artery provide? The posterior?
-The anterior spinal artery supplies the cord with about 75% of it’s neccessary blood supply
-The posterior spinal arteries supply the cord with about 25%
-Great radicular artery/ Radicular artery of Adamkiewicz; this artery provides the anterior cord with 2/3rds of it’s blood supply (especially to the lower parts of the cord)
-GRA will enter on the left side of the patient in the vast majority of people. Closer to the aorta
Spinal level that is most associated with the GRA connecting to the anterior spinal artery: T10
Typical range: T9-T12 (~75% of people)
Absolute range where it could be found: T5-L5
How many anterior radicular feed arteries do we typically have?
What about the posterior side?
-Vary person to person
-Usually two anterior feed arteries in the neck
-Two to three anterior feed vessels in the thorax
-One to two anterior feed arteries in the lumbar area
We will typically have more feed vessels on the posterior side, but we do not need as many
What can help with prolonged ischemia? Reperfusion injury?
Spinal Cord Perfusion Pressure
What increases CSF pressure in the spine?
-Surrounded by the meninges, but more leeway than in the brain.
-Not as concerned with perfusion pressure to the spinal cord in comparison to the brain, but still a big deal
-Cross-clamping the aorta is something that would cause an increase in CSF pressure in the spine (~10mmHg)
-Drugs that slow down the metabolic rate of the cord
-Drugs that reduce inflammation in the cord
Ischemia reperfusion injury can occur, creating toxic reactive oxidative species
Spinecerebellar Tracts; Anterior & Posterior pathways
-Spinocerebellar Tracts; cerebellum helps us coordinate complex movements
Two tracts: Will have one of each at each level of the cord
- Anterior/ventral spinocerebellar tract
-Ascends information up to the cerebellum regarding the amount of activity taking place in the anterior horn.
-Travels to the cerebellum via the ventral spinocerebellar tract into the superior cerebellar peduncle - Posterior/dorsal spinocerebellar tract
-Sends golgi tendon (can actually shut down the entire muscle if it needs to) and muscle spindle information to the cerebellum
-Ascends the dorsal spinocerebellar tract into the inferior cerebellar peduncle –> fans out throughout the inferior cerebellum
Pain Threshold
High & Low. Chronic pain does what?
-Pain threshold: The ease or difficulty of elliciting a pain response. Genetics and environment play a role
-High threshold: It takes much more stimulus to ellicit a response
-Low threshold: Much less stimulus required
Whether or not an action potential is fired and pain is caused depends on where the pain threshold is for that particular tissue and that particular person.
If the threshold is higher, or more positive, then it will be harder for that stimulus to be perceived as painful
The opposite is true; if the threshold is lower, or more negative, it will be easier for the stimulus to be perceived as painful. Chronic pain usually reduces pain threshold
Types of pain; Parietal
Pain of decompression?
-Parietal: Refers to tissue pain. Can occur in an organ, but usually occurs in a superficial structure. Tends to be localized well. Direct conduction into spinal cord from peritoneum, pleura, or pericardium
Ex: the parietal portion of appendix pain would be the lower right quadrant, sharp, stabbing (fast pain). Applying pressure here will elicit lateral inhibition, removing the pressure is what causes pain. Considered “pain of decompression”
Types of pain; Visceral & Referred
Structures that do not transmit pain? Which structure is at T10?
-Visceral: Organ pain transmitted through the autonomic nervous system. Very hard to localize this pain. We usually feel that this pain is occurring in an area of the body that is distinctly separate. Organs have pain sensors, but do not have any other tactile senors, so lateral inhibition would not apply here. Visceral pain is routed through the sympathetic chain–> autonomic ganglia–> and ascends 2-3 levels before entering the pain transmission pathways
Referred pain: Pain felt in a part of the body that is fairly remote from the tissue causing pain. Appendix pain is felt at the level of the umbilicus (T10)
Soft tissue in our lungs do not have pain sensors; that’s why someone can smoke for 30 years without getting any signal that theyre being destroyed
The liver itself does not transmit pain from the internal structures
Why is heart pain referred to the left side?
The heart: The reason pain is typically referred to the left side here is because the right side of the heart is much less prone to ischemia due to the pressures being lower
Stomach: Felt higher than the umbilicus. Can be mistaken for an MI
Kidneys: Lower back
Limbic System. What does it consist of?
-Emotional center of the brain; sits right on top of the brain stem
-Slow pain feeds into the limbic system
- Amygdala
- Hypothalamus
- Cingulate gyrus
Cingulate gyrus; part of the cerebral cortex
Located just out of the corpus callosum
Buried deep in the brain
Nerve Fiber Types
A alpha fibers:
-Muscle spindle fibers (primary ending)
-Golgi tendon fibers
-Skeletal muscles
A beta fibers:
-Lateral inhibition vibration/pressure fibers (pacinian corpuscle, meissner’s)
-Muscle spindle fibers (secondary ending)
A gamma & delta fibers:
-Deep pressure & touch, pricking pain
Tickle, cold, warmth, aching pain travel via C fibers
Skeletal Muscle Physiology
Skeletal muscle functions, storage or what? Do they receive or send info
-Large container within the body
-40% of one’s body mass is attributed to skeletal muscle
-Used to get away from danger
-Communication/expression
-Regulate body temperature
-Storage of glycogen (large starchy compound; large chain of glucose)
-Skeletal muscles are “effectors,” meaning they receive information from the nervous system
-Large store of ions
Musculoskeletal Connections
Ligaments vs tendons
Ligaments:
-Attach one bone to another bone
-Patellar/ACL/MCL
Tendons:
-Vast majority are muscle to bone connections
-Achilles
-There are muscle to muscle connections via an intermediary tendon
Anatomy of a Skeletal Muscle
Sarcomere, myofibril, muscle fiber, fasciculous, muscle
-Sarcomere: Functional unit of the myofibril. This is where we have overlap of the thin & thick filaments. Wherever we have overlap, we have the ability to produce force. Borders of the sarcomere are the Z-discs
-Myofibril: Small cyclinders that contain actin and myosin w/in the muscle cell. Have ~200 myofibrils per muscle cell, but general rule is if the muscle does not need to lift a large amount of weight, there will be less myofibrils. The stronger the muscle, the more myofibrils. Some skeletal muscles are weaker than others allowing us to have precise control over our movements
-Muscle fiber: Single muscle cell
-Fasciculous: Multiple skeletal muscles
-Muscle: Fasciculi grouped together
Motor Units
What is it? How does the nervous system recruit motor units?
A motor unit is a collection of one or more skeletal muscle fibers controlled by a single motor neuro
One motor neuron can control anywhere from one skeletal muscle cell to many skeletal muscle fibers depending on its function.
Smaller motor units typically help us with our fine motor function
As the nervous system needs to produce more force, we tend to progressively activate larger and larger motor units
Skeletal Muscle Classifications; Type 1
-Red due to the iron found in myoglobin
-Specialized to produced slow, sustained contraction
-Have a lot of mitochondria to replace ATP
-Myoglobin; large iron containing protein that helps unload oxygen into the blood within the muscle. This allows the mitochondria to harness that oxygen to create ATP
Ex: Goose breast
Skeletal Muscle Classifications; Type 2
-Considered white muscle
-Can produce force, but not something that can be sustained for a long period of time
Ex: Chicken breast
Examples of Type I and Type II Muscles
-Soleus muscle in the calf; type I; large, weight bearing muscle in the back of the leg. It is a little slower to generate an action potential, but it can sustain a contraction for a long period of time (standing all day)
-Ocular muscles in the eye-socket; just need to be able to respond to instructions very quickly, do not need to do any heavy lifting. Will not have as much myoblin or mitochondria
-Gastrocnemius muscle: In between muscle. Many of our muscles are inbetween Type I and Type II
The duration of action potential will look about the same for all of these muscles, what differentiates them is how long they take to respond and how long they can hold that contraction
What is the sarcolemna?
-Cell wall of the skeletal muscle is called the sarcolemna
-Muscle fibers have specialized ERs called the sarcoplasmic reticulum
-Transverse tubules run perpendicular to the length of the muscle, allowing for the action potential to enter deep into the muscle
-Myofibrils (100s-1000s) make up the skeletal muscle fiber
-Borders of the sarcomere can be seen in this image
Sarcomere anatomy. What makes up the sarcomere?
Z disc, I band, A band, H band, Titan
-Myosin and actin filaments are contained within the sarcomere
-Contraction of the muscle depends on shortening of the sarcomeres
-The border of the sarcomere, where the thin filaments all connect, is called a Z disc. There is a Z disc at each end of the sarcomere
-The I band is an area within the sarcomere where there are only thin filaments located
-Area of the sarcomere where there are only thick myosin filaments is called the H band
-Where thick filament overlaps thin filament (small area) is called the A band
-Stretchy connective tissue that holds everything togethr- Titan
Cross section. Z disc, myosin, I band, mitochondria, T tubule
Contraction of the myofibril
Sliding filament mechanism
The container that holds the sarcomeres are myofibrils
During contraction:
A band does not change width
I band shrinks or disappears
H band shortens
Z discs move closer together
How are proteins transferred down the motor neuron?
What about if a skeletal muscle needs a new protein?
If a protein is needed to build something, or needs to be replaced, the protein is created in the nucles/rough ER of the motor neuron. It is then placed on a cart like apparatus and transffered down the length of the motor neuron
Because skeletal muscles are so long, they are multi-nucleated. The reason for this is that the muscle needs to have a protein production apparatus nearby. Being multi-nucleated makes skeletal muscle unique
Closer look; Myosin Filaments
How many myosin molecules per filament? Light chains?
-Long strings of myosin molecules that are wrapped together at the tip
-Usually ~200 myosin molecules in each myosin filament
-Each myosin molecule has a total of six chains;
**two heavy chains ** wrapped around each other making up the bulk of the myosin molecule. This allows the myosin molecule to connect to other myosin molecules
**four light chains ** promiximal to the myosin head.
-Essential light chains are the pair most lateral. They give the myosin head its ATPase activity
-The light chain pair that is more medial are called the regulatory light chain. These basically alter the activity of myosin heads in different types of muscle. Don’t do much in skeletal muscle
Myosin head has a high affinity for binding to the active site on actin filaments
Closer look; Actin Filaments
F-Actin, Troponin I, T, C
-Alternating strans of two proteins
1. Actin “F”; active sites are found here
2. Tropomyosin; act as a shield. Do not allow inactive muscles to bind to the active site on F-actin
Troponin Complex: How we remove the shield of tropomyosin Three protein complex 1. Troponin I binds to F-actin 2. Troponin T binds to tropomyosin 3. Troponin C sits on top of I and T. It has four binding sites for Ca++. Ca++ binds, and troponin C twists slightly and alters the configuration of the troponin complex. Tropomysosin then moves out of the way--> active sites on F-actin are revealed
Skeletal Muscle; High Energy & Low Energy states of myosin head
Myosin head has two orientations it can have:
1. Low Energy: In this state, there is tension on the myosin head. Bound to ADP and Pi
- High Energy: Not as much tension on the myosin head.
Needs ATP to reset. ATP binds to the myosin head in a low energy state, one phosphate is removed from ATP, leaving ADP and Pi bound to an active myosin head
In a healthy skeletal muscle, our myosin heads should be in a resting, low energy state
If the muscle is in the middle of contracting and there hasnt been a chance to detach from & reset the tension on the myosin head, the myosin head will be in the low energy state
Skeletal muscle; cross-bridge cycling
- Cross-bridge cycling starts in the “released” state, meaning ATP binds to the myosin head, and releases it from the actin filament. The ATP is then metabolized, pulling a phosphate off, and harnessing that enery to place tension back on the myosin head
- Myosin head is in an active, resting state with ADP and Pi attached.
- Ca++ enters the skeletal muscle cell, bind to troponin C, causing the tropomyosin to unravel and reveal the active sites on F-actin.
- Myosin head will bind to the active site, and the Pi bound to the head typically falls off during this process.
- Shortly after the phosphate falls off, the head uses the stored tension to pull on the actin molecule at the active site –> essentially “walking the actin backwards” causing the sarcomere to shorten and the ADP to fall off. The myosin head is now in its high-energy requiring state
- At this point, the myosin head is “stuck” to the actin active site. ATP is required in order for the myosin head to release, starting the cross-bridge cycle over
Rigormortus & Cross-Bridge Cycling
Rigormortus occurs because our body is no longer capable of producing ATP. Without ATP, the myosin head cannot detach from the actin filament and the muscles remain “stiff”
Excitation-Contraction Coupling
Where do EC-coupling & cross-bridge cycling begin to overlap?
- Motor neuron depolarizes
- Ca++ fluxes into the motor neuron terminal via P-Type Ca++ channels
- Ca++ interacts with VP-2 vesicles, causing them to fuse with the cell membrane and release ACh
- ACh binds to nACh-r
- Na+ flows in through nACh-r along with Ca++
- Na+ & Ca++ influx generates end plate potential
- End plate potential in a healthy setting will always cause a skeletal muscle to depolarize
- Action potential spreads down the length of the muscle fiber via VG Na+ channels and into the t-tubules
- Dihydropyridine sensors sense the depolarization, pull on the ryanodine receptor (Ca++ release channel)
- Ca++ rushes out of the SR and into the sarcoplasm (this is step 3 in cross-bridge cycling)
- SERCA pump pushes Ca++ back in once the muscle contracts
Length-Tension Relationship; skeletal muscle
Starling forces
The amount of contraction a muscle can generate is going to be dependent on how much surface area is between the myosin and actin.
If the sarcomere is severely overstretched and there is no overlap in the myosin and actin filaments, it’s not going to be able to produce any force. This is unlikely to happen
If the muscle is understretched and doesn’t have any room to shorten, it’s not going to be able to produce any force
The overlap of myosin heads and actin active sites is proportionate to generation of force
Length-Tension Relationship Vocabulary
Passive, Active, and Total
Passive Tension: Stretch or tension on the muscle that is NOT generated by an action potential
Active tension: The amount of force generated by the muscle during an action potential
Total Tension: Passive + Active Tension. The tension from the stretch of the muscle plus the force of contraction generated by an action potential
The green line is active tension
Blue line is passive tension
Red line is total tension
Isometric vs Isotonic Contraction
What example did he show us in class?
Isometric Contraction: The muscle contracts, but doesn’t change lengths and the joint it controls does not move
Ex: Real life: a plank
Class example: A weight secured to the end of the muscle. Tension increases when the muscle contracts, but the length of the muscle stays the same
Isotonic Contraction: The muscle contracts and changes length, while the tension in the muscle remains the same
Ex: A weight secured to the end of the muscle. When the muscle contracts, it shortens in length
How to find active tension here? Total tension- the weight= active tension
Load/Contaction- Velocity Relationship
Where is this important?
The velocity of shortening (contracting) a muscle is related to the load on the muscle
The greater the load, the velocty of shortening the muscle will take much longer
Smaller the load, quicker the velocity
This is most important in the heart. If the heart is pumping against a high afterload, it takes the heart longer to eject blood
Muscle Force Regulation
Quantal, Temporal summation
Quantal Summation: Recruiting more and more motor units in order to generate more force.
-This is typically managed by the amount of voltage (stimulus) used to recruit the motor neurons. A weak stimulus will not allow for proper recruitment of motor units
Temporal Summation: Force generation (voltage) in comparison to rate of stimulation. Measured in hertz; rate of stimulation per second
-Up until about 10Hz, we can see individual muscle contractions separate from each other. After this, the contractions become additive. Meaning, the Ca++ is leaving the SR faster than it can be put back into the SR. Once we reach about 40Hz when stimulating a muscle, we’ve reached tetany
Skeletal Muscle Adaption
Atrophy, Hypertrophy, Hyperplasia
Atrophy: Denervation or disuse causes skeletal muscles to get smaller. There is loss of the myofibril cells leading, and if severe enough, muscle fibers can disappear as well. Very hard to replace once gone
Spinal Cord Injury Ex: If someone has funding to do it or they’re optimistic about the future, can pay for electrode therapy where someone can shock the muscles in order to avoid atrophy
Hypertrophy: Increase in myofibrils in the muscle fibers. Blood vessel network within these muscles will also increase in size. Expansion of cell size due to increase in myofibrils
Hyperplasia: Generation of additional skeletal muscle cells. This happens at an incredibly low rate
Smooth Muscle Vs Skeletal Muscle
-Makes up ~ 10% of our body weight
-Is stronger on a gram per gram basis that skeletal muscle
-Cross bridge cycling is slower because the myosin heads take longer to release, making smooth muscle more efficient
-“Latch” mechanism; ultra low energy state where the myosin head hangs onto the actin, allowing smooth muscle to maintain that same force of contraction without using energy
Smooth Muscle Anatomy
-Cells are much smaller
-Connect to neighbors via gap junctions
-Dense bodies: Where the actin connects
-Actin to myosin ratio 10-20:1
-SR is much less developed, cannot store as much Ca++
-Ca++ leaks into the smooth muscle via VG or ligand gated; more dependent on outside Ca++
Examples of Smooth Muscle
What happens to our blood vessels if we have no Ca++?
-Eye; pupil diameter control (autonomic nervous system)
-Airway smooth muscle
-Small intestine
-Vascular smooth muscle: Because this muscle is dependent on extracellular Ca++ leaking in, if we have no Ca++, we will have no blood pressure due to lack of vasoconstriction
-Esophagus: We have some concious control over our Esophagus. Possibly the only organ with mixed skeletal and visceral smooth muscle?
Visceral vs Multi-Unit Smooth Muscle
-Visceral/Unitary Smooth Muscle: Functions as a unit. What’s happening in one muscle cell is being conveyed to the other smooth muscle cells via gap junctions (permitting movement of Na+ and some Ca++). Allows all cells to then contract as a collective unit
Ex: Intestinal smooth muscle, but also most of our hollow organs are lined with visceral smooth muscle
-Multi-Unit: No pathways for ions to move in between neighboring cells allowing for a more “graded” control. This is useful in an area where we need more delicate control over how much the smooth muscle is squeezing. Very fine tuned, accurate. Dependent on neurotransmitters
Ex: Cilliary muscles, iris in eye
What layer is missing from the capillaries? How do smooth & endo talk?
Blood Vessel Structure
Adventitia, tunica media, endothelial layer
Adventitia: The most external layer of a blood vessel. Function is support & protection
Vascular smooth muscle or tunica media: Lies directly between the adventitia and endothelial cells
Capillaries do not have vascular smooth muscle. Almost exclusively endothelium
Endothelial layer/Tunica Interna: Single layer of endothelial cells
Smooth muscle and endothelium communicate via neurotransmitters or gases (nitric oxide)
Myosin Anatomy in Smooth Muscle
How does it differ from skeletal muscle?
In skeletal muscle, the myosin heads are all oriented at angle that points away from the middle of myosin molecule causing a gap
In smooth muscle, the orientation of the myosin heads all point the same way on one side of the molecule and in the opposite direction on the other side of the molecule, allowing for the smooth muscle to be able to shorten more during contraction. There is no longer an “M” line
Smooth Muscle; Receptors and ACh
What does ACh do in the intestine and vascular smooth muscle?
-Acetylcholine is always the neurotransmitter in smooth muscle
-The function of ACh is dependent on where the receptor is
Ex: ACh in the smooth muscle of the intestine: Causes contraction, increases GI motility
Ex: ACh in the vascular smooth muscle mediate vascular relaxation
How does Ca++ enter & Exit?
Excitation-Contraction Coupling: Smooth Muscle
Ca++ effects on the vascular smooth muscle
-Ca++ enters through a Ca++ channel on the cell membrane (and some is from the SR) –> increasing intracellular Ca++
-Ca++ then binds to Calmodulin forming a Ca++-Calmodulin Complex –> activating MLCKinase
MLCK phosphorylates the regulatory myosin light chain (MLC) leading to cross-bridge cycling in the the smooth muscle
When intracellular Ca++ concentration decreases pumped out of the cell), this process is reversed. Myosin phosphatase removes the phosphate from regulatory-MLC leading to relaxation
Ca++ is pumped our primarily through the Na+, Ca++ exchanger (3 Na+ in, 1 Ca++ out), removed via a plasma membrane Ca++ ATPase pump (PMCA), and moved back into the SR by a SERCA pump
Ca++ enters through:
1. VG L-type Ca++ Channels
2. Ca++ leak channels
3.Ca++ ligand gated ion channels
Begins in the endothelial cells
Nitric Oxide Signaling/Nitrate Activity in the Vascular Smooth Muscle
Pathway, PKG & it’s affects on the smooth muscle
-Reduces the activity of MLCK
-Nitrates hitting the vascular smooth muscle OR L Arginine combines with eNOS to form nitric oxide –>
Guanylyl cyclase turns GTP into cGMP –> cGMP increases levels of PKG–> PKG phosphorylates MLCK –> Reducing the activity of MLCK –> relaxation
PKG can also phosphorylate the Ca++ entry channels on the vascular smooth muscle –> closing them–> relaxation
ACh & Bradykinin binding to mACh-r on the endothelial cells
ACh & Bradykinin bind to the mACh-r on the endothelial cells –> Increasing the amount of Ca++ in the endothelial cell –> Ca++ + Calmodulin in the endothelial cells causes an increase of eNOS
–> NO –> diffuses into VSMC –> Guanylyl cyclase turns GTP into cGMP –> cGMP increases levels of PKG–> PKG phosphorylates MLCK –> Reducing the activity of MLCK –> relaxation
cGMP breakdown & Phosphodiesterase
cGMP is unstable, typically breaking down into GMP on its own. Can speed this process up by increasing activity of phosphodiesterase.
Can inhibit the breakdown of cGMP by giving phosphodiesterase inhibitors
Alpha 1 Receptors
Serotonin follows this pathway as well. Serotonin is only NT to do what?
Gq GPCR –> Phospholipase C activated –> cleaves PIP2 into Dag & IP3 –> IP3 liberates Ca++ from SR , combines with CAM –> Increased cross-bridge cycling of myosin head
DAG –> Activates PKC
Serotonin is the only neurotransmitter that can constrict brain blood vessels. Can be used for headaches
Smooth Muscle & Action Potentials
-Does not need an action potential to contract. Can contract from Ca++ leaking into the cell
-Can produce periodic, oscillatory waves in a rhythmic pattern: Considered pacemaker activity. This is the pattern of the action potentials in our small intestine
-Action potential with a plateau period: Typically in the heart, caused by slow L-type Ca++
Contraction of the cardiac muscle
-Similar arrangement of sarcomeres as skeletal muscle
-Heart has very large T-Tubules. This is where Ca++ sits, and is typically the source of Ca++ that comes through the cell wall
-Na+ induced action potential converts into a Ca++ dependant action potential –>
-Ca++ comes into the cardiac muscle cell initially through T- Type (fast) and later through L-type (slow) Ca++ channels –> causing Ca++ induced Ca++ release from the SR–> ~80% of Ca++ gets put back into SR via calsequestrin binding to Ca++, removing it from solution, making it easier for the SERCA pump to push Ca++ back into the SR
The remaining 20% leaves via the Na+, Ca++ exchanger or the PMCA
~20% of Ca+ being used comes from the ECF, ~80% coming from the SR. 1:4 Ratio
