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LYRICA® (pregabalin) eLearning System Neurobiology Pfizer Inc CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. Copyright © 2009 Pfizer Inc, with respect to proprietary product- and marketspecific information. Copyright © 2009 Whole Systems, with respect to all instructional design and formats. All rights reserved. Printed in the USA. (5/09) No part of this work may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying and recording, or by any information storage and retrieval system without permission in writing from the publisher. TN131X09 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. i Section 1: Overview of Neurobiology Objectives Describe the components of the nervous system from the standpoint of gross anatomy 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 2 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 6 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 1: Overview of Neurobiology CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 8 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 9 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 10 Section 2: Organization of the Nervous System Objectives List the key regions of the brain, and describe the function of each Describe the key anatomical features of the spinal cord List and define the main structures of a neuron 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 15 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 Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 17 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. Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 20 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 Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 23 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 Section 2: Organization of the Nervous System CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 24 Section 3: Neurotransmission and Neurotransmitters Objectives State the major steps in the process of neurotransmission Describe the different types of neurotransmitters Describe the structure and role of an ion channel 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 26 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 27 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 28 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 Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 29 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 30 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 31 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 32 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 Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 34 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 35 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 38 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. Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 39 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 Section 3: Neurotransmission and Neurotransmitters CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 40 Section 4: Perception of Pain Objectives Define and discuss transduction Define and discuss transmission Describe the modulation of pain Discuss the perception of pain Discuss peripheral and central sensitization 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 41 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 43 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 48 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 49 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 51 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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 Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 54 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 55 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 Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 57 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. Section 4: Perception of Pain CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 58 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 59 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 Module Summary CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 60 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. Module Summary CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 61 (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 Module Summary CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 62 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 Module Summary CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 63 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. Module Summary CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 64 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 65 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 66 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 67 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 Module Glossary CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 68 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 69 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 CONFIDENTIAL — EDUCATIONAL AND TRAINING MATERIALS. DO NOT DETAIL OR DISTRIBUTE TO ANY THIRD PARTIES. 70 Bibliography ....International Association for the Study of Pain. IASP Pain Terminology. Available at: www.iasp-pain.org/terms-p.html. Accessed September 17, 2003. Adams RD, Victor M. Principles of Neurology. 5th ed. New York: McGraw-Hill Inc; 1993. American Pain Society. Guideline for the Management of Fibromyalgia Syndrome Pain in Adults and Children. Glenview, IL: American Pain Society; 2005. 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