Function | Pain

Physiology of Pain

Stepping Stone to the Clinical Strategies in Pain Program

James Armstrong PA

Ashley Davidoff MD

Introduction and Principles

The conceptual basis of any of the functional units in the body include an ability to receive, process and produce.

In this context, the sensory pain units receive a signal, process it and produce a result, usually by cognition and transmission of a modified stimulus to another functional unit. There are three separate functional transmission units that take the stimulus from the periphery to the brain, then to a matrix of interconnected processsing units before an integrated response is produced. The first, second and third order neurons play a relatively simple role in this process. However the chain of reactions that they cause in the processing units is complex and in many instances not well understood. Subsequently, the adaptation to the painful stimulus is designed to be protective and individualized to a given patient founded upon their character and experience.

The first order neuron receives a stimulus from an internal or external environment of which it has some cognition based on the type of receptor stimulated and it then has to convert that stimulus into electrical activity. This process is called transduction. The fiber then transports the electrical activity along a selected neuron or group of neurons appropriate for the stimulus to a processing station, which for the neuron is a synapse. This second process is called transmission.

The synapse in the dorsal horn of the spinal cord acts as a processing station and is itself a functional unit. It receives stimuli from many sources, coordinates them from other sensory and biochemical impulses in the tissues and input from descending fibers, and transmits a modified stimulus to the second order neuron. The second order neuron receives and transmits the impulse in the spinal cord to the thalamus.

The thalamus receives the impulses, separates the stimuli into two discrete functional groups, provides some cognitive perception of the pain, and transports and directs the impulse to two main areas of the brain. These are the somatosensory cortex where cognitive localization is achieved and the affective-motivational system where behavioral, emotional, and cortical functions are utilized.

The somatosensory cortex, limbic and autonomic systems and the motor, cingulate, and prefrontal cortices coordinate effort and produce a response which may be in the form of a withdrawal, a cry or an autonomic response. In addition, a fourth order process occurs as modulation messages are sent via a descending tract to the synapses between first and second order neurons.

Each of these processes is a complex physiological and biochemical event and requires feedback mechanisms and control mechanisms. We will follow the process chronologically.

Generation of the Afferent Stimulus

The stimulus from the external or internal environment is recognized for what it is ie a light pressure, heavy pressure, cut, pinprick, hot cold vibration. or aberrant chemical. An approriate sensory receptor or group of sensory receptors is excited. The stimulus has to be converted into an electrical force. This process of changing the stimulus of the environment to an electrical impulse as noted is called is called transduction.

Transduction

Transduction is the conversion of an environmental stimulus into an electrical signal within a cell. For some cells, the external signal may be hormonal as with the action of insulin on the insulin receptor of the cells to enable the entry of glucose. For other situations, the signal may be a peptide, a protein, or a drug. In the sensory system and more specifically the pain pathway a mechanical, thermal or chemical stimulus is converted into an electrical signal.

The major actor in the generation of the electrical gradient is the sodium ion which under basal resting conditions is actively pumped out of the neuron. When the neuron is stimulated, a brief and rapid influx of sodium changes the electrical milieu, and transduction takes place.

Transduction

Converting the Stimulus into an Electrical Impulse

The diagram shows sensory stimuli including sharp pressure, generalized pressure, extreme heat and cold, and chemical substances stimulating the free nerve endings of the nociceptors. The nociceptors are linked to the myelinated A delta fibers and non myelinated C fibers. When the free nerve endings are stimulated by a mechanical thermal or chemical stimulus, the sensation causes the sodium gates to open and allows sodium to rush in creating a new electrical environment and thus changing the stimulus into an electrical signal. This process is called transduction

87559pc08b07.8s pain free nerve ending nociceptor A delta fibres heat cold pressure mechanical transduction electrical stimulus positive negative prick afferent somatosensory nerves somatic anatomy normal Davidoff art Copyright 2008

The deformation of the nociceptor caused by a mechanical force in turn causes an increase in ion conductance. Consequentially, there is depolarization of the receptor by an increased sodium influx into the neuron. A similar increase in conductance is created by thermal receptors where a change in calcium, potassium and sodium ions create the electrical gradients. A change in the chemical environment such as may occur with a chemical injury will, by nature of the reagents, cause a change in the electrical environment as well.

The mere presence of change in the electrical environment within a neuron does not necessarily imply that the stimulus will go to the next step of transmission. The membrane potential has to reach a finite threshold in order to generate a sufficient voltage difference. This generates an action potential, and subsequently an electrical wavefront.

Thresholds of Nerves

The threshold of a nerve is the minimal stimulus needed to elicit an electrical impulse that will be conducted.

The threshold of a nociceptor is the minimal painful stimulus required to induce transmission of the stimulus along the first order of neurons. The threshold for pain can be altered by disease processes like inflammation which decrease the threshold and subsequently sensitize the environment and promote pain. Theoretically, this is an adaptive and protective phenomenon to promote rest and healing.

Basal Electrical Potentials

Electrical potentials occur across virtually every cell in the body, but only nerves and muscles are excitable tissues with an ability to transmit an electrochemical signal. Under basal conditions in the non excited state, there is a slightly negative charge on the inside of the cell membrane and a slightly positive charge on the outside, so that there is a resting membrane potential of -70mV to -90mV across the semipermeable membrane. This balance is achieved by an active process of transporting sodium ions out of the cell and to lesser extent, potassium ions into the cell across the membrane. The Na+K+ATPase pump uses energy to move 3Na+ out for every 2K+ into neuron. The imbalance in voltage creates a positive charge on the outside and negative on the inside. In addition, the ionic gradient causes a smaller passive diffusion of sodium ions across the membrane, and to a lesser extent, passive diffusion of potassium.

The Sodium Potassium Pump – Resting Membrane Potential

Cell membranes in general and the neurons more specifically have resting membrane potentials of betweeen -70mV to -90mV The inside wall is relatively negative compared to the outside charge on the other side of the membrane which is relatively positive. This is due to the sodium and potassium pump. Sodium (orange) is the major player and under basal resting conditions it is forcefully and actively evicted from the cell by a pump (big orange arrow). To a lesser extent, potassium is pushed into the cell (big purple arrow). The chemical gradients that result cause passive but lesser movements of sodium into the cell (small orange arrow) and potassium out of the cell (small purple arrow).

72045b04.800 nerve conduction force electricity electric force positive force negative force sodium pump Na pump Patassium pump K+ pump diffusion conduction of impulses Davidoff drawing Davidoff art Davidoff MD

There are a variety of terms related to the electrical potentials we have to be familiar with.

The resting potential is the basal ionic steady state across the cell membrane caused by the Na+ K+ ATPase pump that creates a negative polarity of -70mV to -90mV with the inside of the membrane being negative and the outside positive.

The threshold electrical potential is the minimal electrical potential required to induce an action potential. To acquire the threshold level, the electrical potential has to change from a resting value of about about -70mV to about -55mV. This change infers that the inside of the cell has become more positive. This positivity occurs as a result of early sodium (Na+) influx into the cell.

Depolarization is the term used to define a relatively positive change of the resting potential inside the cell that is caused by a stimulus in the internal or external environment. The mechanism is primarily induced by the rush of sodium ions (Na+) into the cell.

The action potential is an electrical surge that occurs inside the cell once the the threshold potential is reached. It has an all or nothing quality. If the threshold is not reached, an action potential is not generated. If the threshold potential is achieved, then an action potential is generated that has a peak potential of about +30mV. At that level, there are changes in the cell that cause the repolarization to occur so that the electrical mileu returns to its resting level of -70mV.

Repolarization is the term used to describes a return to the basal negative potential of the cell after depolarization occurs.

Potentials Across the Membrane

The diagram illustrates some of the terms described in reference to the yellow nerve where resting potential (green) is -70mV, threshold (teal) is -55mV, and the peak voltage reached (red) is +30mV.

72045 d01b03b02.8s nerve resting membrane potential negative positive threshold potential peak electrical gradient normal physiology Davidoff art Copyrght 2008

The series of diagrams below follows the stimulus from the time it arrives at the receptor to the time it induces an integrated response. The first elemental event happens in milliseconds but has taken thousands of years of evolution to refine. It is so complex that it takes volumes of texts and years of research to refine. The explanation below only touches the surface of complexity. Many aspects are still not understood but generally chemical and electrical forces are recruited and each induces a chain of “action-reaction” events. ie “this does this and causes this to happen which then causes this to happen.”

The Stimulus Causing Sodium Gate to Open

The first event after the stimulus (red asterisk and red arrow) is mainly one of opening an ionic gate that will allow sodium to rush into the cell.

When stimulated, the major event is the transient influx of sodium into the neuron which, if sufficient, will depolarize the cell and change the internal negative charge to a positive charge.

Initiation of the Electrical Pulse

The stimulus has to be of sufficient intensity to enable appropriate quantities of sodium to enter the receptor during the stimulation. If the ionic threshold is not achieved, the designated charge is not created and nothing results; ie the stimulus does not warrant a reaction.

Sodium Gate Opened

When the nerve fiber is stimulated, the sodium gate is opened. If the stimulus is not intense enough, the threshold is not reached, an action potential is not generated and the stimulus is not sensed. In this diagram, the red arrow and red star reflect the stimulus, the sodium gates on the top of the diagram ope and sodium ions rush in, and the upward trend of the orange line on the graph is caused by the influx of sodium through the open gates. Since the threshold level of -55mV has not been reached, no action potential is generated, and the stimulus therefore is not sensed or recognized.

72045 d01b04h01.81s stimulus sodium gate open sodium rushes in depolarisation not to threshold stimulus is strong enough to keep gates open and sodium continues to rush in nerve resting potential threshold stimulus sodium gate opened Davidoff art copyright 2008

The severity of a pain stimulus depends on may other factors including the chemical mileu. In disease, and specifically in inflammation, the chemical balance is changed and sensitivity to pain may be increased causing a relative decrease in the threshold level. The single neuron however knows only this; ” If you inspire me, I give you only one response. I will take your message to the next synapse at the God given speed I have been endowed with. If you do not inspire me, your message is left undelivered! All I need to take your message, is a potential across my membranes of -55mv, and a relatively positive feeling inside of me.” The neuron is a simple structure as one unit, endowed with the ability to either act or not. It will then create a single end result of stimulus transmission but in combination with other signals. In concert with other processing stations, it can create a complex cognitive and adaptive response that is far from all or nothing.

If there is sufficient reversal of the negative charge to reach a membrane potential of -55mV then the action potential is initiated. If the stimulus does not depolarize the neuron and accomplish the magic number of -55mV then there is no further action. If the stimulus generates a membrane potential of 100mV then the same action potential and signal is generated; ie the intensity of the stimulus and the action potential generated on a single neuron is not a graded response.

If a greater amplitude does not give rise to a greater action potential, then how does the body distinguish between a strong as and a weak stimulus? The answer is that a strong stimulus will induce a greater frequency of action potentials and it is the frequency that translates to intensity of the stimulus.

Cause of Depolarisation

In this instance, the threshold level of -55Mv following the stimulus (red arrow and red star) has been reached and an immediate action potential is generated that causes depolarization to +30mv. This action occurs in about .5milliseconds and is the result of the entry of sodium ions into the cell while the sodium gate is open. The inside of the cell at that point of the action potential is now positive and the outside is negative.

72045 d01b04j.8s stimulus sodium gate open sodium rushes in depolarisation to threshold sodium continues to rush in action potential all or nothing physiology normal peak electrical potential of 30mV nerve resting potential threshold stimulus sodium gate opened Davidoff art copyright 2008

Once the action potential has been generated, the sodium entry gates close. Two major events result. First, a positive charge induced inside the cell will start a chain reaction down the cell fiber enabling the stimulus to propagate. The second event is the opening of the potassium “exit gates” allowing K+ to rush out of the neuron. The subsequent loss of positive charge enables the inside of the cell at the site of the stimulus to begin to return to a negative potential.

Beginning of Repolarization

After the discharge or depolarization and resulting action potential, (orange line) the sodium gates close and the potassium gates open allowing potassium (purple arrow) to rush out of the cell.

72045 d01b04l.8s stimulus potassium gate open potassium rushes out and start of repolarisation action potential all or nothing peak electrical potential of 30mV potassium gates open potassium rushes out physiology normal peak electrical potential of 30mV nerve resting potential threshold stimulus sodium gate opened Davidoff art copyright 2008

More potassium ions are lost to the inside of the cell than is necessary and there is a small overshoot causing the potential of the membrane to drop transiently below the resting potential.

Repolarization and a Little More

The diagram shows a return of the potential to below base levels (purple line) caused by a more than enough exit of potassium ions through the potassium “exit gate”

72045 d01b04n.8s stimulus potassium gate open potassium rushes out and start of repolarisation action potential all or nothing peak electrical potential of 30mV potassium gates open potassium rushes out physiology normal peak electrical potential of 30mV nerve resting potential threshold stimulus sodium gate closed more potassium than necessary exits causing an overshoot of baseline Davidoff art copyright 2008

At this stage, the Na+ K+ ATPase pump starts to work again with active eviction of 3 Na+ and importation of 2 K+ ions. Consequentially, the original action potential and thus basal conditions are restored at the site of the original stimulus. This process takes about 5 milliseconds.

But that is not the end of the story. As previously stated, there is a chain reaction that has been started in an “after me the flood” mode. The original positivity inside the cell and negativity outside the cell has consequences of huge magnitude down the long process of the neuron.

Action Potential Complete

Propogation Initiated

Early on at the peak of positivity of the orange line before the potassium gate opened, a region of the fiber was relatively positive on the inside and relatively negative on the outside (black positive signs on inside of cell). In addition the rest of the fiber during this time was opposite in charge with the inside of the cell negative and the outside positive. (basal conditions) So what now? There are positives and negatives that have to be electrically neutralized.

72045 d01b13a02.8s nerve action potential complete propogation initiated physiology normal sodium gate closed potassium gate closed action potential Davidoff art Copyrght 2008

Propagation and Transmission

Due to the initial influx of sodium ions, we noted that two events occur. We have dealt with the potassium gate and now we are going to look at propogation.

If you recall and review the diagram above, the consequence of sodium influx causes the charge on the inside of the membrane to become positive while the outside becomes negative. However, downstream and upstream in along the lengthy nerve process, there is the opposite environment of a negative charge on the inside and a positive charge on the outside. The opposite forces are too much to bear and so begins the cascade of positive to negative currents that generate a series of multiple circuits that occur both upstream and downstream. This process enables transmission and propagation of the electrical pulse to the nerve cell and ultimately via the short process to the synapse in the anterior horn of the spinal cord.

Start of Propagation Setting up of A local Circuit

The sodium that moved into the fiber caused a positive charge inside the cell and a negative on the outside which is in distinct contrast to basal conditions. Subsequently, circuits caused by movement of the charge from positive to negative are set up enabling the electrical impulse to proceed down the fiber. The diagram illustrates a fiber with a completed action potential at its peak. The black positive inside the fiber is shown with a yellow negative outside in one area of the nerve fiber. This area is juxtaposed to opposite charges of the resting conditions and circuit of movement of the charges positive to negative is set up.

72045 d01b13a04.8s propogation of electrical charge nerve sensory nerve action potential propogation both ways down the nerve fibre depolarise repolarise normal physiology nerve conduction Davidoff art copyright 2008

Local Repolarization

A cascade of electrical movements occurs along the gradient set up along the nerve, as charges move and create new circuits.

72045 d01b13a06b.8s propogation of electrical charge transmission nerve sensory nerve action potential propogation both ways down the nerve fibre depolarise repolarise normal physiology nerve conduction Davidoff art copyright 2008

Transmission and Return to the Baseline

As the impulse is propagated, the resting potential returns with a negative charge on the inside and a positive charge on the outside.

72045 d01b13a05e.8s progressive resestablishment of negative charge on the inside and positive charge on the outside propogation of electrical charge nerve sensory nerve action potential propogation both ways down the nerve fibre depolarise repolarise propagation normal physiology nerve conduction Davidoff art copyright 2008

The Propagation Continues

Returning To Resting Conditions

72045d01b13a054b.8s progressive resestablishment of negative charge on the inside and positive charge on the outside propogation of electrical charge nerve sensory nerve action potential propogation both ways down the nerve fibre depolarise repolarise propagation normal physiology nerve conduction Davidoff art copyright 2008

The transmission process executed through the mechanism of propagation proceeds along the long A delta fibers and C fibers, via the dorsal root ganglion. The signal then enters the spinal cord via the short process of the neuron where it synapses in the dorsal horn with other neurons.

The synapse in the dorsal horn of the spinal cord acts as a processing station and is itself a functional unit. It receives stimuli from many sources, coordinates the stimuli from other sensory and biochemical sources and descending fibers, and transmits a modified stimulus to the second order neuron.

The Synapse in the Dorsal Horn

The diagram shows the synapse (red ring) that enables the connection between the incoming neuron with a “processing unit” in the dorsal horn of the spinal cord that coordinates the input of multiple other stimuli and influences. The long process of the first order neuron brings the stimulus from the periphery to the nerve cell in the dorsal root ganglion. The short process takes the stimulus from there and transmits it to the synapse.

83066b08e.8s nociceptor A delta fober C fiber pain stimulus neuron receptor afferent pathway sensory dorsal ganglion dorsal column sensory pathway synapse presynaptic ending post synaptic ending synaptic cleft Davidoff Art Copyright 2008

Structurally the synapse has a presynaptic ending that is the end of the short process, a synaptic cleft that is the space between the two interacting neurones and a post synaptic ending which is the most upstream end of the next neuron.

Synapse

The synapse consists of a presynaptic ending, a synaptic cleft or space between the two connecting neurons, and a post synaptic ending.

72046b04a.8s mitochondria transmitter vesicles presynaptic terminal post synaptic terminal soma of neuron synaptic cleft acetyl choline norepinephrine dopamine serotonin forces chemical energy function principles Davidoff art Davidoff drawing Davidoff MD

The presynaptic ending contains synaptic vesicles, neurotransmitters, mitochondria and other cell organelles. The synaptic cleft which measures about 20nm is empty when the nerve is quiescent. The cleft becomes the venue for neurotransmitter activity when these compounds are released. The post synaptic ending contains receptor sites for the neurotransmitters.

The presynaptic ending also contains voltage gated channels that are sensitive to the voltage change elicited by the propagated stimulus. The postsynaptic ending has chemical gated ion channels that are sensitive to the chemistry of the neurotransmitters.

Smaller Components of the Synapse

Within the presynaptic ending there are vesicles that contain the neurotransmitters and a voltage sensitive gate that releases calcium ions when stimulated called the voltage gated calcium channel. It also contains mitochondria and other organelles that are responsible for the production and packaging of the neurotransmitters. Within the post synaptic ending, there are gated ion channels with chemical receptors that enable the generation of electrical signals.

72046b04d.8s presynaptic ending synaptic ceft post synaptic ending voltage gated calcium channel chemical gated ion channel neuroceptors synaptic vesicles containing neurotransmitters membrane voltage mitochondria nerve sensory berve synapse dorsal horn first order neuron second order neuron normal mitochondria voltage gated calcium channel synaptic cleft chemical gated ion channel organelles synaptic vesicle neurotransmitters physiology Davidoff art copyright 2008

Like all cells in the body and more specifically all nerves, there is a resting membrane potential created by the Na+ K+ ATPase pump to about -70mV.

Resting Membrane Potentials in Both Neurons

The resting membrane potential is created in both the first order neuron and the nerve it is linked to in the synapse. In both instances the resting potential is created by the Na+ K+ ATPase pump measures about -70mV.

72046b04b03.8s presynaptic ending synaptic ceft post synaptic ending voltage gated calcium channel chemical gated ion channel neuroceptors synaptic vesicles containing neurotransmitters membrane voltage mitochondria nerve sensory berve synapse dorsal horn first order neuron second order neuron normal physiology Davidoff art copyright 2008

The Signal Arrives at the Synapse

In this diagram, the orange arrow indicates the direction of the electrical impulse and depolarization that has reached the synapse and caused a relatively positive charge on the inside and negative charge on the outside. When this charge is felt by the voltage gated calcium channel on the presynaptic nerve, a reaction takes place.

72046b04b04.1.8s presynaptic ending synaptic cleft post synaptic ending voltage gated calcium channel chemical gated ion channel neuroreceptors synaptic vesicles containing neurotransmitters membrane voltage mitochondria nerve sensory nerve synapse dorsal horn first order neuron second order neuron impulse propagation transmission normal physiology Davidoff art copyright 2008

When the impulse from the short process of the first order neuron reaches the synapse, the voltage wavefront causes the voltage in the gated calcium channels to open and release calcium ions.

Voltage Gated Calcium Channel

Calcium Released

The electrical impulse at the presynaptic terminal stimulates the release of the calcium ions.

72046b04b04.2.8s presynaptic ending synaptic ceft post synaptic ending voltage gated calcium channel chemical gated ion channel neuroceptors synaptic vesicles containing neurotransmitters membrane voltage mitochondria nerve sensory berve synapse dorsal horn first order neuron second order neuron impulse propogation transmission voltage gated calcium channel releases calcium ions normal physiology Davidoff art copyright 2008

When calcium is released, it combines with intracellular chemicals and incites the release of neurotranmitter from the synaptic vesicle by exocytoses. The synaptic vesicle is a mere 40nm in diameter.

The Influence of the Ca++ ions on the Synaptic Vesicles

The electrical charge created by the calcium ions stimulate the release of the neurotransmitters into the synaptic cleft from the synaptic vesicles.

72046b04b07.8s presynaptic ending synaptic ceft post synaptic ending voltage gated calcium channel chemical gated ion channel neuroceptors synaptic vesicles containing neurotransmitters membrane voltage mitochondria nerve sensory berve synapse dorsal horn first order neuron second order neuron impulse propogation transmission voltage gated calcium channel releases calcium ions stimulates synaptic vesicles normal physiology Davidoff art copyright 2008

Release of the Neurotransmitters in the the Synaptic Cleft

Release of neurotransmitters such as glutamate and substance P into the synaptic cleft causes the chemical gated ion channel on the receiving neuron to open and allow entry of sodium into the post synaptic ending. This again changes the electrical balance and allows the impulse to be transmitted.

72046b04b09.8s presynaptic ending synaptic cleft post synaptic ending voltage gated calcium channel chemical gated ion channel neuroceptors synaptic vesicles containing neurotransmitters membrane voltage mitochondria nerve sensory nerve synapse dorsal horn first order neuron second order neuron impulse propagation transmission voltage gated calcium channel releases calcium ions stimulates synaptic vesicles to release neurotransmitters into the cleft which attach and stimulate specific receptors called chemical gated ion channel which results in sodium entry into the cell normal physiology. Davidoff art copyright 2008

The neurotransmitters released by the synaptic vesicles on the dorsal horn neurons include glutamate and other peptides like substance P. These act in a complex fashion to transmit the impulse and to sensitize the neurons in the synapse. Glutamate for example has its effect on local neurons while substance P has more far reaching effects. In essence, an influx of sodium (K+ Cl- or Ca++) into the post synaptic neuron will induce a positive charge and again set up a new action potential and electrical current for transmission. The neurotransmitter is then either destroyed or reabsorbed.

A New Action Potential

The end result of the complex changes in the synapse is a net influx of positive charge dominated by sodium ions causing depolarization of the post synaptic neuron. If the charge is sufficient enough to supercede the threshold level, an action potential is initiated and an impulse is generated.

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The synapse however is a complex and compound collection of many neurons all of which affect the message that is sent to the second order neuron. These factors modify and temper the primary stimulus by a variety of influences and is called modulation.

Modulation

Modulation is the process that modifies the primary sensory stimulus in the gray matter synapses of dorsal horn of the spinal cord. Modulation enables multiple influences to affect the stimuli emanating from the synapse to the second order neuron. A variety of factors including the effect of A beta fibers (non nociceptor) from other sensory events play a role.Other extraneous variables within the cortical, limbic, and autonomic systems modulate the signal by virtue of their functional characteristics. These include imminence of danger, visual and auditory cues, emotion, wakefulness, memory, experience, sympathetic and parasympathetic tone. They all influence first level discriminative, cognitive, and compound results.

Modulation

Inputs on the Synapse

The orange fiber is one of many carrying the original pain stimulus as the first order neuron. It joins many nerves that synapse with the second order neuron in the dorsal horn, including the white A beta non nociceptor fiber, ascending (yellow) and descending (purple) tracts from other levels of the spinal cord, and descending tracts from the cortex, thalamus and other hgiher levels (green).

77533b01e05.8s modulation C fiber A delta fiber A beta neuron cortical input RAS autonomic nervous system frontal cortex sensory cortex thalamus descending pathway spinal input gate control theory synapse first order neuron Davidoff art copyright 2008

Gate Control Theory

The gate control theory of Melzack and Wall in 1965 describes a mechanism that revolves around the modulation of the pain sensation at the spinal cord level influenced both by the afferent sensory fibers ( A beta, A delta, and C neurons) as well as by the descending modulation system. The descending mechanism originates at the levels of the cortex in regions that relate to emotion, memory, and experience. The integrated result sends a message via descending tracts to block (or enhance) pain sensation in the spinal cord where first and second order neurons synapse. The A delta and C fibers carry pain and the A beta fibers carry pressure, touch, vibration, and normal temperature sensation. The latter is able to inhibit the pain sensation by closing the gate for transmission of painful stimuli from the pain fibers. The location of the gate is at the level of the substantia gelatinosa (SG). When the the stimuli on the SG from the pain fibers dominate, the gate is open and there is a positive stimulus on the tract cells and second order neurons are activated and the pain stimulus is transmitted to the thalamus. On the other hand when the SG is stimulated by A beta fibers the gate is closed and there is inhibited activity on the tract cells and hence reduced or even inhibited signal to the thalamus via the spinothalamic tract.

Opening and Closing the Gate – at the Substantia Gelatinosa

The diagram illustrates the gate control theory. The incoming pain fibers are carried by the A delta fibers and the C fibers seen on the bottom left of the diagram. They enter the substantia gelatinosa (SG) and through the connection with tract cell (T) they will cause the gate to be open and cause the pain to be transmitted. The A beta fibers on the other hand carry pressure signals and through the SG will cause the gate to be closed and prevent the pain fiber from being transmitted.

gate contrrol theory pain A beta fibers A delta neurons c fibers substantia gelatinosa T cells dorsal horn of the spinal cord open gate gate closed Davidoff art Courtesy Ashley Davidoff MD copyright 2008 83168b06.8s

Second Order Neuron

The second order neuron shown in blue in all the diagrams is a group of nerves that receive a modified stimulus from the dorsal horn of the spinal cord and transport that stimulus to the contralateral side of the spinal cord to two major tracts; the spinothalamic tract and the spinomedullary tract. They transports information that relates to the intensity, character (sharp vs aching) and location of the pain. It should also be stated that when the stimulus is particularly noxious such as the hotplate example, a spinal reflex is created and there is a direct synapse with an efferent nerve to cause immediate withdrawal without complex modulation.

Second Order Neurone with Modified and Modulated Impulse

The pain fibers cross over the spinal cord via the second order neuron (blue) to the spinothalamic tract. There are two components to the anterolateral spinothalamic tract. The lateral spinothalamic tract (darker blue) carries the fibers for pain and temperature sensations and the anterior spinothalamic tract (light blue) carries sensation of simple touch.

The fibers are spatially arranged so that those coming from the cervical region (c), from the thorax (t) , lumbar (l) and sacral (s) regions are positioned in specific locations. Additionally within these tracts, the A delta and C fiber information is kept discrete allowing for qualitative cognition, while quantitative (ie intensity) information is also retained .

orange = sensory nerve carrying stimuli from periphery

yellow white pink and green fibers – modifying neurones affecting the synapse through the process of modulation

blue fiber – second order neuron

blue tract = anterolateral spinothalamic tract

dark blue tract = lateral spinothalamic tract

light blue tract = anterior spinothalamic tract

83067b05b07.8s There are two parts to the spinothalamic tract. The lateral spinothalamic tract and the anterior spinothalamic tract There are two parts to the anterolateral spinothalamic tract. The lateral spinothalamic tract and the anterior spinothalamic tract. The lateral spinothalamic tract carries slow and fast fibers for pain and temperature sensations and the anterior spinothalamic tract carries sensation of simple touch. orange = sensory nerve carrying stimuli from peripheryblue = anterolateral spinothalamic tract dark blue = lateral spinothalamic tract light blue = anterior spinothalamic tract Davidoff art Courtesy Ashley Davidoff MD copyright 2008

The second order neurons now ascend in the spinal cord, dominantly in the anterolateral spinal tract passing through the medulla, midbrain and then to the thalamus. En route the C fibers activate the reticular activating system (RAS).

RAS

The reticular activating system (aka RAS, ascending reticular activating system) is an ill defined part of the nervous system that structurally represents the upper part of the reticular formation which is a loosely arranged network of neurons distributed throughout the brainstem wherever there are no specific neural tracts or nuclei. It lies between the medulla oblongata and midbrain and is connected to the thalamus.

Functionally it is a part of the brain considered to be the center of arousal and motivation. It indirectly relates to our state of consciousness, and is involved with the control of the circadian rhythm, respiration, cardiac rhythms, and sexual function. Since it is connected to the thalamus it becomes by definition connected to many parts of the cerbral cortex, in addition to the basal regions and the medulla.

In the instance of pain, the RAS is activated by the C fibers and hence enables a painful stimulus to arouse us from sleep, create a sense of urgency, and can cause changes in heart rate or respiration rate. The proposed mechanisms are initially mediated through the release of chemical transmitters that create a change in the electrical mileu and the induction of a new electrical impulse in the RAS.

It appears that the opiate derivatives may block the action of the RAS and thus reduce and help treat and manage pain.

The C fibers of the Spinothalamic Tract Activate the RAS

The reticular activating system (aka ascending reticular activating system, RAS) (red herring bone) is a part of the brain considered to be the center of arousal and motivation. Structurally it lies betweent the medulla oblongata and midbrain and is connected to the thalamus. (orange)

In the instance of pain, the RAS is activated by the C fibers and hence pain can arouse us from sleep through the RAS, can create a sense of urgency, and can cause changes in heart rate or respiration rate. ascending spinothalamic tract

Functional Role of the Thalamus

The thalamus is a relay station to and from all parts of the spinal cord and brain and serves as an interpreter of information.

In the context of the pain process, it receives pain fibers (second order neurons) via the spinothalamic tract and directs them to the posterior medial and posterior lateral nuclei. The lateral pain system (venteroposteriorlateral VPL) projects via the lateral thalamic nuclei to somatosensory cortex where localization and duration of the stimulus is perceived. The medial pain system, (venteroposteriormedial VPM) projects through medial thalamic nuclei to the prefrontal and anterior cingulate cortices where the unpleasantness and emotional aspects of the pain is perceived.

Nuclii in the Thalamus

Thalamic pain centres dominantly involve the ventroposteriorlateral (VPL) and venteroposteromedial (VPM) nuclei centeromedian and pulvinar nuclei

pain thalamus pulvinar MRI T2 weighted Courtesy Ashley Davidoff MD 38694c03b01.8s

The lateral thalamic nuclei give rise to the third order neurons that connect with the somatosensory parietal lobe cortex in spatial specificity and “homunculus” distribution as described in the previous chapter. This implies that there are certain ares in the somatosensory cortex that represent bodily parts and that some organs like hands feet and mouth have much larger representation than others and by implication are more sensitive.

It should also be stated that the thalamus has cognitive function. It is not merely a relay center for the ascending fibers but has a processing function. It is able to perceive pain at a low level, but also has discriminative, affective and motivational contributions.

In addition it is a relay staion for a group of descending fibers called the reticulospinal tract that pass from the the sensory cortex and RAS to the dorsal horn synapses thus participating in the modulation response at the synaptic level in the dorsal column.

The High Centres of Pain Physiology

Pain is a serious matter and evolution has taken it seriously, and has a developed systems that deal with immediate threats in the form of a simple and effective reflex arc to systems that recruit almost every part of the nervous system is potentially recruited to deal with pain in a compound manner. The best way to approach the complexity of the elements in the brain that particpate in the process is to divide it into two categories; the sensory discriminative process and the affective-motivational component.

Sensory Discriminative Process

The sensory discriminative component of pain is a process that occurs in the brain that measures the pain as accurately and as objectively as possible in order that a planned and effective response can be executed.

Structurally the process occurs in the post central gyrus of the parietal lobe also known as the somatosensory cortex (aka SI).

From a functional standpoint it receives input from the thalamus that has packaged and preprocessed the information so that it gets sent to the appropriate locations in the somatosensory cortex. The neural basis for this function is based in the somatotopic (spatially accurate representation) organization of nociceptive neurons in the dorsal horn, lateral thalamus, and the primary somatosensory cortex. It is also packaged according to the magnitude of the stimulus as well as the quality of the pain based on which of the nocicepors that were stimulated. The somatosensory cortex (SI) processes, measures, and interprets stimulus localization, intensity, and quality. The output is to an experiential level of the mind that allows the pain to be perceived but also to a variety of secondary levels that include the secondary somatosensory cortex, prefrontal cortex, limbic system, autonomic nervous system, and basal ganglia.

The Primary Somatosensory Cortex

The primary somatosensory cortex (salmon pink) lies in the front of the parietal lobe just posterior to the motor cortex. The next diagram advances the anatomy.

83029b01.8s brain somatosensory cortex pareital lobe medial longitudinal fissure medially central sulcus anteriorly postcentral sulcus posteriorly lateral sulcus inferiorly location of primary somatosensory cortex main sensory receptive area touch. maps sensory space homunculus in this location The Common vein Davidoff art

The Somatosensory Cortex – Post Central Gyrus

The somatosensory cortex is overlaid in light rose pink lies posterior to the motor cortex (blue) which is part of the frontal lobe, behind the central sulcus and in front of the post central sulcus. It serves to perceive, localize and evaluate intensity of the pain, as well as initiate the response to the pain.

83029b01.b1.81s brain somatosensory cortex pareital lobe medial longitudinal fissure medially central sulcus anteriorly postcentral sulcus posteriorly lateral sulcus inferiorly location of primary somatosensory cortex main sensory receptive area touch. maps sensory space homunculus in this location pink = somatosensory cortex in post central gyrus blue = motor cortex The Common vein Davidoff art copyright 2008

Somatosensory Cortex in the Parietal Lobe

Localization and the Homunculus Man

When we view the primary somatosensory cortex in a coronal plane on this MRI we get reintroduced to the homunculus man whose body parts are draped over the somatosensory cortex. The homunculus man (literally the “little man”) is the distorted figure drawn to reflect the concept of size of organ paralleling the size of the sensory innervation. Those structures with a high density of sensory receptors are represented by a larger size, while those with a lesser concentration of sensory apparatus are shown as being “smaller” in size. Hence the mouth lips, hands feet and genitalia have a relatively large representation. The diagram also reflects the relative functional sensory space each body part occupies in the somatosensory cortex.

somatosensory cortex (sensory homunculus) spinothalamic tract spinal cord thalamus sensory cortex homunculus man penis clitoris genitals genitalia foot body thigh abdomen chest and face mouth eyes lips viscera somatosensory Davidoff art Copyright 2008 38610b09.46k.8s

Secondary Somatosensory Cortex

The secondary soamtosensory cortex (S2 or lateral system) that lies in the parietal operculum and is dominated by the insular cortex in the upper portion of the Sylvian fissure which projects to the limbic system which is a group of structures that are involved with emotion and memory. (see brain map) It is of cortical origin and has both an anterior and posterior areas that are mostly situated in the operculum. It is intimately related also to the limbic sensory system and the amygdla.

Lateral Somatosensory Cortex (SII) Operculum and Insula

The lateral somatosensory cortex is centered around the Sylvian fissure (red) It incorporates the insula (purple) the upper lid of the operculum which is part of the parietal cortex (pink) as well as parts of the frontal cortex, and the lower lid of the operculum (green) which is part of the temporal lobe.

38610c06b07.8s brain pain thalamus sensory affective somatosensory cortex S1 SII S2 parietal lobe Sylvian fissure lateral sulcus operculum insula affect emotional response limbic structures MRI T1 weighted Courtesy Ashley Davidoff MD copyright 2008

The Insula and the Operculum from the Inside (Coronal) and Outside (Sagittal View)

This diagram is utilized to demonstrate the operculum as seen from the inside in the first image (a) and from the outside in the second (b) Its cortical components consist of frontoparietal regions (pink) and temporal portions (green). The insula cortex is not visible from the outside (b) since it lies deep and medial (purple a). The Sylvian fissure is overlaid in red.

71060c07.8c01.8s brain pain pathway somotosensory cortex S 2 SII insula operculum parietal lobe temporal lobe frontal lobe lateral sulcus Sylvian fissure MRI T1 weighted Courtesy Ashley Davidoff MD copyright 2008

The function of the lateral somatosensory cortex is to connect to the limbic system via neocortical components of the brain, even though there are direct connections to the limbic system from the primary somatosensory cortex as well (see below)

Affective Motivational Process

The affective-motivational component of pain is a secondary process that occurs in the brain that involves a wide variety of tools that the somatosensory cortex employs and accrues in an attempt to deal with and resolve the pain.

The structural components of this process include many of the systems in the brain which as a group are called the somatosensory association areas. The more prominent of these areas include the limbic system, prefrontal cortex, basal ganglia, autonomic nervous system, and an afferent descending pathway down the spinal cord that helps the modulation process at the the synapse in the dorsal horn.

From a functional aspect the process represents protective response to the unpleasant stimulus. The system receives input from the somatosensory cortex, RAS, and the thalamus. Each component processes the information according to specific function, and the response comprises a combination of muscular, endocrine, autonomic, emotional and behavioral changes and adaptations. A grimace, a shout of “ouch!”, a surge of adrenalin, a rise in heart rate, or an angry glance reflect examples of response to pain which is different in individuals based on finite factors such as age and experience and other subjective factors such as emotional and character makeup, also with the potential ability to control such response. A child who sees the doctor with needle in hand will have have the same response of a scream, a surge of adrenalin, an angry glimpse, tears, dilated pupils, even before the pain is real as somebody who has actually been physically injured. The manner in which supratentorial structures can control the response to pain is notable.

Parts of the Affective Motivational Process

The more prominent parts of the affective motivational process include the limbic system, basal ganglia, autonomic nervous system, prefrontal cortex, and afferent descending pathway.

The Limbic System

The limbic system, or Paleomammalian brain is embryologically the first part to develop and from an evolutionary standpoint the oldest part of the brain. Limbus is the Latin word belt and was presumably used to name the complex because of the belt like shape of many of the structures. It is made up of a group of cortical and subcortical brain structures that are responsible for very basic instinctual functions that regulate emotion and behaviour.

Structurally there are many parts that are commonly associated with the system and others that have been traditionally associated with the system. The primary structures include the amygdala, hippocampus, parahippocampal gyrus, cingulate gyrus, fornix, hypothalamus as well as anterior thalamic nuclii. Other structures that have been associated with the limbic system include mamillary body, pituitary gland, fornicate gyrus, olfactory bulb, orbitofrontal cortex, nucleus acumbens and dentate gyrus. It has important connections to the prefrontal cortex.

Functionally the limbic system contains and controls some of the basic instinctual components necessary for survival. The limbic system is intimately integrated with the endocrine system the autonomic nervous system and the prefrontal cortex. The functions include basic behavioural characteristics such as fear, pleasure, sexual arousal, sleep, wakefulness, thirst, hunger, flight or fight response, long term memory, all of which are integrated with the prefrontal cortex – a concious element of the system.

In the context of pain the response of the person to pain is individualized so that one talks of the threshold to pain among different individuals. The response to pain is in part related to factors such as memory, experience, tied into the autonomic nervous system and concious prefrontal cortical modification. It is remarkable to witness the difference in response to the pain between young adult men and women who are undergoing a liver biopsy usually for the evaluation of hepatitis. I cannot recall one woman who has had an autonomic vagal fainting response to a liver biopsy. On the other hand there have been inumerable occasions that I have had to treat young men who have fainted or had near faints during the procedure. I am sure that woman of that age have been through painful menstrual cycles and perhaps painful child birth as well and over time have learned and memorized mechanisms to deal with pain whereas men of that age have had not had the equivalent experiences.

Major Parts of the Limbic System

The diagram is an overlay of a sagittal view of the brain using a T2 weighted image that traverses the centre of the brain. The limbic system is a bilateral relatively centrally placed system. The top and largest belt (light green) is the cingulate gyrus. (cing) The second, smaller and inner belt (olive green )represents the fornix (for) superiorly and the hippocampus (hip) inferiorly that terminates in the amygdala (amyg, yellow) The amygdala is in close association with the thalamus (orange) and hypothalamus (hyp – teal blue). The mamillary body (royal blue can be seen at the anterior and inferior end of the fornix.

Basal Ganglia

The basal ganglia are a group of nuclii in the brain that are situated deep in the white matter of the cerebral cortex.

From a structural point of view there are 5 major components including the caudate nucleus, putamen, globus pallidus, subthalamic nucleus and the substantia nigra. The nucleus accumbens is also considered part of the basal ganglia while the claustrum and amygdala which were previously considered part of the system, have been demoted. Additionally other names have been used to create combinations of the major parts including striatum (caudate nucleus, putamen and nucleus accumbens), corpus striatum (striatum and globus pallidus) and lenticular nucleus (putamen and globus pallidus).

Basal Ganglia

38610c06c05.8s brain pain basal ganglia striatum caudate nucleus putamen globus pallidus subthalamic nucleus. The striatumreceives cortical input globus pallidus exports to thalamus divided internal and external segment The substantia nigra is a midbrain structure that is reciprocally connected with the basal ganglia of the forebrain. globus pallidus subthalamic nucleus. striatum receives cortical input to the basal ganglia and can be divided into the cand the putamen. MRI T1 weighted coronal projection Courtesy Ashley Davidoff MD copyright 2008

From a functional point of view, the basal ganglia are mostly thought of as an inhibitory mechanism of motor function opposing, balancing, and complementing the excitatory function of the cerebellum to enable smooth movement. The disease of either will change the balance and result in loss of smooth movement. Impairment of either will change the balance and result in loss of smooth movement. They also have a role in the sensory system and, in the context of pain, are involved in the affective dimension, in modulation and sensory gating of nociceptive information, and possibly on the sensory-discriminative cognitive dimension. (Chudler), The sensory aspect of the basal ganglia is a relatively new development in the neurosciences, and the exact mechanisms and manifestations are yet to be established.

The caudate nucleus and the putamen are the doorway to the basal ganglia and they receive input from both the sensory cortex and motor cortex. They distribute the signals to the globus pallidus substantia nigra and subthalamic nuclii. The latter (two subthalamic nuclii and substantia nigra) process the signal and send the result back to the globus pallidus which in turn sends the signal back to the thalamus.

The transmitters in the basal ganglia include acetyl choline, gamma amino butyric acid (GABA) and dopamine.

Basal Ganglia

Signals coming up the spinothalamic tract into the thalamus (blue arrow) and then into the cortex White arrow to pink somatosensory cortex) are transmitted to the basal ganglia (teal arrow) including the caudate nucleus (c) and putamen. They distribute the signal to the other basal ganglia including the globus pallidus (gp), substantia nigra (sni), and subthalamic nuclii (sni) . The globus pallidus acts as the exit point for the basal ganglia (orange arrow) for the return of the processed signal to go to the thalamus.

38610d10.8s A simplified drawing of the connections between the caudate nucleus (orange, the sensory cortex (salmon pink) and the basal ganglia is shown. After the stimulus has reached the sensory cortex for quantification and qualification it connects to the basal ganglia through the caudate nucleus and putamen. Each of these connect with the two parts of the globus pallidus (gp) which feed back to the thalamus. The caudate nucleus also feed back and forth to the substantia nigra (sni) and the subtalamic nucleus (snu) brain basal ganglia connections functional thalamus sensory cortex putamen= p caudate nucleus = cn globus pallidus = gp substantia nigra = sni subthalamic nucleus = snu Davidoff art MRI T1 Copyright 2008

Autonomic Nervous System

The association and integration of the autonomic nervous system with the pain response is easier to understand than the involvement of the basal ganglia mechanism. The elevation of heart rate and blood pressure during a painful experience is well known sequelae identified by all caregivers who have monitored patients in pain. Additionally fainting from an intense and painful experience as a result of autonomic vagal stimulation is a well known response even to the layperson.

The autonomic nervous system (aka visceral nervous system) is an involuntary part of the peripheral nervous system.

Structurally it consists of the sympathetic and parasympathetic systems.

It controls the function of the viscera, commonly affecting the rate at which they function. It receives stimuli through sensory afferents from the viscera, passes the signals through the lower brainstem and medulla oblongata and pituitary, each of which processes the signals, and then via efferents provide direction for appropriate hormonal and neural response.

The sympathetic function is encapsulated by the axiom “fight or flight” while the parasympathetic function is encapsulated by “rest and digest” .

Hypothalamus

The hypothalamus is part of the autonomic nervous system’s central controlling mechanism.

Structurally it is situated below the thalamus, on either side of the third ventricle and consists of periventricular nuclii paraventricular nuclii, medial and lateral nuclii.

From a functional standpoint it receives input from the the vagus nerve, reticular formation, retina, limbic and olfactory systems, processes the information and sends output to the autonomic nervous system via the vagus and descending tracts in the spinal cord and subsequently to the autonomic ganglia.

The hypothalamus also sends signals to the posterior pituitary causing the release of oxytocin and vasopressin, and to some extent causes the anterior pituitary to release ACTH, and thyroid stimulating hormone.

Functionally it has similar traits to the limbic system in that it is responsible for some basic instinctual functions such as hunger thirst, response to pain, pleasure, sexual feelings, anger, aggression. Since it controls the autonomic nervous system, it will therefore also be involved in visceral responses including heart rate and pressure as described above.

Hypothalamus

The hypothalamus is centered in the midline around the third ventricle. The coronal image of a T2 weighted MRI shows the third ventricle in the midline (white) immediately surrounded by a the thinnest layer of paraventricular component, which in turn is surrounded by a slighly thicker layer of periventricular component (orange followed laterally by a pair of medial nuclii and then a single larger lateral component. The image below is a magnified version to enable you to appreciate the two inner layers better.

60528.8c11.8s hypothalamus brain pain autonomic nervous system parasympathetic nervous system sympathetic nervous system third ventricle 3rd ventricle periventricular nuclii optic tract pituitary paraventricular nuclii lateral nuclii medial nuclii optic tract MRI T2 weighted image Courtesy Ashley Davidoff MD copyright 2008

Hypothalamus Magnified

The slightly magnified view of the coronal image of a T2 weighted MRI shown above again shows the third ventricle in the midline (white). The thinnest inner layer is a mere pencil thin yellow line (paraventricular layer) and is barely seen even in this magnified view. The periventricular layer surrounds it. (orange)

60528.8c09.8s hypothalamus brain pain autonomic nervous system parasympathetic nervous system sympathetic nervous system third ventricle 3rd ventricle periventricular nuclii optic tract pituitary paraventricular nuclii lateral nuclii medial nuclii optic tract MRI T2 weighted image Courtesy Ashley Davidoff MD copyright 2008

In the setting of acute pain the usual response of the hypothalamus and autonomic nervous system is to increase the sympathetic tone, (“fight or flight”) unless the stimulus is so intense that a vagal response is induced. With increased sympathetic tone the patient initially increases heart rate and pressure, and becomes pale, sweaty, associated with dilated pupils .

Prefrontal Cortex

We have evolved the notion over the module that response to pain is complex and not a black and white reaction. Modulation takes place at all levels both automatically and conciously.

There are inumerable examples of sportsmen, soldiers, in the heat of the moment and with horrendous injuries who were not cognitive of the pain they were really in. The combination of sympathetic tone, limbic, basal ganglia, and precortical inputs collectively were able to mask the severe pain. The prefrontal cortex has a major role in the patients psychological ability to control the response to pain. Many of the other structures discussed above are automatic and responses are beyond the control of the patient, and often defined by genetic factors.

The prefrontal cortex, is the part of the frontal lobe which lies in front of the motor area, and is closely linked to the limbic system. Besides apparently being involved in rationalization, thought, making plans, organization, and taking action, it also appears to be involved in the same dopamine pathways as the ventral tegmental area, and plays a part in the sensation of pleasure.

The Prefrontal Cortex

In this artistic rendering of the brain, the prefrontal cortex is outlined in light purple. The prefrontal cortex of the brain is the anterior part of the frontal lobes and is positioned anterior to motor and premotor areas. It is divided into the lateral, orbitofrontal and medial prefrontal areas, Functionally it is said to have executive function in that it orchestrates thoughts and actions, discriminates between good and bad, positive and negative . It is responsible for planning, cognitive behaviors, personality expression and moderating correct social behavior.

83029d.8s brain somatosensory cortex prefrontal cortex executive function The prefrontal cortex of the brain is the anterior part of the frontal lobes and is positioned anterior to motor and premotor areas. It is divided into the lateral, orbitofrontal and medial prefrontal areas, Functionally it is said to have executive function in that it orchestrates thoughts and actions, discriminates between good and bad, positive and negative . It is responsible for planning, cognitive behaviors, personality expression and moderating correct social behavior. Executive Function relates to abilities to differentiate among conflicting thoughts, determine good and bad, brain frontal lobe prefrontal cortex concious control thalamus basal ganglia caudate nucleus putamen globu pallidus operculum CTscan Courtesy Ashley Davidoff MD copyright 2008 The Common vein Davidoff art copyright 2008

Prefrontal Cortex

The axial or transverse CTscan of the brain taken at the level of the third ventricle. The prefrontal cortex is outlined in light purple.

The prefrontal cortex of the brain is the anterior part of the frontal lobes and is positioned anterior to motor and premotor areas. It is divided into the lateral, orbitofrontal and medial prefrontal areas.

The Prefrontal Cortex in Geographic Context

This transverse image of the brain at the level of the third ventricle and thalamus, is presented to show some of the structures discussed above in context to the prefrontal cortex dark pink or light purple). In this image, the thalamus (orange), Sylvian fissure (black), insular cortex (dark purple) and components of the basal ganglia (blue) are shown.

38568c12.8s The prefrontal cortex of the brain is the anterior part of the frontal lobes and is positioned anterior to motor and premotor areas. It is divided into the lateral, orbitofrontal and medial prefrontal areas, Functionally it is said to have executive function in that it orchestrates thoughts and actions, discriminates between good and bad, positive and negative . It is responsible for planning, cognitive behaviors, personality expression and moderating correct social behavior. Executive Function relates to abilities to differentiate among conflicting thoughts, determine good and bad, brain frontal lobe prefrontal cortex concious control thalamus basal ganglia caudate nucleus putamen globu pallidus operculum CTscan Courtesy Ashley Davidoff MD copyright 2008

Afferent Descending System

There are many corticospinal fibers, mostly originating from the postcentral gyrus and thalamus that terminate on the dorsal horn of the spinal cord modifying the reaction to the sensory stimuli including painful stimuli. Other sites that effect the primary synapse include the periaquaductal gray matter, reticular formation, and medulla.

Conclusion

Pain is no joke, and it has not been a joke for millions of years. It is noxious and obnoxious, but a necessary and sometimes a lifesaving response to injury. Biology has complex ways of dealing with it, with varying success. Adaptive pain is a physiological response to an acute injurious agent forcing one to remove the body part from imminent danger. In the acute, subacute and chronic form it is also a physiological response forcing one to rest the injured part to allow healing. On the other hand, when pain physically or psychologically evolves into a counterproductive result, it is considered non-adaptive and pathological.

The components and mechanisms of the nervous system that have been recruited to deal with pain are highly complex. In the module on “Applied Anatomy and Physiology of Pain” we discuss some of the structures and mechanisms involved with the pain complex as a forerunner to the next module where the basic sciences are applied to disease, diagnosis and treatment.

http://www.nursingceu.com/courses/214/index_nceu.html

(see brain map)

Chudler

Descending tracts that affect ttehe gate theory

Central Biiasing

Endogenous Opiate (pituitary)

http://vanat.cvm.umn.edu/NeuroLectPDFs/LectNociceptionI.pdf

http://www.ucel.ac.uk/load/docs/pain/nociceptive%20RLO%20outline.ppt#1

http://www.pages.drexel.edu/~mab337/Pain%20Lecture.ppt#5

neuroscience at a glance – Google book

The mind/body connection provides the foundation from which pain derives its function. Pain is sensed by actual or impending injury to the body and then expressed through the mind. It is the clinician’s objective to understand what the pain is trying to tell the patient. However, variables like age, social background and mental status can affect the way the mind processes pain. For example, a distressed child with abdominal pain may be too overwhelmed to describe his/her discomfort while an adult with low back pain may easily discern muscular from sciatic symptoms. To overcome these factors requires an understanding of variations in pain sensitivity and tolerance.

Sensitivity

The pain threshold is achieved the moment an insulting stimulus is perceived by the brain. Interpretation of pain varies widely among humans due to genetic influences on neurophysiology that are further affected by gender, race, age and ethnicity. Painful stimuli are received, then mitigated by endogenous opioids in the pain center of the brain located in the thalamus. Receptors in the mu-opioid system, when bound, promote the release of opioid compounds that dampen the pain impulses before they are perceived by the physical, emotional and intellectual regions of the brain. These areas are respectively; the somatosensory cortex, the limbic system and the frontal lobe. The numbers of mu-opioid receptors and thus their pain reducing effects differ among individuals.

In addition, the neurotransmitter dopamine competes for the mu-opioid receptors when the separate process of pleasure is experienced. Dopamine is then metabolized by the enzyme catechol-O-methyltransferase (COMT) which frees up the receptors. There are genetic variations in COMT production that account for differing rates of dopamine breakdown and thus mu-opioid receptor availability. This genetic phenomenon therefore plays an additional role in differing sensitivity to pain among humans.

Although they are poorly understood, psychosocial factors, coping mechanisms, motivation and previous pain experiences are important concepts that also play a role in the variety of sensory responses humans have to pain. Knowledge of their influence is key to understanding pain sensitivity.

Tolerance

Tolerance of pain is similar to sensitivity in its subjectiveness and dynamic properties. Pain is sensed but endured until a tolerance threshold is reached where the patient seeks to remove or relieve the insult. Humans have varying levels of tolerance to pain duration and intensity until the threshold is reached. The same neurophysiological, genetic and extraneous factors that affect sensitivity also influence pain tolerance. An effective technique for understanding how pain ails a patient includes methodical interview questioning using a set of established scales and descriptors.

References

Chudler EH, Dong WK.The role of the basal ganglia in nociception and pain.Pain. 1995 Jan;60(1):3-38

Hucho T., Levine J.D., Signaling Pathways in Sensitization: Toward a Nociceptor Cell Biology. ‘‘Neuron.’’ 55. (2007)

Morgan, G. Edward, Mikhail, Maged S. , Murray, Michael J. Clinical Anesthesiology Published by McGraw-Hill Professional, 2005

ISBN 0071423583, 9780071423588

1105 pages

Web References

http://www.biologymad.com/NervousSystem/nerveimpulses.htm (Nice animated diagram of the sodium potassium pump mechanism)

see http://www.sjsu.edu/at/docs/Neuroanat2001.ppt#9

http://www.medscape.com/viewarticle/456762_9 nice review cox and prostaglandins

http://www.sonoma.edu/users/h/hanesda/b324/chap06.html (excellent article)chronic pain treated through limbic system – behavioural responses

http://williamcalvin.com/Bk1/bk1ch10.htm RAS and pain

medscape 5 str http://www.medscape.com/viewprogram/2441 5 articles including Clifford Woolfs

Harvard Brain Anatomy

Vargas Gray – Pain Mind over … Mind How aAttention Modulates Pain

(Rewference Kandell Scwartz and jessel)