Introduction

We've been looking at how our bio-electrical system works.

• A current is passed along the wires (excitable cells) of our bioelectrical systems.
• Charge (a current) is the only thing that moves in an electrical circuit.
• The current is pushed by a voltage.
• Bioelectrical systems have such a high internal resistance that the voltage to keep the current moving must be continually recreated along the path of the current.
• The physiological event that recreates the voltage along the pathway is called an action potential.
• The triggering event for an action potential is the increase in membrane potential increase caused by the rapidly dissipating currrent created directly upstream from the site of the AP.
• We call this membrane potential increase a generator potential.
• An AP is always caused by a generator potential.
• In our sensory system, the first generator potential is created by a receptor cell.
• Every sensory receptor cell has solved a transduction problem.
• The transduction problem that was solved was how to create a current that is proportional in magnitude to the particular phenomenon being sensed (sound, touch, taste, smell, etc.)
• The receptor cell therefore creates the first generator potential along the sensory pathway.
• In some cases, the solution is to distort the receptor cell or appendages on the receptor cell to mechanically open ion channels that create the generator potential (pressure, hearing, balance).
• In some cases, the solution is to use a sensing protein that is sensitive (changes its structure in response) to the environmental phenomenon.
• This structural change is detected by an intracellular signalling system (e.g., the G-protein system) that will then activate a ligand gated ion channel that creates the generator potential.
• The ligand attachment site is in the cytosol, rather than the extracellular fluid (as was the case for transfer of the current across a synapse).
• Examples: vision, smell (olfaction), some tastes (e.g., sweet).
• The current that is passed from the sensory receptor cell to the brain is periodically broken by the end of one neuron and the beginning of another.
• A synapse consists of the terminal bulb-gap-section of the dendrite/cell body that handles all the steps of recreating the current on the other side of the gap between the cells.
• (the synaptic cleft is the gap between the cells).
• The details of the process were handled in earlier readings.
• The magnitude of the generator potential created in the receiving neuron determines whether the current is passed along the next neuron.
• The magnitude of the generator potential from a single terminal bulb can be augmented by the next generator potential from the same terminal bulb (temporal summation).
• The frequency of the AP's in the preceeding neuron must be great enough to support rapid sequential synaptic transmissions.
• OR multiple terminal bulbs from the same neuron must be involved (spatial summation).
• In either case, the neurotransmitting substance must be excitatory (resulting in opening of ligand gated Na channels on the down-side of the synapse).
• It is also possible to suppress current transmission.
• Terminal bulbs are either excitatory OR inhibitory (they cannot be both, they cannot change function).
• Terminal bulbs from a different neuron may prevent the passage of a current (or reduce it's magnitude) through the use of inhibitory neurotransmitting substances.
• Inhibiting NTS activates ligand gated potassium or ligand gated choride channels to reduce the magnitude of the generator potential by decreasing the positive charge concentration.

The afferent neurons that carry information to the brain are hard wired into the parts of the brain that will initiate the processing of the information.
 

Somatic senses: (touch, pressure, heat, cold, and pain) are hard wired into the brain. These are are passed up the brain stem. All but pain are routed to the somatic sensory cortex located along a strip across the top surface of the brain. Pain signals communicate with the cortex and with other parts of the brain. All the other sensory inputs have centers located in different parts of the brain.

The figure at right shows the somatic sensory cortex on the left side of the brain. The sensory cortex in the left brain receives information from the somatic neurons from the right side of the body, and vice-versa.  As illustrated by the figure, somatic inputs are not evenly distributed along the body surface: Face, tongue, hands, and genitals have greater somatic sensitivity than arms, legs, back, etc.

• Sensory receptors are sometimes stand alone cells and sometimes modified dendrites connected to a much larger neuron.

Notice the nucleus in the hair cell.  The receptor is a fully functional cell not dependent upon the sensory neuron for control, resources, etc. Taste and vision receptors were similar.

For other receptors, the sensory apparatus is mounted on modified dendrites of the neuron that also carries the signal. Pacinian corpuscles and olfactory neurons are like this. Many of the pain receptors that we will talk about today are also "modified nerve endings".

Repeating something ...

In addition to solving the transduction problem, sensory recptors have solved a much more basic problem.

They have solved the problem of how to create a current in our electrical system.

• We have the wires.
• Wires don't produce currents.
• Where do the currents that pass through the wires come from?
• Now we know about the currents that tell us about our environment.
• What about the current that constitutes a decision to act or a thought (that originates in the brain)? Where do these currents come from?

Rods and cones are photo receptors. The other receptors respond to chemicals (chemoreceptors) or mechanical events (streching, movement of stereo cilia, etc., mechanoreceptors)
 

You saw last time that light must pass through the ganglion and bipolar cells before it reaches the light sensitive receptor cells. The pigment that responds to photons is located within the rod or cone.

Here is a closeup showing the arrangement of pigment discs within a rod.

On the left is another view of the disks in a rod.  On the right is the protein rhodopsin in the structural mesh that makes up the disc.  Rhodopsin contains the 11-cis retinol that allows vision to occur.

When a photon strikes the retinol, it causes a C-C bond to break and the cis-retinol changes its conformation (into the trans form).  The retinol is embedded within the protein rhodopsin. What do you think happens to the rhodpsin when the retinol changes conformation? What do you think this initiates?

Just for review: here is the sequence of events that we dicussed last time.

 

More Review: Neural Superhighways. In an earlier reading, we referred to aggregates of neurons that are bundled together in the central nervous system. recall that their myelin came from oligodendricytes rather than Schwann cells.  Note that bundles of neurons (each having it's own covering) are called fascicles.  You will see this term again when we get to skeletal muscles.

Courtesy J.R. Schiller, Austin Peay State University

Pain

We haven't talked much about the brain yet. We'll start to do so (a bit) today.

Pain is fundamentally different than our other sensations.

• Not in the methods used to generate currents.
• Pain is pretty conventional, in that sense.

• Rather, it differs in what it is looking at and where it goes when it arrives in the brain and How it is processed.
• In all of the other senses, we are solving the transduction problem for a specific environmental event or process.
• Salt in your mouth.
• Photon intensity, density, and wavelength in your eyes.
• Pressure waves in your ear.
• With pain, we are looking for artifacts of damage.
• Burning
• Intense cold
• Ripping of tissue
• Intense pressure
• Events related to disease.
• All of these relate to specific types of damage.

Also, for sight, hearing, touch, smell, and taste, there are specific regions of the brain to which the neurons for that particular sense are "hard wired".

• Flinching dogs.
• Long term debilitating effects of torture.
• The anticipation of the syringe is usually worse than the fact.
• This is a very different response than we have to other electrical inputs through our afferent sensory neurons.

Pain Receptor Cells Pain receptors do not fall into a neat package. In fact, it's such a hodge-podge that if it wasn't so important I would skip it. But it is important and we will step through some of the basic information on how the pain transduction problem works.

For most of our senses, it's just a transduction problem, and we are aware of the specific entity that we sense:

• Photons in the visible range - sight
• Compressional waves in air - hearing
• Chemicals floating around in the air - smell
• Pressure on our skin - touch
• Chemicals dissolved in our saliva - taste

• "The pH has dropped in my finger." Instead, we say ouch!
• "A cell in my finger has split open." Instead, we say ouch!
• "The potassium concentration of the extracellular fluid in my finger has increased." Instead, we say ouch!

But this is what the sensors that perceive pain (the "nociceptors") respond to.

The Role of Pain

• Pain differs from other systems in that it is a "damage alert" system.
• Vision, smell, and hearing may alert you that a predator is approaching.
• The pain of the attack alerts you that the predator has inflicted damage.
• Purpose of pain?
• Avoidance of additional damage (eat on the other side of your mouth).
• Allow healing to occur (rest).

• In the Transport class, you should have learned that there is no such thing as heat.
• There is thermal kinetic energy that our temperature receptor cells respond to and we perceive as "heat" or "cold".
• Similarly, there is no such thing as pain.
• There are pain receptor cells (called nociceptors) that respond to a variety of environmental events.
• When they create a current in response to one or more of these events, we perceive it as pain in the pain centers of the brain.
• There is also nueropathic pain (e.g., referred pain, phantom pain, pinched nerves) that is a currents in a pain conducting neuron that is initiated somewhere (other than the receptor) along the elctrical neural pathway.
• Pain receptors are found in many parts of the body (skin, muscles, joints, some internal organs

There are 5 general types of nociceptors:  Thermal - Detect hot or cold noxious stimuli.  Different than receptors that respond to a little bit warm or cool. Mechanical - Detect noxious pressure or deformation, such an an incision. Are activated only by extreme deformation (e.g., stretching or pressure). Chemical  - Respond to many different types of chemicals.  Polymodal "Sleeping" or  "silent" - Only respond to post-injury inflammation.

Many sensory receptors are just modified dendrites of a generalized neural cell (they resemble pacinian corpuscles, in that respect).  The modification consists of the actual receptor sites located on neural dendrites.  We saw this appraoch (different chemical receptors on otherwise identical cells) when we discussed olfaction (smell).

Courtesy University of Southern California

Nociceptors are the undifferentiated terminals of small myelinated or unmyelinated neurons.

Pain Receptors. There are a number of receptors involved in transduction of the pain stimuli into a current carried to the brain.

Heat sensitive receptors. Above a threshold of 43 C these heat activated channels will open, allow cations (Na⁺ in particular) to flow into the cell, thus causing a depolarization. The greater the stimulus temperature above threshold the greater the current (the greater the frequency of action potentials). These neurons are distinct from the heat sensitive sensory neurons which will respond to increasing temperatures that are non-painful. The two types of sensory neurons are active in different temperature ranges).

Receptors associated with tissue damage. A number of chemoreceptors respond to chemical changes associated with tissue damage.

After a significant injury several things happen in the vicinity of the damage:
 

There is a local decrease in pH as the contents of cells spills into the tissue, as cell interiors are generally more acid than the extracellular space. There is an outflow of potassium ions from ruptured cell contents. There is an outflow of ATP from ruptured cell contents. Leakage of plasma occurs from damaged capillaries. The leaking plasma contains a variety of chemicals and enzymes which influence the local tissue cells.  The most important for pain production is bradykinin.

Receptor types that respond to these chemical changes include:

• pH-gated channels. These are H⁺ sensing channels that responds to pH below 6.5 .
• These receptors are also stimulated by exercise (a carbon dioxide increase associated with exercise lowers pH in the vicinity of the exercising muscle).
• This appears to be the same mechanism as capsaicin receptor (taste that detects spiciness of chili peppers).
• Both Na and Ca flow through same channels and contribute to the generator potential.
• ATP gated channels. ATP is released from damaged cells. ATP-gated ion channels are found in nociceptors (ATP is the ligand in these ligand gated channels).
• Bradykinin. Damaged cells release proteolytic enzymes which result in the break down of a preprotein into a peptide called bradykinin.
• Bradykinin binds to a receptor that activates a G protein sequence.
• The G protein sequence includes a second messenger that acts as the ligand for a ligand gated Na⁺ channel to depolarize the sensory neuron (as seen in olfaction)

Other substances increase sensitivity of nociceptors (make them more liable to create currents):

• Potassium leakage from ruptured cells.
• Potassium increases membrane potential without opening channels.
• Increasing [K]_out  decreases the negative current (leakiness of the cell membrane to potassium) and raises the nernst potential.
• This results in increased membrane potential (as described by the Goldman equation).
• Serotonin. Released from platelets (platelets are cell fragments that originate in bone marrow and are essential for clotting).
• Histamine. Released from mast cells (mast cells are what control many of the body's allergic reactions). When the body comes into contact with an allergen, the mast cells release histamine-containing granules. A series of events unfold, ultimately causing swelling.

• substance P  - released from active nociceptors - provides additional excitation along the neural pathway (summation) to make the pain more "noticable".

The mode of action in hypersensitivity is still under investigation:

• In some cases, receptor cells implicated in hypersensitivity create a cross membrane curent which increases membrane potential, moving it closer to the threshold required for a generator potential to initiate a current to the brain.
• In this case, a smaller generator potential in the nociceptor results in a current to the CNS indicating a painful experience.
• In other cases, it appears that the chemicals alter the protein conformation of the receptor, directly increasing the receptor's sensitivity to the noxious stimulus.
• In this case, the receptor responds at a lower level of stimulation, producing a generator potential that leads to an AP with a smaller provocation (e.g., a very light bump).

Visceral Pain

"Visceral pain is pain that results from the activation of nociceptors of the thoracic, pelvic, or abdominal viscera (organs).

• Visceral structures are highly sensitive to distension (stretch), ischemia (loss of oxygen supply),  and inflammation.
• They are relatively insensitive to other stimuli that normally evoke pain such as cutting or burning.
• Visceral pain is diffuse, difficult to localize and often referred to a distant, usually superficial, structure.
• It may be accompanied by symptoms such as nausea, vomiting, changes in vital signs as well as emotional manifestations.
• The pain may be described as sickening, deep, squeezing, and dull." (paraphrased from Wikipedia).

Referred Pain

The presumption that pain originates at the perceived site of that pain can be incorrect. Sometimes the neural signal that tells us that a particular part of the body "hurts" does not originate at a receptor cell but rather along the path between the receptor cell and the brain. This is called "referred" pain.

Referred pain is pain from a malfunctioning or diseased area of the body that is perceived as though it was originating in another area, often far from the actual site of damage or disease. A common example is found in a person having a heart attack. In this case, pain may be experienced down the inside of the left arm and forearm. There are other common manifistations, including:

• the gall bladder referring pain on the top of the right shoulder.
• a diaphragm problem may be felt in the shoulder and neck.
• stomach problems may refer to the spine between the shoulder blades.
• kidney pain may be felt in the groin area.
• a problem in the throat may be referred to the ear.
• intestinal dysfunction may be felt in the middle or low back.

In the case of referred pain associated with heart problems, it is known that pain from angina or myocardial infarction (the term for an actual heart attack is "myocardial infarction") is transported via afferent nerve fibers that enter the spinal cord on the left side (see figure at right). In the process of entering the spinal cord, the afferent neuron from the heart passes close to the primary and secondary somatic neurons that communicate pain from the left arm.

The actual process of how a current in one neuron creates a current in an adjacent neuron is not completely understood. The conventional wisdom, at present, is that the unmyelinated afferent pain neuron connecting the organ to the spinal column passes near to the cell body or dendrites of a secondary afferent neural pathway that services another part of the body (the "area of referral" in the figure at right). A complete neural pathway consists of multiple neurons (see figure, far right), For receptor pathways, the primary neuron carries the current from the receptor to the spinal cord. A secondary neuron then carries the current to the brain (usually the thalamus) where it is passed off to a tertiary neuron that transports the current within the brain (usually to a location in the cerebral cortex). The local electrical activity along the unmyelinated deep organ path appears to create a generator potential in the secondary neuron that services the area of referral. Since the axon of the primary neuron that services the arm is myelinated, it is less likely that the induced generator potential would occur there. It is more likely to induce the generator potential in a dendrite or the cell body of the secondary neuron. In this way, a current is created that appears to indicate that pain is coming from the area of referral. In the case of a myocardial infarction (heart attack) the referral area is the left arm.

• For other internal organs the same phenomenon involves other referral areas. These are shown, below.
  

How Does a Local Anesthetic Work? (source: Stan Lee-Son)

Local anesthetics block conduction along nerve pathways by inhibiting the creation of action potentials.

• During depolarization, the major excitatory process is the opening of sodium channels to allow Na⁺ ions into the neuron.
  
•  If you can block depolarization, you will block or reduce the propagation of the current to the part of the brain that processes pain.
  

A local anesthetic binds to sodium channels, blocking Na+ transport during depolarization.  In myelinated neurons, it is assumed that 3 consecutive nodes of Ranvier must be effected to halt action potential propagation.  This is partly because it is difficult to block all of the sodium channels at any one node of Ranvier under physiological conditions. It is also because a very strong receptor potential (generator potential created by the receptor) may be strong enough to propagate a current to the next location where an AP occurs, if the first location fails to depolarize.

The figure at right shows the response of a myelinated rat neuron to increased concentrations of lidocaine.  The neuron was electrically stimulated. Dosing was adjusted to create the lidacaine concentrations at The measurements were taken at a site beyond the effected nodes of Ranvier. Notice the attenuated response at 30 uM and the complete loss of activity at 100 uM. At 30 uM, the primary observable response downstream from the effected nodes is a reduction in the frequency of the measured AP's. The rate of each depolarization/repolarization that we see has not changed very much. It is the generator potential reaching beyond the effected sites that has been reduced. We know that this is true because the frequency of depolarizations has decreased.  Using 100 uM concentrations at the effected nodes of Ranvier completely eliminated the current downstream along the pathway. Notice also the "washout" diagram (shown here to illustrate that the nerve returned to approximately initial condition after tests). Question: One of the reasons that three nodes of Ranvier must be effected is that it can be difficult to block enough Na channels to prevent depolarization from occurring at a node of Ranvier. Would complete elimination of all APs at one node of Ranvier necessarily be sufficient to completely block pain from passing to the brain?

Courtesy British Journal of Anaesthesia (linked to original paper)

Lidocaine in a living organism diffuses away from the sodium channel. That's why Lidocaine "wears off" after a few hours. The rate of diffusion increases with increasing perfusion with blood. Since most local anaesthetics also cause vasodilation (relaxing smooth muscles by the same mechanism), it has been suggested that methods to promote vasoconstriction could enhance the effects of many local anaesthetics.

Fine Control of Movements by the CNS

We mentioned in passing that finely controlled body movements require detailed control of body musculature. We will be starting the "muscles" section of this course soon. We will anticipate a little of the muscle material in today's discussion of muscular control by neurons.

In our bodies, movements of the skeleton involve contraction and relaxation of specific muscles arranged around joints connecting two bones.

• Every muscle that pulls a joint in one direction is opposed by a muscle whose contraction leads to the opposite movement (i.e., flexors and extensors).
  
• Muscles consist of bundles of cells called muscle fibers that shorten when stimulated.
  
• Motor neurons synapse with muscle fiber cells. Each muscle fiber has one excitatory synapse from a motor neuron using acetylcholine as a neurotransmitter.
• The magnitude of the current received from the motor neuron determines how much each muscle cell contracts and how many muscle cells are recruited (you'll see how this works, later).
• The magnitude of the current sent through a neuron depends upon the size of the generator potential that creates it.
• This is true of a current created by a receptor cell that is sent through an afferent neuron or the current sent from your brain through an efferent neuron.
• Generator potentials that arise from a receptor cell can be referred to as "receptor potentials."
  
• Generator potentials that can be varied (which is really all of them) in either afferent or efferent neurons are often referred to as "graded potentials."
  

A reflex is one instance in which the receptor potential that occurs in the afferent neuron is equal to the graded potential that determines the current in the motor neuron. How do we know this is true?
 

Reflexes

We spoke briefly about reflex arcs in a previous document. Reflexes are involuntary movements initiated by sensory stimuli.

Recall the stretch sensor in the knee jerk reflex. Sensory stimuli (like the stretch sensor) activate interneurons that are part of simple circuits in brainstem and spinal cord. These circuits coordinate excitation and inhibition of motorneurons to initiate simple, highly stereotyped movements such as the stretch reflex and the pain reflex ("crossed extension reflex"). The advantage of having reflexes is that they permit rapid responses when necessary (flight behavior in many animals). The disadvantage is that movements occur without input from higher centers and are "unrefined" (i.e, they lack the capacity for a graded response). Example: when your daughter tickles you while you are carrying a full cup of coffee.
 

The sensors, which we called "spindle fibers" are also called "proprioceptors" (sensors that sense themselves - i.e., the state of the entity that they are part of).

Courtesy J.R. Schiller, Austin Peay State University

 

Stretch: deformation (stretching) opens sodium gates.  There are two kinds of muscle spindles:  AP frequency is proportional to the speed of stretch AP frequency is proportional to the degree (amount) of stretch.  Also important in providing information that relates to maintenance of posture.

Stretch Reflex. A stretch reflex is a reflex excitation of extensors or flexors to maintain fixed body position against a disruptive force such as gravity (e. g. knee jerk reflex) or change in load on a muscle (see below). It's purpose is to work against the applied load (push toward the stimulus) so that the position of the body is not greatly changed (for example, as the weight of the mug in the figure below increases we want the mug to remain in approximately the same location).

It's initiated by stimulation of a stretch receptor in a muscle and it results in increased excitation of synergistic muscles (muscles that help to reach the end result of the reflex - i.e., the flexor in the figure below) and inhibition of antagonist muscles (those muscles that would work against the purpose of the reflex - i.e., the extensor in the figure below).

The stretch reflex shown below is also an example of a graded response. The amount of flexor contraction appropriate to maintain the position of a filling mug is different than the amount of contraction appropriate to maintain position if someone puts a 50 lb sack of cement into your arms. The sack of cement will result in a greater stretching rate than the filling mug. Muscle spindles that respond to the stretch rate will produce AP's at greater frequency in response to the heavier object and so the reflex response will be a more vigorous muscular response.
 

The example shown above is essentially the same as the "hammer-knee" example from last reading. Stretching of the propioceptor results in an AP that arcs back to an excitatory terminal bulb at the flexor and an inhibitory terminal bulb at the extensor. The amount of force generated by the reflex is a function of the rate of stretching of the proprioceptor. A rapid stretch results in a burst of high frequency AP's that results in a more vigorous muscular contraction (e.g., being passed a mug of a drink or a bag of cement results in a different degree of muscular response).
 

Pain Reflex (“Crossed Stimulation”). There are times when you would rather have a reflex that pulled away from a stimulus rather than pushing toward it. Stepping on a tack is an example of such a time.  A pain receptor sends a message that is routed both to your consciousness ("Ouch!") and to a reflex circuit.  Using the figure at right, the reflex excites the motor neuron to the right side flexor (to pull your foot back) and inhibits the motor neuron to your right extensor (to cooperate with the flexor signal).  At the same time, it does the opposite to your left leg: inhibiting the flexor and exciting the extensor. This helps you to maintain balance while getting off the tack as expeditiously as possible.