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LYRICA® (pregabalin)
eLearning System
Neurobiology
Pfizer Inc
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Contents
Introduction
Section 1: Overview of Neurobiology
1
Section 2: Organization of the Nervous System
11
Section 3: Neurotransmission and Neurotransmitters
25
Section 4: Perception of Pain
41
Module Summary
60
Glossary
65
Bibliography
71
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Introduction
The information contained in this training module is for your educational purposes
only. This training piece is designed to provide you with information you need on
the product, the disease, and the competitive environment. It is not to be used in
detailing or distributed to any third parties.
The nervous system is central to a myriad of complex, interrelated functions,
including thought, mood, perception of pain and other sensory input, regulation of
sleep, and control of movement. The interactions among the functional components
of the nervous system are central to its effective function. When imbalances in their
actions occur, a variety of disorders can result.
One of these disorders is neuropathic pain — that is, pain that is initiated or
caused by a primary lesion or dysfunction in the nervous system itself. Neuropathic
pain is sometimes perceived at a location remote from the actual site of injury, the
pain is often out of proportion to the stimulus, and the duration of the pain may be
prolonged. Two of the key types of neuropathic pain are painful diabetic
peripheral neuropathy (pDPN) and postherpetic neuralgia (PHN). However,
before you can understand how neuropathic pain occurs, you first need to
understand the normal actions of the nervous system.
Another one of these disorders is fibromyalgia, a common condition that is
characterized by the hallmark symptom of chronic, widespread pain. Today, much
evidence suggests that fibromyalgia is caused by an alteration in the physiology of
the central nervous system that results in disturbances in pain processing.
Epilepsy is another disorder that results from imbalances in functional components
of the nervous system. In epilepsy, patients experience unprovoked recurrent
seizures, which are paroxysmal episodes of brain dysfunction that usually lead to
sudden changes in behavior.
This module provides the background knowledge on the anatomy and function of
the nervous system that you will need as you discuss LYRICA® (pregabalin) with
healthcare professionals. It begins with an overview of neurobiology, introducing the
key anatomic and physiologic components and describing the different ways that
these components are often discussed. Section 2 describes the anatomical
organization of the nervous system and the functions of each component. Section 3
describes the cellular physiology of neurotransmission, which is how the nervous
system actually carries out its functions. Section 4 describes the sequence of
events involved in the perception of pain and introduces neuropathic pain. The
module concludes with a summary, a glossary of medical terms, and a bibliography.
Module Introduction
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i
Section 1: Overview of Neurobiology
Objectives
ƒ Describe the components of the nervous system from the standpoint of gross anatomy
ƒ Describe the components of the nervous system from the standpoint of function
Neurobiology arguably remains the most complex and challenging realm of human
physiology. Breakthroughs in neural imaging and molecular biology have greatly
advanced our understanding of how the brain develops and regulates behavior, how
different parts of the nervous system communicate, and, most recently, the role that
genes play in the pathogenesis of inherited neurologic disorders.
This section is designed to provide you with a basic understanding of the major
components of the nervous system and to familiarize you with important terminology
regarding their structure and function. It introduces the different types of neurons
found in the nervous system, their functions, and the method by which information is
transmitted through these neurons. The importance of these structures and
communication processes will become apparent as you progress through this
module and to other learning modules that discuss neuropathic pain and its
treatment.
Section 1: Overview of Neurobiology
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1
Describe the components of the nervous system from
the standpoint of gross anatomy
Anatomical Descriptions of the Nervous System
A description of the gross anatomy of the nervous system usually begins by dividing
it into:
• the central nervous system (CNS)
• the peripheral nervous system (PNS)
The central nervous system consists of the brain and spinal cord. It provides overall
coordination and interpretation of information, and directs responses. The peripheral
nervous system consists of all the nervous system outside the CNS.
Anatomical description of the nervous system can also include a description of the
cells that make up nervous tissue. The 2 key types of cells are:
• neurons
• glial cells (glia)
Neurons are the key cells of the nervous system that are responsible for the
transmission of the electrical and chemical signals representing information within
the nervous system. In addition to neurons, there are also several other types of
nervous tissue cells, collectively called neuroglia, that perform a number of
important functions, including:
• providing the brain with structure and nutrition as they support neurons
• producing myelin that insulates parts of nerve cells
• removing debris after neural injury or death
• helping to promote efficient signaling between neurons
Glial cells far outnumber neurons in the nervous system; there are between 10 and
50 times as many glial cells as neurons in the nervous system.
Section 1: Overview of Neurobiology
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Describe the components of the nervous system from the standpoint of gross anatomy
Figure 1A schematically illustrates these concepts.
Figure 1A: Anatomic Descriptions of the Nervous System
The cell body of a neuron is the site of cellular metabolism and contains the cell
nucleus, which houses the cell's genetic material. Extending from the cell body are
tubular extensions that receive electrical impulses from other neurons (called
dendrites) and tubular extensions that transmit impulses to other neurons (called
axons). Dendrites branch out in a tree-like fashion, while the axon is a single
filament that extends away from the cell body. Axons are organized into bundles
called nerves in the PNS and tracts in the CNS.
Section 1: Overview of Neurobiology
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3
Describe the components of the nervous system from the standpoint of gross anatomy
Figure 1B schematically illustrates nerves and tracts.
Figure 1B: Nerves and Tracts
Click on the icon to reinforce what you have learned about the anatomy
of nerves.
Section 1: Overview of Neurobiology
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4
Describe the components of the nervous system from the standpoint of gross anatomy
Progress Check
1.
The 2 key types of cells that make up nervous tissue are:
A
B
C
2.
neurons and glial cells.
neurons and Schwann cells.
basal cells and ganglia.
Which of the following statements regarding neurons is (are) true? (There is more than 1
correct answer.)
A
B
Dendrites receive electrical impulses from other neurons.
Dendrites are single filaments that extend away from the neuronal cell body.
C
D
Axons are organized as nerves in the PNS and tracts in the CNS.
all of the above
Section 1: Overview of Neurobiology
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5
Describe the components of the nervous system from
the standpoint of function
Functional Descriptions of the Nervous System
From a functional point of view, the nervous system can be described in several
ways:
• by the role different neurons perform as sensory, motor, and relay neurons
• by what controls the neurons as voluntary or involuntary
• by the cellular physiologic processes that allow the nervous system to actually
carry out its functions
Sensory, Motor, and Association Neurons
Neurons are often grouped into functional systems according to their roles in
performing a task. These systems include:
• sensory (afferent) system: collects information from organs of perception, such
as the skin and eyes, and sends it to the brain and spinal cord
• motor (efferent) system: carries signals from the brain and spinal cord to
muscles, glands, blood vessels, and other organs
• association (interneurons): relay signals between neurons; they are especially
prevalent in the gray matter of the brain and spinal cord
The nerve fibers in the PNS are often similarly described as either sensory nerve
fibers or motor nerve fibers. Most nerves (in the PNS) contain both sensory and
motor nerve fibers. However, most tracts (in the CNS) contain only sensory or
motor nerve fibers. The cell bodies of the sensory neurons (that is, the neurons
whose axons make up the sensory nerve fibers) lie just outside of the spinal cord in
the dorsal root ganglia. These neurons have sensory nerve endings on their
axons, bringing sensory information such as touch, temperature, pressure, and pain
into the dorsal horn of the spinal cord. The motor neurons that serve the body lie
within the ventral horn of the spinal cord. The axons of these neurons form the
ventral root fibers that pass to muscles and glands. Nearly all of the neurons that
supply both sensory and motor fibers to the peripheral nerves of the head and face
lie within the brainstem. These nerves are called cranial nerves. The organs or
tissues that receive nerve stimulation from these neurons are referred to as
effectors.
Section 1: Overview of Neurobiology
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Describe the components of the nervous system from the standpoint of function
The following animation describes these concepts.
Involuntary and Voluntary Nervous Systems
Another functional description of the nervous system is based on control of its
functions. The peripheral nervous system is divided into the:
• autonomic nervous system
• somatic nervous system
The autonomic (or involuntary) nervous system helps regulate the body's internal
environment (homeostasis). Its functions — for example, heart rate or the dilation
and constriction of blood vessels — are not under an individual's conscious control.
Section 1: Overview of Neurobiology
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7
Describe the components of the nervous system from the standpoint of function
The somatic (or voluntary) nervous system allows interaction with the external
environment. Its functions — such as movement of skeletal muscles — are under
an individual's control. These nervous system divisions are schematically illustrated
in Figure 1C.
Figure 1C: Voluntary and Involuntary Nervous Systems
Cellular Physiology
The functional description of the nervous system can also focus on how information
is transmitted at the level of cellular physiology. This description includes the:
• neurotransmitters, which are chemical messengers that translate electrical
signals to chemical information, and, thus, mediate signal transmission from a
presynaptic neuron to a postsynaptic neuron
• receptors, which are complex protein molecules on the surfaces of cells that
recognize and bind neurotransmitters, initiating the next steps in the
communication sequence
• ion channels, which are pores in the cell membrane that open and close in
response to neurotransmitters that bind to receptor subunits comprising or
adjacent to the channel; ion channels regulate the movement of ions in and out
of the cell, determining whether the message is propagated or inhibited
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Describe the components of the nervous system from the standpoint of function
One example of an ion channel that is important to our discussion of neuropathic
pain is voltage-gated calcium channels. This type of calcium channel regulates the
entrance of calcium ions into neurons, which, in turn, modulates the release of
certain excitatory neurotransmitters. Figure 1D schematically illustrates
neurotransmitters, receptors, and ion channels.
Figure 1D: Neurotransmitters, Receptors, and Ion Channels
Section 1: Overview of Neurobiology
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Describe the components of the nervous system from the standpoint of function
Progress Check
1.
2.
3.
Sensory or _____________ neurons collect information from organs, while motor or
_____________ neurons carry signals from the CNS to the organs and tissues.
A
efferent; afferent
B
afferent; efferent
The ________________________ controls the body's involuntary functions, such as heart
rate and respiration.
A
somatic nervous system
B
autonomic nervous system
C
afferent nervous system
Complex protein molecules on cell surfaces that recognize and bind to neurotransmitters are
called:
A ions.
B effectors.
C
D
receptors.
histamines.
Section 1: Overview of Neurobiology
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10
Section 2: Organization of the Nervous
System
Objectives
ƒ List the key regions of the brain, and describe the function of each
ƒ Describe the key anatomical features of the spinal cord
ƒ List and define the main structures of a neuron
ƒ Describe the key anatomical and functional features of the peripheral nervous system
The organization of the nervous system has a direct relationship to its function, and
understanding this organization can also help you understand how imbalances can
result in a variety of disorders. This section begins by describing the brain and
spinal cord, which together are known as the CNS. The CNS acts as the control
center of the entire nervous system, interpreting incoming information and issuing
responses. The section then describes the peripheral nervous system (PNS), which
includes all nervous system structures external to the CNS.
Section 2: Organization of the Nervous System
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11
List the key regions of the brain, and describe the
function of each
Regions of the Brain
The brain is composed of 6 major regions, each of which can be further subdivided
into several functionally and anatomically distinct areas. As shown in Figure 2A, the
6 major regions of the brain include the:
• cerebrum (cerebral hemispheres)
• diencephalon
• midbrain
• pons
• medulla oblongata
• cerebellum
Figure 2A: Major Regions of the Brain
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12
List the key regions of the brain, and describe the function of each
The Cerebrum
Masses of gray matter consisting of nerve cell bodies and white matter consisting
of axons and dendrites comprise the cerebrum. The cerebrum is the largest region
of the brain, which controls perceptual, motor, and cognitive functions, including
memory and emotion. The cerebrum is subdivided into 4 large sections called
lobes, which are named after the overlying cranial bones: frontal, parietal, temporal,
and occipital. The parietal lobe plays a key role in the perception of pain because it
is a major processing region for sensory information from other parts of the nervous
system.
The cerebrum is divided into 2 cerebral hemispheres, which are separated by a
deep groove. The 2 hemispheres are interconnected by the corpus callosum, a
massive bundle of fibers that connect symmetrical regions in both hemispheres.
These fiber tracts coordinate the actions of the 2 brain halves, which is essential for
many of the body's movements.
The Cerebral Cortex
The surface of the cerebral hemispheres is called the cerebral cortex and is
organized into cell layers. The number of layers varies throughout the cortex, but
the most typical cortical form contains 6 layers. These layers are highly convoluted
in humans and higher primates and form fissures and grooves (sulci) that separate
elevated regions called gyri. The different layers of the cortex are populated by
different types of neurons, which help organize the input and output of signals from
this brain structure. Pain signals, for example, are relayed through the thalamus to
structures in the cortex.
The interior of the cerebrum, underneath the cerebral cortex, is known as the white
matter. White matter consists of nerve fibers sheathed in myelin, a white fatty
insulating material. The neuron fiber tracts of white matter connect different regions
of the cortex with each other and the cortex with other parts of the brain and spinal
cord. Three deep-lying structures of the cerebral hemispheres are the:
• basal ganglia, which control fine movements and coordination
• amygdala, which has a role in social behavior and emotion, and autonomic
responses to pain
• hippocampus, which has a role in learning and memory
The Thalamus and Hypothalamus
The diencephalon contains the thalamus, which is a link for all sensory impulses
(excluding the sense of smell) traveling from receptors in the PNS to processing
regions in the cerebral hemispheres. Also contained in the diencephalon is the
hypothalamus, which regulates many bodily functions and helps maintain
homeostasis in the body. Its functions include modulating growth, eating, drinking,
and maternal behavior by regulating the hormonal secretions of the pituitary gland.
The hypothalamus also plays an essential role in regulating motivational behaviors
and in controlling circadian rhythms. The hypothalamus is also involved in many
of the autonomic responses to pain, such as increased heart rate and respiration.
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13
List the key regions of the brain, and describe the function of each
The Brainstem
The brainstem includes the midbrain, pons, and medulla oblongata. These areas
regulate autonomic (involuntary) behaviors and reflexes, such as respiration, cardiac
function, sneezing, coughing, swallowing, and vomiting reflexes. The brainstem is
also heavily involved in the modulation and transmission of pain impulses from the
spinal cord to the brain.
The Cerebellum
The cerebellum coordinates the movement of skeletal muscles, including balance,
gait, and fine motor movements. It is also involved in speech and other cognitive
functions.
Table 2A summarizes the functions of the major regions of the brain.
Click on the icon to reinforce what you have learned about the major
regions of the brain.
Section 2: Organization of the Nervous System
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14
List the key regions of the brain, and describe the function of each
The Limbic System
Emotions, particularly fear, rage, and emotions related to sexual behavior, are
largely regulated by an area of primitive cortical tissue called the limbic system that
encircles the upper brainstem and underlying cortical structures. The limbic system
has no universally accepted definition and is often described in terms of complex
neuronal pathways that connect parts of the cerebrum, diencephalon, and
brainstem. The structures of the limbic system are interrelated with many other
parts of the brain and have additional functions besides their role in regulating
emotions (pleasure and pain) and memory. The hippocampus, one part of the
limbic system, is responsible for the formation of long-term memories about our daily
experiences.
Pain can also elicit intense emotion, particularly fear and anxiety, so it is not
surprising that the limbic system plays a key role in the emotional component of
pain. One structure in the limbic system, the amygdala, is especially involved in the
response to painful stimuli, particularly in relation to fear and suffering. Autonomic
responses to pain, such as sweating, changes in heart rate and blood pressure, and
dry mouth, are initiated by the amygdala. Even the suggestion of pain can trigger
these responses, as animal experiments have shown. Animals that have undergone
removal of the amygdala lose their ability to express emotion, including fear.
The major structures of the limbic system are schematically depicted in Figure 2B.
Figure 2B: The Limbic System
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List the key regions of the brain, and describe the function of each
Progress Check
1.
2.
The surface of the cerebral hemispheres is called the _____________ and is organized into
6 primary layers.
A
corpus callosum
B
hippocampus
C
cerebral cortex
The brainstem is primarily responsible for controlling:
A higher cognitive functions such as language and learning.
B
C
3.
involuntary behaviors and reflexes.
coordination and fine motor movements.
Which of the following statements about the limbic system is (are) true?
A The limbic system is formed from complex neuronal pathways that connect parts of the
cerebrum, diencephalon, and brainstem.
B The limbic system is involved in the emotional aspects of pain, such as fear and anxiety.
C Autonomic responses to pain, such as sweating and increased heart rate, are initiated in
a structure of the limbic system called the amygdala.
D
all of the above
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16
Describe the key anatomical features of the spinal cord
The Spinal Cord
The spinal cord provides a pathway for the transmission of sensory impulses from
the periphery to the brain, and motor impulses from the brain to the periphery. The
spinal cord also receives sensory information from internal organs.
The spinal cord is protected by the vertebral column as well as the meninges, which
also surround the brain. The animation below illustrates a cross-sectional view of
the spinal cord. The H-shaped internal core of gray matter in the spinal cord is
made up primarily of neuronal cell bodies and dendrites and is subdivided into
regions known as horns: The dorsal horns are closer to the back, while the ventral
horns are closer to the front of the body. Nerve fibers that transmit pain signals from
tissues in the body terminate in the dorsal horns. The white matter of the spinal cord
consists of myelinated nerve fibers and serves as the conduit for impulses traveling
to and from the brain.
Thirty-one pairs of spinal nerves emerge from the spinal cord through openings
between the vertebral bones. Each spinal nerve is attached to the lateral surface of
the spinal cord by 2 roots: a dorsal, or sensory, root and a ventral, or motor, root.
The dorsal root contains sensory neurons and conducts impulses from the
peripheral nerves into the spinal cord. The ventral root contains motor neurons and
conducts impulses from the spinal cord back to the periphery.
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Describe the key anatomical features of the spinal cord
The following animation shows descending and ascending nerve tracts. A tract is a
bundle of nerve fibers (that is, axons) in the CNS that interconnects the brain and/or
spinal cord.
Click on the icon to reinforce what you have learned about the
anatomical features of the spinal cord.
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18
Describe the key anatomical features of the spinal cord
Progress Check
1.
Nerve fibers that transmit pain signals from the body's periphery terminate in the
______________ located in the spinal cord.
A ventral roots
B axon terminals
C
D
dorsal horns
meninges
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19
List and define the main structures of a neuron
Neurons
The neuron, or nerve cell, is the basic functional unit of all nervous system tissue.
The cell bodies of neurons are primarily found in the CNS, while their axons may
extend from the CNS into the PNS or remain within the CNS. The neuronal cell
bodies that do reside in the PNS are usually grouped together in clusters called
ganglia (eg, dorsal root ganglia). The animation below illustrates the basic features
of a neuron, including its:
• cell body
• dendrites
• axon
The cell body of the neuron contains the nucleus and other organelles that carry out
the processes that maintain the life of the cell. Each neuron has 1 or more
dendrites, which are branched extensions that receive nerve signals from other
neurons and conduct these signals to the cell body. Although neurons can have
several dendrites, they have only 1 axon, a tubular extension that carries nerve
impulses away from the cell body toward other neurons. Each axon ends in many
fine branches that have specialized endings called terminals, the regions at which
neurons transmit signals to other neurons.
Surrounding the axons of many neurons is a myelin sheath formed by specialized
glial cells that wrap themselves around the axons, like insulation around a wire. The
myelin sheath insulates the axons and increases the transmission rate of impulses.
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List and define the main structures of a neuron
Progress Check
1.
Dorsal root ganglia are the cell bodies of afferent nerve fibers.
A
B
true
false
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21
Describe the key anatomical and functional features of
the peripheral nervous system
Peripheral Nervous System
The peripheral nervous system (PNS) includes all nervous system structures
external to the CNS. Although the PNS is anatomically distinct from the CNS, the 2
are functionally intertwined. Included in the PNS are the cranial and spinal nerves
that emerge from and enter the CNS, and their terminal projections — the axon
terminals that synapse with muscle fibers or glands. These peripheral nerves relay
impulses from the sense organs or peripheral receptors (such as pain receptors) to
the CNS, and from the CNS to muscles and glands throughout the body.
Nerve fibers within the peripheral nervous system are classified by their function as
sensory or motor fibers. The animation below illustrates these types of nerve fibers,
showing transmission by a sensory nerve fiber to the spinal cord, an association
neuron within the spinal cord, and transmission of a response by a motor nerve fiber
from the spinal cord. The chain of transmission shown in the animation has been
simplified for the sake of illustrating these concepts.
Nerves are bundles of nerve fibers that course along the same path in the PNS.
While some nerves contain only sensory or only motor nerve fibers, most nerves are
mixed nerves that contain both sensory and motor nerve fibers.
Click on the icon to reinforce what you have learned about types of
nerve fibers.
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22
Describe the key anatomical and functional features of the peripheral nervous system
The peripheral nervous system may be further subdivided into:
• the somatic (voluntary) nervous system
• the autonomic (involuntary) nervous system
Somatic Nervous System
The somatic nervous system allows interaction with the external environment.
Sensory nerve fibers of the somatic nervous system convey sensory information
about the world, including pain, temperature, and tactile information; sights, sounds,
smells, and tastes; and information about the movement and positions of the body's
own muscles and joints. Somatic motor neurons, which control skeletal muscles,
have axons that extend to the periphery and are considered part of the somatic
system, even though the cell bodies are located in the CNS.
Autonomic Nervous System
In contrast, the autonomic nervous system helps regulate the body's internal
environment. Sensory nerve fibers of the autonomic nervous system convey data
about the status of internal organs and tissues, including pain information. In turn,
motor nerve fibers of this system influence bodily functions, such as heart and
respiration rates, gastrointestinal motility, blood pressure, and the secretion of
chemicals from glands.
The autonomic nervous system is further divided into functional subdivisions that
work in concert to regulate the body's internal environment. Two of the main
functional subdivisions, the sympathetic nervous system and the
parasympathetic nervous system, are briefly described in Table 2B.
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Describe the key anatomical and functional features of the peripheral nervous system
Progress Check
1.
The _________________ branch of the autonomic nervous system is responsible for the
"flight or fight" response to a stressful situation.
A
B
sympathetic
parasympathetic
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Section 3: Neurotransmission and
Neurotransmitters
Objectives
ƒ State the major steps in the process of neurotransmission
ƒ Describe the different types of neurotransmitters
ƒ Describe the structure and role of an ion channel
ƒ Describe the major types of receptors
The process of neurotransmission, the communication of a nerve signal from one
neuron to the next, involves the coordinated action of a variety of nervous system
components. This section describes how neurotransmission occurs and provides a
more detailed look at the roles of neurotransmitters, receptors, and ion channels in
neurotransmission.
Section 3: Neurotransmission and Neurotransmitters
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25
State the major steps in the process of
neurotransmission
Chemical Neurotransmission
Chemical neurotransmission is the process of passing a nerve impulse from one
neuron to another. It is important for you to understand this process because it is at
this critical juncture that pregabalin has its effect.
Information is transmitted along a neuron by means of a moving electrical charge.
However, this electrical charge must then be transmitted from one neuron to the
next neuron across a gap known as the synaptic cleft. In most cases, the electrical
charge must be translated into a chemical signal, the neurotransmitter, that can
cross the synaptic cleft. The complete juncture between an axon terminal and
another cell is known as the synapse. The synapse consists of the surface of the
axon terminal, known as the presynaptic surface, and a postsynaptic surface, which
is most often on a dendrite of an adjoining cell. As shown in the animation below,
there are receptors and ion channels on both the presynaptic and postsynaptic
surfaces.
Section 3: Neurotransmission and Neurotransmitters
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State the major steps in the process of neurotransmission
Neurotransmitter Release
Synaptic vesicles containing neurotransmitters are located in the axon terminal of
the presynaptic neuron. When triggered by an electrical impulse, ion channels in the
presynaptic membrane open, allowing calcium ions (Ca2+) to flow into the cell. This
influx of Ca2+ causes the vesicles to release the stored neurotransmitters into the
synaptic cleft. The neurotransmitters diffuse across the synaptic cleft and bind to
specific receptors on the postsynaptic membrane. This binding causes ion channels
in the postsynaptic membrane to open or close.
Signal Propagation or Inhibition
Depending on the type of ion channel and the ions that move into or out of the
postsynaptic cell, the cell is either activated and propagates the electrical signal
(action potential), or is inhibited from propagating the signal. A propagating or
excitatory electrical signal often results from the opening of sodium ion (Na+)
channels in the postsynaptic membrane. An excitatory signal makes it easier for the
impulse to be propagated. Influx of Na+, and in some cases Ca2+, depolarizes the
postsynaptic cell membrane (makes the inside of the cell membrane more positive
relative to the outside). As shown in the animation below, sufficient depolarization
can initiate an action potential (nerve impulse) in the axon of the postsynaptic
neuron; voltage-gated Na+ channels in the axon open and Na+ enters. Almost
immediately after Na+ enters the axon, potassium ions (K+) exit through voltagegated K+ channels and the membrane is repolarized. This rapid shift from
depolarization back to polarization propagates down the length of the axon.
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State the major steps in the process of neurotransmission
Conversely, an inhibitory electrical signal makes the inside of the postsynaptic
membrane more negative, a process called hyperpolarization. When this
happens, generation of a nerve impulse is even more difficult than normal and may
even be inhibited. However, since each neuron may receive impulses from many
other neurons, some excitatory and some inhibitory, the behavior of a neuron is
determined by the sum of the incoming impulses it receives.
The following animation illustrates the basic sequence of events that occurs in
neurotransmission.
Neurotransmitter Removal
The binding of a neurotransmitter to a receptor is reversible. When the complex
formed between the neurotransmitter and the receptor dissociates, both
neurotransmitter and receptor are free to function again.
While the discussion to this point has focused on a neurotransmitter crossing the
synaptic cleft and binding to a postsynaptic receptor, timely removal of a
neurotransmitter from the synaptic cleft is essential for neurotransmission. This is
most often accomplished by reabsorption of the neurotransmitter by the presynaptic
terminal in a process known as reuptake. Specific pumps in the membrane of the
presynaptic cell carry neurotransmitter molecules from the synaptic cleft back into
the axon terminal. Once in the axon terminal, the neurotransmitters are either
reincorporated into vesicles or broken down by enzymes. Without these processes,
the neurotransmitter would linger in the synaptic cleft and prevent new signals from
getting through.
Click on the icon to reinforce what you have learned about the process
of neurotransmission.
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State the major steps in the process of neurotransmission
Progress Check
1.
In order for most nerve impulses to be propagated from one neuron to another across the
synaptic cleft:
A calcium ions must first enter the postsynaptic neuron.
B
2.
the electrical charge must be translated into a chemical signal, the
neurotransmitter.
An inhibitory signal causes the postsynaptic membrane to become more _____________ in
relation to the outside of the membrane.
A positive
B
negative
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Describe the different types of neurotransmitters
Neurotransmitters
Neurotransmitters may be either synthesized and held in vesicles in the axon
terminals or synthesized in the cell body, transported down the axon, and held in
vesicles until their release into the synaptic cleft. Although many chemicals found in
the body, such as hormones, affect organs and glands in some way, only a limited
number of substances are defined as neurotransmitters. Generally, a substance is
called a neurotransmitter if it fills each of the following 4 criteria:
• it is synthesized within the neuron
• it is present in the presynaptic terminal and is released in sufficient quantities to
exert a defined action on the postsynaptic neuron or effector organ
• when administered artificially (as a drug, for example), it mimics the actions of the
same chemical produced in the body
• a specific mechanism exists for removing the substance from the synaptic cleft
There are several different groups of neurotransmitters, as listed in Table 3A.
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Describe the different types of neurotransmitters
Neuropeptides
A group of chemical compounds called neuropeptides, while also considered
neurotransmitters, differ quite significantly from the substances described above in
the way they are synthesized and in their effects. Instead of being produced in the
presynaptic terminals, neuropeptides are synthesized within the cell body of neurons
and then slowly transported to the ends of the nerve fibers. Neuropeptides also
differ from small-molecule neurotransmitters in that they are many times more potent
and their effects are much more prolonged, due to their slow removal from the
synaptic cleft. These effects can include changes in metabolism and activation or
deactivation of specific genes, which in some cases may last for months or even
years.
Neuropeptides can cause excitation, inhibition, or both. Some of these compounds,
such as substance P and enkephalins, are concentrated in regions of the CNS
involved in pain perception; other substances regulate the body's response to stress.
Neuropeptides are grouped into families according to their amino acid sequence.
Table 3B lists the 7 main families; at least 10 have been identified.
Neuropeptides and other neurotransmitters often coexist within the same neuron.
These substances often work synergistically at the target cell.
Click on the icon to reinforce what you have learned about
neuropeptide neurotransmitters.
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Describe the different types of neurotransmitters
The importance of neurotransmitters is illustrated particularly well when discussing
disorders of the nervous system that are caused by or influenced by an imbalance of
neurotransmitters in the brain. Table 3C describes some recognized neurologic
disorders associated with specific neurotransmitters.
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Describe the different types of neurotransmitters
Progress Check
1.
2.
Which of the following statements about neurotransmitters is (are) true? (There is more than
1 correct answer.)
A
B
Neurotransmitters are synthesized within the neuron.
All neurotransmitters are removed from the synaptic cleft by the same mechanism.
C
Certain drugs can mimic the actions of some neurotransmitters.
Match the following:
D
major inhibitory neurotransmitter in the
nervous system
C
major inhibitory neurotransmitter in the spinal
cord
A
transmits impulses that signal the muscles to
contract
B
major excitatory neurotransmitter in the
nervous system
A.
B.
C.
D.
Acetylcholine
Glutamate
Glycine
GABA
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33
Describe the structure and role of an ion channel
Ion Channels
Ion channels float within cell membranes and are the primary excitatory elements of
nerve, striated and smooth muscle, and secretory cells. Ion channel proteins form
macromolecular pores that open in response to changes in the voltage across the
cell membrane. Through this action, they produce and translate electrical signals,
and, as a result, ion channels are the basic components that allow the brain and
peripheral nervous system to rapidly convey information. Ion channels:
• open and close like a gate in response to specific signals
• recognize specific ions
• allow specific ions to pass through them when the pores are open
The following animation illustrates an ion channel.
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Describe the structure and role of an ion channel
There are several different types of ion channels, each with ionic selectivity, so that
they preferentially allow only ions of a certain type to cross the cell membrane. For
example, there are specific channels each for potassium (K+), sodium (Na+), calcium
(Ca2+), and chloride (Cl-), among others. Membranes of most cells (including
neurons) have a charge of about 60 mV (0.06 volts), with the cytoplasm negative
with respect to the extracellular fluid. If this voltage is reduced by excitation, ion
channels typically open. In the case of sodium or calcium channels, this causes a
depolarizing signal that can propagate within the excitable cell. Thus, the sequential
activation of sodium channels can cause action potentials that propagate long
distances down a neuronal axon. Calcium channels are very important to synapses,
where they translate a membrane depolarization into the rapid release of
neurotransmitters that activate postsynaptic receptors. Consequently, neuronal
synapses require presynaptic calcium channels in order to function normally.
The Alpha2-delta Subunit
Important to Know
Information regarding the interaction
of pregabalin with the alpha2-delta
binding site on voltage-gated calcium
channels is derived from work in
preclinical experimental animal
models. The clinical significance of
this interaction in humans is currently
unknown.
One type of ion channel subunit that plays an important role in
neuropathic pain is the alpha2-delta (abbreviated as α2δ or A2D) subunit
of certain voltage-gated calcium channels. This subunit is particularly
relevant because it is a primary binding site for pregabalin and
gabapentin*, which bind with high affinity and specificity for this subunit. When
pregabalin binds, it changes the shape of the alpha2-delta subunit. The modulation of
the alpha2-delta subunit regulates the entrance of calcium ions into the presynaptic
terminal. This, in turn, modulates the release of certain excitatory neurotransmitters.
The animation below illustrates the alpha2-delta subunit on a voltage-gated calcium
channel and its role in neurotransmission.
* Gabapentin and pregabalin and are the only drugs currently known to bind to the alpha2-delta
subunit of voltage-gated calcium channels.
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Describe the structure and role of an ion channel
While the alpha2-delta binding site is on voltage-gated calcium channels, it is
important to note that pregabalin is not a vascular calcium channel blocker.
Vascular calcium channel blockers (for example, such as amlodipine):
• bind to the alpha1 subunit of L-type calcium channels
• directly block the channel pore, preventing the movement of calcium ions
• produce their effects in the peripheral vascular smooth muscle, and their actions
result in a decrease in blood pressure
In contrast, pregabalin binds to the alpha2-delta subunit (a different protein). Instead
of blocking the channel pore and calcium ion movement, pregabalin modulates
(reduces) calcium ion influx into hyperexcited neurons. Furthermore, pregabalin
works in the central nervous system and does not affect blood pressure or heart
rate.
Click on the icon to reinforce what you have learned about pregabalin
binding to calcium channels.
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36
Describe the structure and role of an ion channel
Progress Check
1.
The alpha2-delta subunit is found on certain ___________________ and has been shown to
play a role in neuropathic pain.
A sodium channels
B
C
voltage-gated calcium channels
voltage-independent potassium channels
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37
Describe the major types of receptors
Receptors
Receptors are complex proteins with configurations that allow specific molecules,
such as neurotransmitters, to bind to them in a lock and key relationship. This
binding to the receptor then causes a change in the postsynaptic cell, such as the
opening of an ion channel. Neurotransmitter receptors are located on both the
presynaptic and postsynaptic cell surfaces. Presynaptic receptors primarily act to
regulate the release of neurotransmitters from that neuron. Postsynaptic receptors
primarily act to regulate the propagation or inhibition of the impulse in the
postsynaptic cell.
Various receptor subtypes exist for each neurotransmitter. Differences in the
structures of these receptor subtypes determine their affinity for specific
neurotransmitters or drugs. For example, at least 9 CNS receptors and a number of
subtypes have been identified for serotonin (5-HT). Several serotonin receptor
subtypes, such as 5-HT2, are involved in the treatment of migraine headaches.
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Describe the major types of receptors
Table 3D lists some of the receptor subtypes for key neurotransmitters. It should be
noted that additional subtypes continue to be identified.
Click on the icon to reinforce what you have learned about the different
types of receptors.
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Describe the major types of receptors
Progress Check
1.
Presynaptic receptors primarily act to regulate the propagation or inhibition of the impulse in
the postsynaptic cell.
A true
B
false
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Section 4: Perception of Pain
Objectives
ƒ Define and discuss transduction
ƒ Define and discuss transmission
ƒ Describe the modulation of pain
ƒ Discuss the perception of pain
ƒ Discuss peripheral and central sensitization
ƒ Describe the key differences between nociceptive pain and neuropathic pain
In order to understand the differences between neuropathic pain in general and
nociceptive (musculoskeletal) pain, it is first important to understand how pain is
perceived.
Pain is an unpleasant sensory and emotional experience associated with actual or
potential tissue damage, or described in terms of such damage. The perception of
pain in response to tissue injury or inflammation is called nociception. Nociception
is a complex sequence of electrochemical events that takes place between the site
of tissue damage and the brain.
This section describes the sequence of events in nociception, which are:
• transduction
• transmission
• modulation
• perception
Peripheral sensitization and the theory of central sensitization, 2 processes in which
the perception of pain becomes unbalanced, are also described. This section
concludes by introducing neuropathic pain.
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Define and discuss transduction
Transduction
Transduction is the stimulation of sensory nerve endings and the translation of
noxious stimuli into electrical impulses. Neurons that collect sensory information
are called afferent neurons. Afferent neurons that collect information about pain are
called nociceptors. There are several types of nerve fibers that can function as
nociceptors. They are classified by their diameter, conduction speed, and presence
or absence of myelin. Table 4A describes 2 key types of nociceptors, and they are
illustrated in Figure 4A.
Figure 4A: A-delta and C Fibers
In normal circumstances, nociceptors are activated when incoming stimuli reach
threshold. The naturally occurring chemicals that surround the nociceptors in the
skin determine this baseline sensitivity and activation threshold. The signal is then
passed upward in the nervous system through transmission.
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42
Define and discuss transduction
Progress Check
1.
Which of the following are characteristics of A-delta nerve fibers? (There is more than 1
correct answer.)
A small diameter
B
myelinated
C
D
conduct pain impulses very quickly
responsible for about 95% of nociceptive input
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Define and discuss transmission
Transmission
After the nociceptors collect information about pain and translate it into electrical
impulses, these pain impulses then travel along neural pathways, a process known
as transmission. First, the impulses travel from the sensory nerve endings of each
nociceptive neuron toward its cell body. The pain signals then travel away from the
cell body again, along the axon of the neuron. The axons of these neurons
terminate in the dorsal horn of the spinal column. At the dorsal horn, pain impulses
are filtered, attenuated, or amplified.
Click on the icon to view an animation that illustrates transmission to
the dorsal horn.
Click on the icon to reinforce what you have learned about the steps
involved in pain transmission to the dorsal horn.
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44
Define and discuss transmission
Flexion Reflex
A flexion reflex, or withdrawal reflex, is a specific type of pain impulse pathway that
allows the body to respond to painful stimuli very quickly. In this type of reflex, the
sensory stimulus excites motor neurons that cause flexor muscles to contract, while
inhibiting extensor muscles of that limb.
For example, if a person steps on a tack, a flexion reflex running between the leg and
the spinal cord causes automatic withdrawal of the leg even before the individual feels
pain. In this example, nociceptors in the toes transmit an impulse along the leg to the
spinal cord, where the impulse is sent to a motor neuron running back down the leg.
The motor neuron conducts the impulse to a muscle, which contracts and causes the
leg to withdraw. The following animation illustrates this response.
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45
Define and discuss transmission
Transmission From the Spinal Cord to the Brain
Another possible fate for nerve impulses that reach the dorsal horn is transmission
to the brain. Within the dorsal horn, the peripheral nerves form synapses with
neurons that may modulate sensory input. Ascending tracts in the spinal cord
carry pain impulses to the thalamus and other regions of the brain. Impulses from
the A-delta nociceptive fibers are usually transmitted to the thalamus and relayed
from there to the cerebral cortex. Impulses from the C fibers travel to the brainstem,
thalamus, hypothalamus, limbic system, and cerebral cortex. The distinction
between these 2 central pain pathways is consistent with the differing perceptions of
pain impulses carried in the 2 types of nociceptive fibers. Figure 4B illustrates the
transmission of pain impulses from the spinal cord to the brain.
Figure 4B: Transmission to the Brain
Click on the icon to reinforce what you have learned about the steps
involved in pain transmission to the brain.
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46
Define and discuss transmission
Progress Check
1.
A specific type of pain impulse that travels from the injured site to the spinal cord and directly
back to motor neurons is called a:
A nociceptive spike.
B
C
flexion reflex.
gated response.
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47
Describe the modulation of pain
Modulation of Pain
The transmission of pain impulses may be modified by other impulses traveling in
the nervous system through the following processes:
• spinal gate control
• descending tracts
Spinal Gate Control
Both nociceptive nerves and non-nociceptive sensory nerves (such as those
sensitive to touch rather than pain), converge in the dorsal horn. Impulses from nonnociceptive afferent nerves can inhibit the transmission of pain sensations. This
inhibition of pain transmission is called spinal gate control.
The mechanism of this process is not fully understood, but it is thought to involve
specific inhibitory interneurons that reside in the spinal cord and regulate the
transmission of impulses to the CNS. These cells "close the gate" on pain impulses
when non-nociceptive nerves are stimulated. Stimuli that appear to activate this
mechanism include massage and electrical stimulation of nerve fibers in the skin.
This explains why rubbing or massaging a sore spot following an injury may relieve
pain: the fibers stimulated by massage inhibit activity of pain-transmitting fibers.
Figure 4C illustrates the gate control mechanism for pain inhibition.
Figure 4C: Spinal Gate Control
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Describe the modulation of pain
Descending Tracts
Sensations of pain may also be modified by impulses from the brain, carried by
descending tracts in the spinal cord. One of the key mechanisms for this process is
a descending circuit involving several structures in the hypothalamus and brainstem.
This circuit selectively controls the activity of spinal pain-transmission neurons by
releasing neurotransmitters that inhibit the transmission of pain from the spinal cord
to the brain. For example, serotonin can modulate pain by inhibiting nociceptor
neurons in the dorsal horns. In addition, norepinephrine can block pain transmission
by binding to α2-adrenergic receptors in the superficial layers of the dorsal horn.
Important to Know
Pregabalin binds to the alpha2-delta
subunit of voltage-gated calcium
channels in nervous system tissues,
as demonstrated in animal models.
Pregabalin is not active at opioid
receptors.
In addition to serotonin and norepinephrine, endogenous opioids can
act to inhibit pain transmission in the spinal cord. Endogenous opioids
act by binding to opioid receptors in afferent neurons in the spinal cord.
This blocks pain impulses traveling along these neurons toward the
brain. A number of opioid peptides produced in the body, including the enkephalins
and endorphins, are active in this modulatory process. Opioid analgesics are also
thought to work by the same mechanism.
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Describe the modulation of pain
Figure 4D illustrates the modulation of pain by descending tracts.
Figure 4D: Pain Modulation by Descending Tracts
Click on the icon to reinforce what you have learned about the
modulation of pain.
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50
Describe the modulation of pain
Progress Check
1.
Which of the following neurotransmitters can block or mitigate pain transmission?
A serotonin
B norepinephrine
C enkephalin
D
all of the above
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Discuss the perception of pain
Perception of Pain
The process of interpreting pain impulses is called perception. The perceived
intensity of pain produced by an injury may differ considerably from individual to
individual. Even in a single individual, the experience of pain may vary in different
circumstances. This is because the brain interprets pain impulses in a context of
multiple psychologic, behavioral, and emotional factors. Furthermore, the perceived
intensity of pain is modulated through the descending tracts.
The cerebral cortex plays a major role in the perception and interpretation of pain,
while the limbic system is thought to be involved in processing the emotional
component of pain. In addition, structures outside the CNS contribute somatic and
autonomic input, and changes in tissues and glandular secretions all factor into the
overall experience of pain.
Summary of Nociception
Figure 4E summarizes information on nociception.
Figure 4E: Nociception
Click on the icon to reinforce what you have learned about the
perception of pain.
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52
Discuss the perception of pain
Progress Check
1.
The cerebral cortex plays a major role in the perception and interpretation of pain, while the
__________ is thought to be involved in processing the emotional component of pain:
A medulla oblongata
B
C
limbic system
substantia nigra
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53
Discuss peripheral and central sensitization
Peripheral and Central Sensitization
Sensitization of nociception can occur at several points in the process. This
sensitization can lead to situations in which an individual's perception of pain is out
of proportion to the stimulus, or occurs in the seeming absence of a stimulus. In
some cases, the sensitization is part of the process by which pain serves as a
warning signal to the body. However, sensitization can also result in neuropathic
pain, when pain exists in the absence of noxious stimuli. One common mechanism
for sensitization is thought to be hyperexcitability at peripheral and central sites,
termed peripheral and central sensitization.
Peripheral Sensitization
In normal circumstances, nociceptors are activated when incoming stimuli reach
threshold. The chemical mediators that surround the terminals of the nociceptors
determine this baseline sensitivity and activation threshold.
However, intense or prolonged pain stimuli, applied in the presence of tissue or
nerve damage or inflammation, can result in a variety of changes:
• surrounding cells can increase production of chemical mediators or produce
different chemical mediators
• the destruction of neurons can also result in a shift in the amounts or types of
chemical mediators
These events can all lower the activation thresholds of nociceptors and increase
their firing rates, a process called peripheral sensitization. In tissues that have been
sensitized by this process, even stimuli that are normally harmless can feel painful.
The Theory of Central Sensitization
Nociceptor sensitization is only partially explained by the changes that occur with
peripheral sensitization. Following injury, a secondary zone of increased
responsiveness develops in the uninjured tissue surrounding the injured site. This
zone is thought to arise due to changes that occur in the dorsal horn of the spinal
cord, and the process is known as central sensitization. The end result of central
sensitization is increased pain.
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Discuss peripheral and central sensitization
Central sensitization occurs when the dorsal horn neurons receive a massive
discharge of signals from nociceptors. The barrage of sensory signals causes
changes in the dorsal horn neurons, including:
• a progressive increase in the activity of the dorsal horn neurons (sometimes
referred to as wind-up), so that the neurons are more sensitive to other input
• response by the neurons to stimuli that would normally be outside their receptive
area
• an increase in the magnitude and duration of response
• a reduction in threshold, so that stimuli that would not normally be perceived as
pain now activate nociceptors
The wind-up phenomenon is mediated by the NMDA receptor, which is a type of
glutamate receptor. Glutamate is an excitatory neurotransmitter in the spinal cord.
When NMDA receptors are activated, the excitability of the neurons is increased.
Dysregulation of GABA is also thought to be involved in central sensitization.
Peripheral nerve injury may reduce the amount of inhibitory control over dorsal horn
neurons, resulting in a decrease in GABA. This increases the likelihood that a
neuron will fire spontaneously or in an exaggerated way in response to afferent
input.
Table 4B summarizes information on peripheral and central sensitization.
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Discuss peripheral and central sensitization
Progress Check
1.
2.
Peripheral sensitization occurs when: (There is more than 1 correct answer.)
A
cells surrounding nociceptors increase or change production of chemical
mediators.
B
C
the activation thresholds of nociceptors are lowered and firing is increased.
dorsal horns in the spinal cord undergo increased activity (wind-up).
A(n) __________ in the amount of GABA is thought to play a role in the theory of central
sensitization.
A increase
B
decrease
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56
Discuss the key differences between nociceptive pain
and neuropathic pain
Key Differences between Nociceptive Pain and
Neuropathic Pain
When classified by etiology, pain can be described as:
• nociceptive pain, which arises in response to injury of musculoskeletal or
visceral tissues; serves as a warning sign to the body that it is being harmed and
has a protective function; once the causative factor is removed or addressed,
pain is eliminated or diminished
• neuropathic pain, which is initiated or caused by a primary lesion or dysfunction
in the nervous system; has no protective function; pain is generally chronic and
does not respond to standard analgesic treatment
Neuropathic pain arises primarily from dysfunction in the nervous system as
opposed to the excitation of nociceptors. Depending on the location of the
dysfunction or damage in the nervous system, neuropathic pain syndromes are
often classified as:
• peripheral neuropathic pain, which refers to pain due to lesions in peripheral
nerves; examples include painful diabetic peripheral neuropathy (pDPN) and
postherpetic neuralgia (PHN)
• central neuropathic pain, which refers to pain due to lesions in the CNS
• mixed, which refers to cases in which both nociceptive and neuropathic pain are
present
Key features of neuropathic pain include:
• hyperalgesia: exaggerated or amplified response to painful stimuli
• allodynia: pain from a stimulus not normally painful
• analgesia: loss of pain sensation
• hypoalgesia: impairment of pain sensation
Neuropathic pain is usually described as burning, tingling, shooting, stabbing, searing,
or electric shock-like. Neuropathic pain is also generally chronic and fails to respond
to standard analgesic interventions. Neuropathic pain may be a consequence of
nerve damage from a number of different conditions, diseases, or injuries. Frequently,
neuropathic pain is classified according to these causes.
Click on the icon to reinforce what you have learned about nociceptive
and neuropathic pain.
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Discuss the key differences between nociceptive pain and neuropathic pain
Neuropathic pain is diagnosed by means of patient history and physical
examination. The presence of medical conditions, such as diabetes, herpes zoster,
HIV infection, or chemotherapy treatment may be associated with neuropathic pain.
Key features to be assessed for diagnosis of neuropathic pain include:
• patient descriptions of the pain, particularly in terms of the quality, timing, and
distribution of pain
• key physical signs
Various pain rating scales and quality-of-life measures have been developed to aid
patients in describing their pain experiences to clinicians and researchers.
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Discuss the key differences between nociceptive pain and neuropathic pain
Progress Check
1.
_____________ describes pain from a stimulus that is not normally painful and is a feature of
neuropathic pain.
A Analgesia
B
C
D
Allodynia
Hyperalgesia
Hypoalgesia
Section 4: Perception of Pain
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Module Summary
(1) Descriptions of the nervous system: The nervous system is divided into:
• the central nervous system (CNS)
• the peripheral nervous system (PNS)
The central nervous system consists of the brain and spinal cord, while the
peripheral nervous system consists of all nervous system structures outside the
CNS. The 2 key types of cells in the nervous system are neurons and glial cells
(glia). Neurons are responsible for the transmission of electrical and chemical
signals within the nervous system. Glial cells, which outnumber neurons by a
factor of 10- to 50-fold, provide a number of important functions, including
providing the brain with structure and nutrition, producing myelin, and promoting
efficient neuronal signaling.
Extending from the cell body of a neuron are dendrites, which receive impulses
from other neurons, and axons, which transmit impulses to other neurons.
Dendrites branch out in a tree-like fashion, while axons are formed of single
long filaments. Axons form nerves in the PNS and tracts in the CNS.
Neurons are grouped according to their functions into systems, which include:
• sensory (afferent) system: collects information from organs of perception
• motor (efferent) system: carries signals from CNS to muscles and organs
• association (interneurons): relay signals between neurons
Most nerves in the PNS contain both sensory and motor nerve fibers.
However, most tracts in the CNS contain either sensory or motor nerve fibers.
The cell bodies of sensory neurons lie just outside the spinal cord in the dorsal
root ganglia. These neurons have sensory nerve endings on their axons, which
terminate in the dorsal horn of the spinal cord and receive information about
temperature, pressure, and pain.
The nervous system can also be described according to its control of functions.
The peripheral nervous system is divided into the:
• autonomic (involuntary) nervous system: regulates the body's internal
environment; actions are not under an individual's control
• somatic (voluntary) nervous system: controls voluntary functions, such as
movement of skeletal muscles
(2) Regions of the brain: The brain is subdivided into 6 major regions, which are
the:
• cerebrum
• diencephalon
• midbrain
• pons
• medulla oblongata
• cerebellum
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The cerebrum is the largest region of the brain and controls perceptual, motor,
and cognitive functions. It is separated into the following 4 large sections:
• frontal lobe
• parietal lobe
• occipital lobe
• temporal lobe
The 2 halves of the cerebrum (hemispheres) are interconnected by the corpus
callosum. The surface of the cerebral hemispheres is organized into layers of
neurons and is called the cerebral cortex. The layered structure helps to
organize the input and output of signals from the cerebral cortex.
The interior of the cerebrum is known as the white matter, which consists of
nerve fibers sheathed in myelin, a fatty insulating material. The deep-lying
structures of the cerebral hemispheres are the:
• basal ganglia
• amygdala
• hippocampus
The diencephalon contains the thalamus and the hypothalamus. The thalamus
is a link for all sensory impulses (excluding smell) traveling from the PNS to
processing areas in the cerebral hemispheres. The hypothalamus helps to
regulate many body functions, including growth, eating, drinking, and maternal
behavior. The brainstem regulates many reflexes, such as respiration,
sneezing, coughing, and swallowing. The cerebellum controls the timing and
coordination of movement.
The limbic system: The limbic system is composed of a number of brain
structures and is responsible for the feeling of many emotions, particularly fear
and rage. It also plays a key role in the emotional component of pain, such as
fear and anxiety. One structure in the limbic system, the amygdala, regulates
the autonomic reactions to pain, such as increased sweating, heart rate, and
blood pressure.
The spinal cord: The spinal cord is the pathway for the transmission of
sensory impulses from the periphery to the brain, and motor impulses to the
periphery. The spinal cord has an H-shaped core of gray matter made up
primarily of neuronal cell bodies and dendrites. The white matter of the spinal
cord consists of myelinated nerve fibers that serve as conduits for nerve
impulses.
Neurons: Neurons are the basic functional unit of the nervous system. The
cell body of a neuron contains a nucleus and other organelles; each neuron has
1 or more dendrites, but only 1 axon. Surrounding the axons of many neurons
is a myelin sheath formed by special glial cells that wrap themselves around the
axons. The myelin sheath insulates the axons and increases the rate of signal
transmission.
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(3) Chemical neurotransmission: Information is transmitted along neurons by
means of an electrical charge. This charge is transformed into a chemical
signal so that it can move from one neuron to the next across the synaptic cleft,
the gap between 2 neurons. The complete juncture between an axon terminal
and another cell is known as the synapse. The synapse consists of the surface
of the axon terminal, known as the presynaptic surface, and a postsynaptic
surface, which is most often on a dendrite of an adjoining cell.
When triggered by an electrical impulse (action potential), ion channels in the
presynaptic cell open, allowing calcium ions to enter. This causes
neurotransmitters stored in vesicles to be released into the synaptic cleft. The
neurotransmitters diffuse across the synaptic cleft and bind to receptors on the
postsynaptic membrane. Depending on the type of ions that move into or out of
the cell, the impulse is either propagated or inhibited. The neurotransmitter is
then removed from the synaptic cleft to be used again or degraded.
Neurotransmitters: Neurotransmitters are chemical messengers synthesized
within the neuron that exert a defined action on the postsynaptic neuron or
effector organ. Examples of neurotransmitters include acetylcholine, glutamate
(the major excitatory neurotransmitter), and GABA (the major inhibitory
neurotransmitter). Neuropeptides comprise another group of neurotransmitters
that differ chemically and functionally from the small-molecule
neurotransmitters. They are many times more potent and their effects are
much more prolonged. These compounds include substance P and
enkephalins, which are involved in pain perception.
Ion channels and receptors: Ion channels are pores in the cell membrane
that play a key role in propagating a nerve impulse; they:
• open and close like a gate in response to specific signals
• recognize specific ions
• allow specific ions to pass through them when the pores are open
The alpha2-delta subunit of certain voltage-gated calcium channels has been
shown to play a role in neuropathic pain, as demonstrated in animal models.
Various receptor subtypes exist for each neurotransmitter. For example, at
least 9 CNS receptors and a number of subtypes have been identified for
serotonin. Several subtypes are involved in pain and are targets for
medications that treat migraine headache. New receptor subtypes continue to
be identified.
(4) Perception of pain: The perception of pain in response to tissue injury or
inflammation is called nociception. Nociception is a complex sequence of
electrochemical events that includes:
• transduction
• transmission
• modulation
• perception
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Transduction: Transduction is the stimulation of sensory nerve endings and
the translation of noxious stimuli into electrical impulses. Afferent neurons that
collect information about pain are called nociceptors. Two key types of
nociceptors are:
• A-delta fibers: myelinated, relatively large diameter fibers that conduct pain
impulses quickly; responsible for initial sharp pain
• C fibers: smaller diameter unmyelinated fibers; responsible for the
secondary dull, aching pain following an injury
Transmission: After nociceptors collect information about pain, the pain
impulses travel along neural pathways, a process called transmission. The
axons of neurons that transmit pain impulses terminate in the dorsal horns of
the spinal column, where the impulses are filtered, attenuated, or amplified. A
special type of pain impulse pathway is called the flexion reflex, which allows
the body to react quickly to a painful stimulus.
Modulation: Modulation describes the modification of pain impulses traveling
through the nervous system. This occurs through:
• spinal gate control: Spinal gate control involves the inhibition of pain
impulses via non-nociceptive afferent nerves in the spinal cord that
effectively "close the gate" on pain impulses. Stimuli that appear to activate
this mechanism include massage and electrical stimulation of nerve fibers in
the skin.
• descending tracts: Pain sensation may also be modified by impulses from
the brain carried by descending tracts in the spinal cord. One such
descending circuit involves structures in the hypothalamus, midbrain, and
brainstem. Serotonin, for example, can modulate pain by inhibiting
nociceptor neurons in the dorsal horns.
Perception: The process of interpreting pain signals is called perception. Pain
perception varies from one person to another and in a single individual under
differing circumstances. The cerebral cortex plays a major role in pain
perception, while the limbic system is thought to be involved in the emotional
component of pain. Other structures outside the CNS also contribute to pain
perception.
Peripheral and central sensitization: Sensitization refers to pain that is out of
proportion to, or occurs in the absence of, noxious stimuli. Peripheral
sensitization occurs when chemical or physical events lower the activation
thresholds of nociceptors and increase their firing rates.
Nerve damage and inflammation can cause changes in chemical mediators
that can result in peripheral sensitization. The theory of central sensitization
occurs when the dorsal horn neurons receive a massive discharge from
nociceptors. This barrage of signals causes a number of changes in the dorsal
horn, including:
• progressive increase in neuronal activity (wind-up)
• response to stimuli normally outside the receptive area of the neurons
• increase in magnitude and duration of response
• reduction in stimulation threshold
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Dysregulation of GABA and glutamate is thought to be involved in central
sensitization through overstimulation of neurons and lack of inhibition.
Neuropathic pain: Neuropathic pain is distinguished from nociceptive
(musculoskeletal) pain in that it is caused by a dysfunction in the nervous
system, has no protective function, is chronic, and generally does not respond
to standard analgesic treatment. Depending on the location of the dysfunction
or damage in the nervous system, neuropathic pain syndromes are often
classified as:
• peripheral neuropathic pain, which refers to pain due to lesions in peripheral
nerves; examples include painful diabetic peripheral neuropathy (pDPN) and
postherpetic neuralgia (PHN)
• central neuropathic pain, which refers to pain due to lesions in the CNS
• mixed, which refers to cases in which both nociceptive and neuropathic pain
are present
Key features of neuropathic pain include:
• hyperalgesia: increased sensitivity to painful stimuli
• allodynia: pain from a stimulus not normally found painful
• analgesia: loss of pain sensation
• hypoalgesia: impairment of pain sensation
Neuropathic pain is often described as burning, tingling, searing, or electric
shock-like. Certain medical conditions, such as herpes zoster, HIV infection, or
diabetes, may be associated with neuropathic pain.
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Glossary
activation threshold
the point at which afferent nociceptors fire in response to stimulation
A-delta fiber
myelin-covered nerve fiber that carries sharp, initial pain sensations; has a larger diameter
and faster conduction speed than a C fiber
afferent
conduction of sensory impulses toward the brain
ascending tracts
nerve tracts found in the spinal cord that carry impulses toward the brain
autonomic nervous system
part of the nervous system that regulates activity of smooth muscle, cardiac muscle, and
glands
axons
tubular extensions of a neuron that carry nerve impulses away from the cell body toward
other neurons
biogenic amine neurotransmitter
one of a group of neurotransmitters (chemical messengers) whose structures are similar to
those of amino acids (the building blocks of proteins)
brainstem
stalk-like portion of brain connecting cerebral hemispheres with the spinal cord
central nervous system (CNS)
a division of the nervous system that consists of the brain and spinal cord; provides overall
coordination and interpretation of information and directs responses
cerebellum
the second largest region of the brain; functions to control skeletal muscles primarily in
coordination and balance
cerebrum
largest region of the brain; controls voluntary motor functions; coordinates physical, sensory,
visual, and auditory sensations; integrates consciousness, memory, use of language, and
emotions
C fiber
nerve fiber that carries persistent, aching pain sensations; has no myelin covering; diameter
is smaller than A-delta fiber, and conduction speed is slower
chorea
irregular, spasmodic, involuntary movements of the limbs or the facial muscles
circadian rhythm
relating to biologic variations or rhythms with a cycle of about 24 hours
corpus callosum
the nerve fibers that connect one side of the brain to the other
cortex
the convoluted layer of gray matter covering each cerebral hemisphere
Module Glossary
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cranial nerves
sensory and motor nerves that supply the head and face; nearly all neurons whose axons
make up the cranial nerves lie within the brainstem
dendrites
highly branched extensions of a neuron that receive nerve signals from other neurons and
conducts these signals to the cell body
descending tract
nerve tract in the spinal cord that carries impulses away from the brain
diencephalon
portion of the brain that contains the thalamus and the hypothalamus
dorsal horn
crescent-shaped projection of gray matter in spinal cord
dorsal root ganglia
clusters of cell bodies of sensory neurons that enter the spinal cord at the dorsal root; these
neurons conduct impulses from the peripheral nerves into the spinal cord; their axons
constitute the dorsal root of a spinal nerve
effector
organ/peripheral tissue that receives nerve impulses and reacts by contraction (muscle),
secretion (gland), or a discharge of electricity
efferent
conduction of motor impulses away from the brain and spinal cord
endogenous opioid
substance originating in the body that has pain-reducing properties
endorphins
amino acid compounds, produced by the brain, that act on the nervous system to reduce
pain
enkephalin
pain-reducing substance released by nerve cells in the spinal cord and brain
epilepsy
a chronic brain disorder characterized by the predisposition to the occurrence of
unprovoked recurrent seizures
extensor
a muscle that contracts to extend a limb or body part; the antagonist of a flexor
extracellular
outside the cell
fibromyalgia
a common condition characterized by the hallmark symptom of chronic, widespread pain;
patients may also present with a wide range of symptoms, including tenderness, sleep
disturbances, fatigue, and morning stiffness
fissure
the deep groove between folds of brain tissue
flexor
a muscle that flexes a joint
gamma (γ)-aminobutyric acid (GABA)
the major inhibitory neurotransmitter in the central nervous system
Module Glossary
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ganglia
clusters of neuron cell bodies in the peripheral nervous system
glutamate
the major excitatory neurotransmitter of the CNS
gray matter
those regions of the brain and spinal cord that are made up primarily of the cell bodies and
dendrites of nerve cells rather than myelinated axons
gyri
prominent rounded convolutions of brain tissue that form the cerebral hemispheres
homeostasis
state of equilibrium with respect to various functions and to the chemical compositions of the
fluids and tissues
Huntington's disease
an inherited neurodegenerative disorder characterized by chorea and dementia; also called
Huntington chorea
hyperalgesia
extreme sensitivity to painful stimuli
hyperpolarization
an increase in the polarization of membranes in nerve or muscle cells; the reverse of
excitatory action
hypothalamus
brain region primarily involved in autonomic (involuntary) nervous system functions,
hormone secretion, and mood; major regulator of homeostasis
ion
a positively or negatively charged atom that carries current
ion channel
an opening in the cell membrane activated by receptors that regulates the movement of
charged particles in and out of the cell, determining whether the message is propagated or
inhibited
limbic system
a group of neuronal pathways that connect parts of the cerebrum, diencephalon, and
brainstem
medulla oblongata
the base of the brain, which is formed by the enlarged top of the spinal cord; directly controls
breathing, blood flow, and other essential functions
meninges
membranes enclosing the brain and the spinal cord, comprising the dura mater, the pia
mater, and the arachnoid membrane
midbrain
also called mesencephalon; the short part of the brainstem just above the pons; the center
for visual reflexes
modulation
process through which pain impulses may be modified by other impulses
myelin
a fatty substance that insulates the nerve fiber and helps to speed nerve impulse
transmission
Module Glossary
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nerve
bundle of nerve fibers in the peripheral nervous system
nerve fiber
the axon of a nerve cell (neuron)
neuroglia
collective name for a variety of nervous tissue cells that provide physical and metabolic
support to neurons
neuron
a nerve cell; the basic functional unit of all nervous system tissue
neuropathic pain
pain that is initiated or caused by a primary lesion or dysfunction in the nervous system; has
no protective function; pain is generally chronic and does not respond to standard analgesic
treatment
neurotransmitter
chemical messenger that transmits signals between nerve cells
N-methyl-D-aspartate (NMDA) receptors
a specific subset of glutamate receptors to which N-methyl-D-aspartate binds; activation of
these receptors initiates production of prostaglandins
nociception
a sequence of responses that occur in the body to pain associated with tissue injury or
inflammation; involves stimulation of specific pain-sensitive nerves (nociceptors)
nociceptive pain
pain arising from tissue injury; also called musculoskeletal pain; serves as a warning sign to
the body that it is being harmed and has a protective function; once the causative factor is
removed or addressed, pain is eliminated or diminished
nociceptor
afferent nerve (a nerve that conveys impulses from the periphery to the central nervous
system) receptor that collects information about pain
noxious
injurious; harmful
nucleus
an organelle that is the location of the genetic material of the cell
organelles
specialized structures that are suspended in the cytoplasm (substance that surrounds the
nucleus) of a cell and perform specific functions
painful diabetic peripheral neuropathy (pDPN)
diabetes mellitus-related damage of the peripheral nervous system; can result in
neuropathic pain
parasympathetic nervous system
a branch of the autonomic nervous system; slows the heart rate, increases the intestinal and
gland activity, and relaxes the sphincter muscle
paroxysmal
relating to a sharp spasm or convulsion
peripheral nervous system (PNS)
part of the nervous system external to the brain and spinal cord
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pons
a prominence on the ventral (front) surface of the brainstem, between the medulla
oblongata and the midbrain
postherpetic neuralgia (PHN)
chronic severe, stabbing, or throbbing pain that continues after the visible evidence of an
episode of shingles (herpes zoster) has resolved
postsynaptic neuron
nerve cell that receives the signal transmitted across the synaptic cleft
presynaptic neuron
nerve cell that transmits the signal across the synaptic cleft by releasing neurotransmitters
receptor
complex protein molecule on the surface of cells that recognizes and binds
neurotransmitters
seizure
a paroxysmal episode of brain dysfunction, usually leading to sudden stereotyped changes
in behavior
somatic nervous system
part of the peripheral nervous system that allows for interaction with the external
environment; composed of afferent and efferent neurons
spinal gate control
premise that pain impulses are inhibited by impulses from non-nociceptive afferent nerves
substance P
a protein involved in nervous system function; stimulates smooth muscle contraction and
the dilation of blood vessels; active in inflammation and pain transmission
substantia nigra
1 of the 4 main regions of the basal ganglia; consists of the pars reticulata and pars
compacta
sulci
shallow grooves or furrows on the surface of the brain
sympathetic nervous system
a branch of the autonomic nervous system that accelerates the heart rate, constricts blood
vessels, and raises blood pressure
synapse
(verb) communicate through chemical transmission at the junction between an axon
terminal and another cell (neuron, muscle, or gland); (noun) the junction between an axon
terminal and another cell (neuron, muscle, or gland)
synaptic cleft
the space between the presynaptic and postsynaptic surfaces
thalamus
brain region located above midbrain; relays sensory information to the cerebral cortex
tracts
bundles of nerve fibers in the central nervous system
transduction
process by which noxious stimuli lead to electrical activity in the pain receptors
transmission
process by which pain impulses travel along neurons and across synapses
Module Glossary
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ventral horn
anterior columns of gray matter in the spinal cord; contain cell bodies of motor neurons
voltage-gated
action depends on the membrane potential, the difference in electrical charge between the
inside and outside of the cell; that is, a change in the electrical charge is necessary to open
or close the ion channel
white matter
bundles of myelinated axons located in the brain and spinal cord
Module Glossary
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