After studying this chapter, you should be able to:
Name the types of touch and pressure receptors found in the skin.
Describe the receptors that mediate the sensations of pain and temperature.
Define generator potential.
Explain the basic elements of sensory coding.
Explain the differences between pain and nociception, first and second pain, acute and chronic pain, hyperalgesia and allodynia.
Describe and explain visceral and referred pain.
Compare the pathway that mediates sensory input from touch, proprioceptive, and vibratory senses to that mediating information from nociceptors and thermoreceptors.
Describe processes involved in modulation of transmission in pain pathways.
List some drugs that have been used for relief of pain and give the rationale for their use and their clinical effectiveness.
We learn in elementary school that there are “five senses” (touch, sight, hearing, smell, and taste); but this dictum takes into account only those senses that reach our consciousness. There are many sensory receptors that relay information about the internal and external environment to the central nervous system (CNS) but do not reach consciousness. For example, the muscle spindles provide information about muscle length, and other receptors provide information about arterial blood pressure, the levels of oxygen and carbon dioxide in the blood, and the pH of the cerebrospinal fluid. The list of sensory modalities listed in Table 8–1 is overly simplified. The rods and cones, for example, respond maximally to light of different wavelengths, and three different types of cones are present, one for each of the three primary colors. There are five different modalities of taste: sweet, salt, sour, bitter, and umami. Sounds of different pitches are heard primarily because different groups of hair cells in the cochlea are activated maximally by sound waves of different frequencies.
TABLE 8–1 Principle sensory modalities.
Sensory receptors can be thought of as transducers that convert various forms of energy in the environment into action potentials in sensory neurons. The cutaneous receptors for touch and pressure are mechanoreceptors. Proprioceptors are located in muscles, tendons, and joints and relay information about muscle length and tension. Thermoreceptors detect the sensations of warmth and cold. Potentially harmful stimuli such as pain, extreme heat, and extreme cold are mediated by nociceptors. The term chemoreceptor refers to receptors stimulated by a change in the chemical composition of the environment in which they are located. These include receptors for taste and smell as well as visceral receptors such as those sensitive to changes in the plasma level of O2, pH, and osmolality. Photoreceptors are those in the rods and cones in the retina that respond to light.
This chapter describes primarily the characteristics of cutaneous receptors that mediate the sensations of touch, pressure, pain, and temperature, the way they generate impulses in afferent neurons, and the central pathways that mediate or modulate information from these receptors. Since pain is one of the main reasons an individual seeks the advice of a physician, this topic gets considerable attention in this chapter. Receptors involved in the somatosensory modality of proprioception are described in Chapter 12 as they play key roles in the control of balance, posture, and limb movement.
SENSE RECEPTORS & SENSE ORGANS
Sensory receptors can be specialized dendritic endings of afferent nerve fibers, and they are often associated with non-neural cells that surround them forming a sense organ. Touch and pressure are sensed by four types of mechanoreceptors (Figure 8–1). Meissner’s corpuscles are dendrites encapsulated in connective tissue and respond to changes in texture and slow vibrations. Merkel cells are expanded dendritic endings, and they respond to sustained pressure and touch. Ruffini corpuscles are enlarged dendritic endings with elongated capsules, and they respond to sustained pressure. Pacinian corpuscles consist of unmyelinated dendritic endings of a sensory nerve fiber, 2 μm in diameter, encapsulated by concentric lamellae of connective tissue that give the organ the appearance of a cocktail onion. Theses receptors respond to deep pressure and fast vibration. The sensory nerves from these mechanoreceptors are large myelinated Aα and Aβ fibers whose conduction velocities range from −70–120 to −40–75 m/s, respectively.
FIGURE 8–1 Sensory systems encode four elementary attributes of stimuli: modality, location (receptive field), intensity, and duration (timing). A) The human hand has four types of mechanoreceptors; their combined activation produces the sensation of contact with an object. Selective activation of Merkel cells and Ruffini endings causes sensation of steady pressure; selective activation of Meissner’s and Pacinian corpuscles causes tingling and vibratory sensation. B) Location of a stimulus is encoded by spatial distribution of the population of receptors activated. A receptor fires only when the skin close to its sensory terminals is touched. These receptive fields of mechanoreceptors (shown as red areas on fingertips) differ in size and response to touch. Merkel cells and Meissner’s corpuscles provide the most precise localization as they have the smallest receptive fields and are most sensitive to pressure applied by a small probe. C) Stimulus intensity is signaled by firing rates of individual receptors; duration of stimulus is signaled by time course of firing. The spike trains indicate action potentials elicited by pressure from a small probe at the center of each receptive field. Meissner’s and Pacinian corpuscles adapt rapidly, the others adapt slowly. (From Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
Some cutaneous sensory receptors are not specialized organs but rather they are free nerve endings. Pain and temperature sensations arise from unmyelinated dendrites of sensory neurons located throughout the glabrous and hairy skin as well as deep tissue. Nociceptors can be separated into several types. Mechanical nociceptors respond to strong pressure (eg, from a sharp object). Thermal nociceptors are activated by skin temperatures above 42°C or by severe cold. Chemically sensitive nociceptors respond to various chemicals like bradykinin, histamine, high acidity, and environmental irritants. Polymodal nociceptors respond to combinations of these stimuli.
Impulses from nociceptors are transmitted via two fiber types, thinly myelinated Aδ fibers (2–5 μm in diameter) that conduct at rates of −12–35 m/s and unmyelinated C fibers (0.4–1.2 μm in diameter) that conduct at low rates of −0.5–2 m/s. Activation of Aδ fibers, which release glutamate, is responsible for first pain (also called fast pain or epicritic pain) which is a rapid response and mediates the discriminative aspect of pain or the ability to localize the site and intensity of the noxious stimulus. Activation of C fibers, which release a combination of glutamate and substance P, is responsible for the delayed second pain (also called slow pain or protopathic pain) which is the dull, intense, diffuse, and unpleasant feeling associated with a noxious stimulus. Itch and tickle are also related to pain sensation (see Clinical Box 8–1).
CLINICAL BOX 8–1
Itch & Tickle
Itching (pruritus) is not a major problem for healthy individuals, but severe itching that is difficult to treat occurs in diseases such as chronic renal failure, some forms of liver disease, atopic dermatitis, and HIV infection. Especially in areas where many free endings of unmyelinated nerve fibers occur, itch spots can be identified on the skin by careful mapping. In addition, itch-specific fibers have been demonstrated in the ventrolateral spinothalamic tract. This and other evidence implicate the existence of an itch-specific path. Relatively mild stimulation, especially if produced by something that moves across the skin, produces itch and tickle. It is interesting that a tickling sensation is usually regarded as pleasurable, whereas itching is annoying and pain is unpleasant. Itching can be produced not only by repeated local mechanical stimulation of the skin but also by a variety of chemical agents including histamineand kinins such as bradykinin which are released in the skin in response to tissue damage. Kinins exert their effects by activation of two types of G protein-coupled receptors, B1 and B2. Activation of bradykinin B2 receptors is a downstream event in protease-activated receptor-2 (PAR-2) activation, which induces both a nociceptive and a pruritogenic response.
Simple scratching relieves itching because it activates large, fast-conducting afferents that gate transmission in the dorsal horn in a manner analogous to the inhibition of pain by stimulation of similar afferents. Antihistamines are primarily effective in reducing pruritis associated with an allergic reaction. In a mouse model exhibiting scratching behavior in response to activation of PAR-2, treatment with a B2 receptor antagonist reduced the scratching behavior. B2 receptor antagonists may be a useful therapy for treating pruriginous conditions.
There are a variety of receptors located on the endings of nociceptive sensory nerves that respond to noxious thermal, mechanical, or chemical stimuli (Figure 8–2). Many of these are part of a family of nonselective cation channels called transient receptor potential (TRP) channels. This includes TRPV1 receptors (the V refers to a group of chemicals called vanilloids) that are activated by intense heat, acids, and chemicals such as capsaicin (the active principle of hot peppers and an example of a vanilloid). TRPV1 receptors can also be activated indirectly by initial activation of TRPV3 receptors in keratinocytes in the skin. Noxious mechanical, cold, and chemical stimuli may activate TRPA1 receptors (A, for ankyrin) on sensory nerve terminals. Sensory nerve endings also have acid sensing ion channel (ASIC) receptors that are activated by pH changes within a physiological range and may be the dominant receptors mediating acid-induced pain. In addition to direct activation of receptors on nerve endings, some nociceptive stimuli release intermediate molecules that then activate receptors on the nerve ending. For example, nociceptive mechanical stimuli cause the release of ATP that acts on purinergic receptors (eg, P2X, an ionotropic receptor and P2Y, a G protein-coupled receptor). Tyrosine receptor kinase A (TrkA) is activated by nerve growth factor (NGF) that is released as a result of tissue damage.
FIGURE 8–2 Receptors on nociceptive unmyelinated nerve terminals in the skin. Nociceptive stimuli (eg, heat) can activate some receptors directly due to transduction of the stimulus energy by receptors (eg, transient receptor potential (TRP) channel TRPV1) or indirectly by activation of TRP channels on keratinocytes (eg, TRPV3). Nociceptors (eg, mechanoreceptors) can also be activated by the release of intermediate molecules (eg, ATP). ASIC, acid-sensitive ion channel; P2X, ionotropic purinoceptor; P2Y, G protein-coupled purinergic receptor.
Nerve endings also have a variety of receptors that respond to immune mediators that are released in response to tissue injury. These include B1 and B2 receptors (bradykinin), prostanoid receptors (prostaglandins), and cytokine receptors (interleukins). These receptors mediate inflammatory pain.
Innocuous cold receptors or cool receptors are on dendritic endings of Aδ fibers and C fibers, whereas innocuous warmth receptors are on C fibers. Mapping experiments show that the skin has discrete cold-sensitive and heat-sensitive spots. There are 4–10 times as many cold-sensitive as heat-sensitive spots.
The threshold for activation of warmth receptors is 30°C, and they increase their firing rate as the skin temperature increases to 46°C. Cold receptors are inactive at temperatures of 40°C, but then steadily increase their firing rate as skin temperature falls to about 24°C. As skin temperature further decreases, the firing rate of cold receptors decreases until the temperature reaches 10°C. Below that temperature, they are inactive and cold becomes an effective local anesthetic.
The receptor that is activated by moderate cold is TRPM8. The M refers to menthol, the ingredient in mint that gives it its “cool” taste. TRPV4 receptors are activated by warm temperatures up to 34°C; TRPV3 receptors respond to slightly higher temperatures of 35–39°C.
GENERATION OF IMPULSES IN CUTANEOUS RECEPTORS
The way that sensory receptors generate action potentials in the nerves that innervate them varies based on the complexity of the sense organ. In the skin, the Pacinian corpuscle has been studied in some detail. The myelin sheath of the sensory nerve begins inside the corpuscle (Figure 8–3). The first node of Ranvier is also located inside; the second is usually near the point at which the nerve fiber leaves the corpuscle.
FIGURE 8–3 Demonstration that the generator potential in a Pacinian corpuscle originates in the unmyelinated nerve terminal. The electrical responses to pressures (black arrow) of 1, 2×, 3×, and 4× are shown. The strongest stimulus produced an action potential in the sensory nerve, originating in the center of the corpuscle. (From Waxman SG: Clinical Neuroanatomy, 26th ed. McGraw-Hill, 2010.)
When a small amount of pressure is applied to the Pacinian corpuscle, a nonpropagated depolarizing potential resembling an excitatory postsynaptic potential (EPSP) is recorded. This is called the generator potential or receptor potential (Figure 8–3). As the pressure is increased, the magnitude of the receptor potential is increased. The receptor therefore converts mechanical energy into an electrical response, the magnitude of which is proportional to the intensity of the stimulus. Thus, the responses are described as graded potentials rather than all-or-none as is the case for an action potential. When the magnitude of the generator potential reaches about 10 mV, an action potential is produced at the first node of Ranvier. The nerve then repolarizes. If the generator potential is great enough, the neuron fires again as soon as it repolarizes, and it continues to fire as long as the generator potential is large enough to bring the membrane potential of the node to the firing level. Thus, the node converts the graded response of the receptor into action potentials, the frequency of which is proportional to the magnitude of the applied stimulus.
Converting a receptor stimulus to a recognizable sensation is termed sensory coding. All sensory systems code for four elementary attributes of a stimulus: modality, location, intensity, and duration. Modality is the type of energy transmitted by the stimulus. Location is the site on the body or space where the stimulus originated. Intensity is signaled by the response amplitude or frequency of action potential generation. Duration refers to the time from start to end of a response in the receptor. These attributes of sensory coding are shown for the modality of touch in Figure 8–1.
When the nerve from a particular sensory receptor is stimulated, the sensation evoked is that for which the receptor is specialized no matter how or where along the nerve the activity is initiated. This principle, first enunciated by Johannes Müller in 1835, has been called the law of specific nerve energies. For example, if the sensory nerve from a Pacinian corpuscle in the hand is stimulated by pressure at the elbow or by irritation from a tumor in the brachial plexus, the sensation evoked is touch. The general principle of specific nerve energies remains one of the cornerstones of sensory physiology.
Humans have four basic classes of receptors based on their sensitivity to one predominant form of energy: mechanical, thermal, electromagnetic, or chemical. The particular form of energy to which a receptor is most sensitive is called its adequate stimulus. The adequate stimulus for the rods and cones in the eye, for example, is light (an example of electromagnetic energy). Receptors do respond to forms of energy other than their adequate stimuli, but the threshold for these nonspecific responses is much higher. Pressure on the eyeball will stimulate the rods and cones, for example, but the threshold of these receptors to pressure is much higher than the threshold of the pressure receptors in the skin.
The term sensory unit refers to a single sensory axon and all of its peripheral branches. These branches vary in number but may be numerous, especially in the cutaneous senses. The receptive field of a sensory unit is the spatial distribution from which a stimulus produces a response in that unit (Figure 8–1). Representation of the senses in the skin is punctate. If the skin is carefully mapped, millimeter by millimeter, with a fine hair, a sensation of touch is evoked from spots overlying these touch receptors. None is evoked from the intervening areas. Similarly, temperature sensations and pain are produced by stimulation of the skin only over the spots where the receptors for these modalities are located. In the cornea and adjacent sclera of the eye, the surface area supplied by a single sensory unit is 50–200 mm2. The area supplied by one sensory unit usually overlaps and interdigitates with the areas supplied by others.
One of the most important mechanisms that enable localization of a stimulus site is lateral inhibition. Information from sensory neurons whose receptors are at the peripheral edge of the stimulus is inhibited compared to information from the sensory neurons at the center of the stimulus. Thus, lateral inhibition enhances the contrast between the center and periphery of a stimulated area and increases the ability of the brain to localize a sensory input. Lateral inhibition underlies two-point discrimination (see Clinical Box 8–2).
CLINICAL BOX 8–2
The size of the receptive fields for light touch can be measured by the two-point threshold test. In this procedure, the two points on a pair of calipers are simultaneously positioned on the skin and one determines the minimum distance between the two caliper points that can be perceived as separate points of stimulation. This is called the two-point discrimination threshold. If the distance is very small, each caliper point is touching the receptive field of only one sensory neuron. If the distance between stimulation points is less than this threshold, only one point of stimulation can be felt. Thus, the two-point discrimination threshold is a measure of tactile acuity. The magnitude of two-point discrimination thresholds varies from place to place on the body and is smallest where touch receptors are most abundant. Stimulus points on the back, for instance, must be separated by at least 65 mm before they can be distinguished as separate, whereas on the fingertips two stimuli are recognized if they are separated by as little as 2 mm. Blind individuals benefit from the tactile acuity of fingertips to facilitate the ability to read Braille; the dots forming Braille symbols are separated by 2.5 mm. Two-point discrimination is used to test the integrity of the dorsal column (medial lemniscus) system, the central pathway for touch and proprioception.
Vibratory sensibility is tested by applying a vibrating (128-Hz) tuning fork to the skin on the fingertip, tip of the toe, or bony prominences of the toes. The normal response is a “buzzing” sensation. The sensation is most marked over bones. The term pallesthesia is also used to describe this ability to feel mechanical vibrations. The receptors involved are the receptors for touch, especially Pacinian corpuscles, but a time factor is also necessary. A pattern of rhythmic pressure stimuli is interpreted as vibration. The impulses responsible for the vibrating sensation are carried in the dorsal columns. Degeneration of this part of the spinal cord occurs in poorly controlled diabetes, pernicious anemia, vitamin B12 deficiencies, or early tabes dorsalis. Elevation of the threshold for vibratory stimuli is an early symptom of this degeneration. Vibratory sensation and proprioception are closely related; when one is diminished, so is the other.
Stereognosis is the perception of the form and nature of an object without looking at it. Normal persons can readily identify objects such as keys and coins of various denominations. This ability depends on relatively intact touch and pressure sensation and is compromised when the dorsal columns are damaged. The inability to identify an object by touch is called tactile agnosia. It also has a large cortical component; impaired stereognosis is an early sign of damage to the cerebral cortex and sometimes occurs in the absence of any detectable defect in touch and pressure sensation when there is a lesion in the primary sensory cortex. Stereoagnosia can also be expressed by the failure to identify an object by sight (visual agnosia), the inability to identify sounds or words (auditory agnosia) or color (color agnosia), or the inability to identify the location or position of an extremity (position agnosia).
The intensity of sensation is determined by the amplitude of the stimulus applied to the receptor. This is illustrated in Figure 8–4. As a greater pressure is applied to the skin, the receptor potential in the mechanoreceptor increases (not shown), and the frequency of the action potentials in a single axon transmitting information to the CNS is also increased. In addition to increasing the firing rate in a single axon, the greater intensity of stimulation also will recruit more receptors into the receptive field.
FIGURE 8–4 Relationship between stimulus and impulse frequency in an afferent fiber. Action potentials in an afferent fiber from a mechanoreceptor of a single sensory unit increase in frequency as branches of the afferent neuron are stimulated by pressure of increasing magnitude. (From Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology. McGraw-Hill, 2008.)
As the strength of a stimulus is increased, it tends to spread over a large area and generally not only activates the sense organs immediately in contact with it but also “recruits” those in the surrounding area. Furthermore, weak stimuli activate the receptors with the lowest thresholds, and stronger stimuli also activate those with higher thresholds. Some of the receptors activated are part of the same sensory unit, and impulse frequency in the unit therefore increases. Because of overlap and interdigitation of one unit with another, however, receptors of other units are also stimulated, and consequently more units fire. In this way, more afferent pathways are activated, which is interpreted in the brain as an increase in intensity of the sensation.
If a stimulus of constant strength is maintained on a sensory receptor, the frequency of the action potentials in its sensory nerve declines over time. This phenomenon is known as receptor adaptation or desensitization. The degree to which adaptation occurs varies from one sense to another. Receptors can be classified into rapidly adapting (phasic) receptors and slowly adapting (tonic) receptors. This is illustrated for different types of touch receptors in Figure 8–1. Meissner and Pacinian corpuscles are examples of rapidly adapting receptors, and Merkel cells and Ruffini endings are examples of slowly adapting receptors. Other examples of slowly adapting receptors are muscle spindles and nociceptors. Different types of sensory adaptation likely have some value to the individual. Light touch would be distracting if it were persistent; and, conversely, slow adaptation of spindle input is needed to maintain posture. Similarly, input from nociceptors provides a warning that it would lose its value if it is adapted and disappeared.
The sensory component of a neurological exam includes an assessment of various sensory modalities including touch, proprioception, vibratory sense, and pain. Cortical sensory function can be tested by placing familiar objects in a patient’s hands and asking him or her to identify it with the eyes closed. Clinical Box 8–2 describes some of the common assessments made in a neurological exam.
One of the most common reasons an individual seeks the advice of a physician is because he or she is in pain. Pain was called by Sherrington, “the physical adjunct of an imperative protective reflex.” Painful stimuli generally initiate potent withdrawal and avoidance responses. Pain differs from other sensations in that it sounds a warning that something is wrong, preempts other signals, and is associated with an unpleasant affect. It is immensely complex because when tissue is damaged, central nociceptive pathways are sensitized and reorganized which leads to persistent or chronic pain (see Clinical Box 8–3).
CLINICAL BOX 8–3
A 2009 report in Scientific American indicated that 10–20% of the US and European populations experience chronic pain; 59% of these individuals are women. Based on a survey of primary care physicians, only 15% indicated that they felt comfortable treating patients with chronic pain; and 41% said they waited until patients specifically requested narcotic pain killers before prescribing them. Nearly 20% of adults with chronic pain indicated that they have visited an alternative medicine therapist. Risk factors for chronic neck and back pain include aging, being female, anxiety, repetitive work, obesity, depression, heavy lifting, and nicotine use. One example of chronic pain is neuropathic pain that may occur when nerve fibers are injured. Nerve damage can cause an inflammatory response due to activation of microglia in the spinal cord. Commonly, it is excruciating and a difficult condition to treat. For example, in causalgia, a spontaneous burning pain occurs long after seemingly trivial injuries. The pain is often accompanied by hyperalgesia and allodynia. Reflex sympathetic dystrophy is often present as well. In this condition, the skin in the affected area is thin and shiny, and there is increased hair growth. This may result because of sprouting and eventual overgrowth of noradrenergic sympathetic nerve fibers into the dorsal root ganglia of the sensory nerves from the injured area. Sympathetic discharge then brings on pain. Thus, it appears that the periphery has been short-circuited and that the relevant altered fibers are being stimulated by norepinephrine at the dorsal root ganglion level.
Chronic pain is often refractory to most conventional therapies such as NSAIDs and even opioids. In new efforts to treat chronic pain, some therapies focus on synaptic transmission in nociceptive pathways and peripheral sensory transduction. TRPV1, a capsaicin receptor, is activated by noxious stimuli such as heat, protons, and products of inflammation. Capsaicin transdermal patches or creams reduce pain by exhausting the supply of substance P in nerves. Nav1.8 (a tetrodotoxin-resistant voltage-gated sodium channel) is uniquely associated with nociceptive neurons in dorsal root ganglia. Lidocaine and mexiletine are useful in some cases of chronic pain and may act by blocking this channel. Ralfinamide, a Na+ channel blocker, is under development for potential treatment of neuropathic pain. Ziconotide, a voltage-gated N-type Ca2+ channel blocker, has been approved for intrathecal analgesia in patients with refractory chronic pain. Gabapentin is an anticonvulsant drug that is an analog of GABA; it has been shown to be effective in treatment of neuropathic and inflammatory pain by acting on voltage-gated Ca2+ channels. Topiramate, a Na+ channel blocker, is another example of an anticonvulsant drug that can be used to treat migraine headaches. NMDA receptor antagonists can be co-administered with an opioid to reduce tolerance to an opioid. Endogenous cannabinoids have analgesic actions in addition to their euphopric effects. Drugs that act on CB2 receptors which are devoid of euphoric effects are under development for the treatment of neuropathic pain.
CLASSIFICATION OF PAIN
For scientific and clinical purposes, pain is defined by the International Association for the Study of Pain (IASP) as, “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” This is to be distinguished from the term nociception which the IASP defines as the unconscious activity induced by a harmful stimulus applied to sense receptors.
Pain is frequently classified as physiologic or acute pain and pathologic or chronic pain, which includes inflammatory pain and neuropathic pain. Acute pain typically has a sudden onset and recedes during the healing process; it can be regarded as “good pain” as it serves an important protective mechanism. The withdrawal reflex is an example of the expression of this protective role of pain.
Chronic pain can be considered “bad pain” because it persists long after recovery from an injury and is often refractory to common analgesic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids.Chronic pain can result from nerve injury (neuropathic pain) including diabetic neuropathy, toxin-induced nerve damage, and ischemia. Causalgia is a type of neuropathic pain (see Clinical Box 8–3).
HYPERALGESIA AND ALLODYNIA
Pain is often accompanied by hyperalgesia and allodynia. Hyperalgesia is an exaggerated response to a noxious stimulus, and allodynia is a sensation of pain in response to a normally innocuous stimulus. An example of the latter is the painful sensation from a warm shower when the skin is damaged by sunburn.
Hyperalgesia and allodynia signify increased sensitivity of nociceptive afferent fibers. Figure 8–5 shows how chemicals released at the site of injury can further directly activate receptors on sensory nerve endings leading to inflammatory pain. Injured cells also release chemicals such as K+ that directly depolarize nerve terminals, making nociceptors more responsive (sensitization). Injured cells also release bradykinin and substance P, which can further sensitize nociceptive terminals. Histamine is released from mast cells, serotonin (5-HT) from platelets, and prostaglandins from cell membranes, all contributing to the inflammatory process and they activate or sensitize the nociceptors. Some released substances act by releasing another one (eg, bradykinin activates both Aδ and C nerve endings and increases synthesis and release of prostaglandins). Prostaglandin E2 (a cyclooxygenase metabolite of arachidonic acid) is released from damaged cells and produces hyperalgesia. This is why aspirin and other NSAIDs (inhibitors of cyclooxygenase) alleviate pain.
FIGURE 8–5 Chemical mediators are released in response to tissue damage and can sensitize or directly activate nociceptors. These factors contribute to hyperalgesia and allodynia. Tissue injury releases bradykinin and prostaglandins that sensitize or activate nociceptors, which in turn releases substance P and calcitonin gene-related peptide (CGRP). Substance P acts on mast cells to cause degranulation and release histamine, which activates nociceptors. Substance P causes plasma extravasation and CGRP dilates blood vessels; the resulting edema causes additional release of bradykinin. Serotonin (5-HT) is released from platelets and activates nociceptors. (From Lembeck F:CIBA Foundation Symposium, London: Pitman Medical; Summit, NJ, 1981.)
In addition to sensitization of nerve endings by chemical mediators, several other changes occur within the periphery and CNS that can contribute to the chronic pain. The NGF released by tissue damage is picked up by nerve terminals and transported retrogradely to cell bodies in dorsal root ganglia where it can alter gene expression. Transport may be facilitated by the activation of TrkA receptors on the nerve endings. In the dorsal root ganglia, NGF increases production of substance P and converts nonnociceptive neurons to nociceptive neurons (a phenotypic change). NGF also influences expression of a tetrodotoxin-resistant sodium channel (Nav1.8) on dorsal root ganglia, further increasing activity.
Damaged nerve fibers undergo sprouting, so fibers from touch receptors synapse on spinal dorsal horn neurons that normally receive only nociceptive input (see below). This can explain why innocuous stimuli can induce pain after injury. The combined release of substance P and glutamate from nociceptive afferents in the spinal cord causes excessive activation of NMDA (n-methyl-D-aspartate) receptors on spinal neurons, a phenomenon called “wind-up” that leads to increased activity in pain transmitting pathways. Another change in the spinal cord is due to the activation of microglia near afferent nerve terminals in the spinal cord by the release of transmitters from sensory afferents. This, in turn, leads to the release of pro-inflammatory cytokines and chemokines that modulate pain processing by affecting presynaptic release of neurotransmitters and postsynaptic excitability. There are P2X receptors on microglia; antagonists of these receptors may be a useful therapy for treatment of chronic pain.
DEEP AND VISCERAL PAIN
The main difference between superficial and deep or visceral pain is the nature of the pain evoked by noxious stimuli. This is probably due to a relative deficiency of Aδ nerve fibers in deep structures, so there is little rapid, sharp pain. In addition, deep pain and visceral pain are poorly localized, nauseating, and frequently are accompanied by sweating and changes in blood pressure. Pain can be elicited experimentally from the periosteum and ligaments by injecting hypertonic saline into them. The pain produced in this fashion initiates reflex contraction of nearby skeletal muscles. This reflex contraction is similar to the muscle spasm associated with injuries to bones, tendons, and joints. The steadily contracting muscles become ischemic, and ischemia stimulates the pain receptors in the muscles. The pain in turn initiates more spasm, setting up a vicious cycle.
In addition to being poorly localized, unpleasant, and associated with nausea and autonomic symptoms, visceral pain often radiates or is referred to other areas. The autonomic nervous system, like the somatic, has afferent components, central integrating stations, and effector pathways. The receptors for pain and the other sensory modalities present in the viscera are similar to those in skin, but there are marked differences in their distribution. There are no proprioceptors in the viscera, and few temperature and touch receptors. Nociceptors are present, although they are more sparsely distributed than in somatic structures.
Afferent fibers from visceral structures reach the CNS via sympathetic and parasympathetic nerves. Their cell bodies are located in the dorsal root ganglia and the homologous cranial nerve ganglia. Specifically, there are visceral afferents in the facial, glossopharyngeal, and vagus nerves; in the thoracic and upper lumbar dorsal roots; and in the sacral dorsal roots.
As almost everyone knows from personal experience, visceral pain can be very severe. The receptors in the walls of the hollow viscera are especially sensitive to distention of these organs. Such distention can be produced experimentally in the gastrointestinal tract by inflation of a swallowed balloon attached to a tube. This produces pain that waxes and wanes (intestinal colic) as the intestine contracts and relaxes on the balloon. Similar colic is produced in intestinal obstruction by the contractions of the dilated intestine above the obstruction. When a visceral organ is inflamed or hyperemic, relatively minor stimuli cause severe pain, a form of hyperalgesia.
Irritation of a visceral organ frequently produces pain that is felt not at that site but in a somatic structure that may be some distance away. Such pain is said to be referred to the somatic structure (referred pain). Knowledge of the common sites of pain referral from each of the visceral organs is of importance to a physician. One of the best-known examples is referral of cardiac pain to the inner aspect of the left arm. Other examples include pain in the tip of the shoulder caused by irritation of the central portion of the diaphragm and pain in the testicle due to distention of the ureter. Additional instances abound in the practices of medicine, surgery, and dentistry. However, sites of reference are not stereotyped, and unusual reference sites occur with considerable frequency. Cardiac pain, for instance, may be referred to the right arm, the abdominal region, or even the back, neck, or jaw.
When pain is referred, it is usually to a structure that developed from the same embryonic segment or dermatome as the structure in which the pain originates. For example, the heart and the arm have the same segmental origin, and the testicle migrated with its nerve supply from the primitive urogenital ridge from which the kidney and ureter also developed.
The basis for referred pain may be convergence of somatic and visceral pain fibers on the same second-order neurons in the dorsal horn that project to the thalamus and then to the somatosensory cortex (Figure 8–6). This is called the convergence–projection theory. Somatic and visceral neurons converge in the ipsilateral dorsal horn. The somatic nociceptive fibers normally do not activate the second-order neurons, but when the visceral stimulus is prolonged, facilitation of the somatic fiber endings occurs. They now stimulate the second-order neurons, and of course the brain cannot determine whether the stimulus came from the viscera or from the area of referral.
FIGURE 8–6 Schematic illustration of the convergence-projection theory for referred pain and descending pathways involved in pain control. The basis for referred pain may be convergence of somatic and visceral pain fibers on the same second-order neurons in the dorsal horn of the spinal cord that project higher brain regions. The periaqueductal gray (PAG) is a part of a descending pathway that includes serotonergic neurons in the nucleus raphé magnus and catecholaminergic neurons in the rostral ventromedial medulla to modulate pain transmission by inhibition of primary afferent transmission in the dorsal horn. (Courtesy of Al Basbaum.)
The sensation evoked by impulses generated in a sensory receptor depends in part on the specific part of the brain they ultimately activate. The ascending pathways from sensory receptors to the cortex are different for the various sensations. Below is a comparison of the ascending sensory pathway that mediates touch, vibratory sense, and proprioception (dorsal column-medial lemniscal pathway) and that which mediates pain and temperature (ventrolateral spinothalamic pathway).
DORSAL COLUMN PATHWAY
The principal pathways to the cerebral cortex for touch, vibratory sense, and proprioception are shown in Figure 8–7. Fibers mediating these sensations ascend ipsilaterally in the dorsal columns of the spinal cord to the medulla, where they synapse in the gracilus and cuneate nuclei. The second-order neurons from these nuclei cross the midline and ascend in the medial lemniscus to end in the contralateral ventral posterior lateral (VPL) nucleus and related specific sensory relay nuclei of the thalamus. This ascending system is called the dorsal column or medial lemniscal system. The fibers within the dorsal column pathway are joined in the brain stem by fibers mediating sensation from the head. Touch and proprioception from the head are relayed mostly via the main sensory and mesencephalic nuclei of the trigeminal nerve.
FIGURE 8–7 Ascending tracts carrying sensory information from peripheral receptors to the cerebral cortex. A) Dorsal column pathway mediates touch, vibratory sense, and proprioception. Sensory fibers ascend ipsilaterally via the spinal dorsal columns to medullary gracilus and cuneate nuclei; from there the fibers cross the midline and ascend in the medial lemniscus to the contralateral thalamic ventral posterior lateral (VPL) and then to the primary somatosensory cortex. B) Ventrolateral spinothalamic tract mediates pain and temperature. These sensory fibers terminate in the dorsal horn and projections from there cross the midline and ascend in the ventrolateral quadrant of the spinal cord to the VPL and then to the primary somatosensory cortex. (From Fox SI, Human Physiology. McGraw-Hill, 2008.)
Within the dorsal columns, fibers arising from different levels of the cord are somatotopically organized (Figure 8–7). Specifically, fibers from the sacral cord are positioned most medially and those from the cervical cord are positioned most laterally. This arrangement continues in the medulla with lower body (eg, foot) representation in the gracilus nucleus and upper body (eg, finger) representation in cuneate nucleus. The medial lemniscus is organized dorsal to ventral representing from neck to foot.
Somatotopic organization continues through the thalamus and cortex. VPL thalamic neurons carrying sensory information project in a highly specific way to the primary somatosensory cortex in the postcentral gyrus of the parietal lobe (Figure 8–8). The arrangement of projections to this region is such that the parts of the body are represented in order along the postcentral gyrus, with the legs on top and the head at the foot of the gyrus. Not only is there detailed localization of the fibers from the various parts of the body in the postcentral gyrus, but also the size of the cortical receiving area for impulses from a particular part of the body is proportional to the use of the part. The relative sizes of the cortical receiving areas are shown dramatically in Figure 8–9, in which the proportions of the homunculus have been distorted to correspond to the size of the cortical receiving areas for each. Note that the cortical areas for sensation from the trunk and back are small, whereas very large areas are concerned with impulses from the hand and the parts of the mouth concerned with speech.
FIGURE 8–8 A lateral view of the left hemisphere showing some principal cortical areas and their functional correlates in the human brain. The primary somatosensory area is in the postcentral gyrus of the parietal lobe, and the primary motor cortex is in the precentral gyrus. (From Waxman SG: Clinical Neuroanatomy, 26th ed. McGraw-Hill, 2010.)
FIGURE 8–9 Sensory homunculus, drawn overlying a coronal section through the postcentral gyrus. The parts of the body are represented in order along the postcentral gyrus, with the legs on top and the head at the foot of the gyrus. The size of the cortical receiving area for impulses from a particular part of the body is proportionate to the use of the part. Gen., genitalia. (Reproduced with permission from Penfield W, Rasmussen G: The Cerebral Cortex of Man. Macmillan, 1950.)
Studies of the sensory receiving area emphasize the very discrete nature of the point-for-point localization of peripheral areas in the cortex and provide further evidence for the general validity of the law of specific nerve energies. Stimulation of the various parts of the postcentral gyrus gives rise to sensations projected to appropriate parts of the body. The sensations produced are usually numbness, tingling, or a sense of movement, but with fine enough electrodes it has been possible to produce relatively pure sensations of touch, warmth, and cold. The cells in the postcentral gyrus are organized in vertical columns. The cells in a given column are all activated by afferents from a given part of the body, and all respond to the same sensory modality.
In addition to the primary somatosensory cortex, there are two other cortical regions that contribute to the integration of sensory information. The sensory association area is located in the parietal cortex and the secondary somatosensory cortex is located in the wall of the lateral fissure (also called sylvian fissure) that separates the temporal from the frontal and parietal lobes. These regions receive input from the primary somatosensory cortex.
Conscious awareness of the positions of the various parts of the body in space depends in part on impulses from sensory receptors in and around the joints. Impulses from these receptors, from touch receptors in the skin and other tissues, and from muscle spindles are synthesized in the cortex into a conscious picture of the position of the body in space.
VENTROLATERAL SPINOTHALAMIC TRACT
Fibers from nociceptors and thermoreceptors synapse on neurons in the dorsal horn of the spinal cord. The axons from these dorsal horn neurons cross the midline and ascend in the ventrolateral quadrant of the spinal cord, where they form the ventrolateral spinothalamic pathway (Figure 8–7). Fibers within this tract synapse in the VPL. Some dorsal horn neurons that receive nociceptive input synapse in the reticular formation of the brain stem (spinoreticular pathway) and then project to the centrolateral nucleus of the thalamus.
Positron emission tomographic (PET) and functional magnetic resonance imaging (fMRI) studies in normal humans indicate that pain activates the primary and secondary somatosensory cortex and the cingulate gyrus on the side opposite the stimulus. In addition, the amygdala, frontal lobe, and the insular cortex are activated. These technologies were important in distinguishing two components of pain pathways. Researchers found that noxious stimuli that did not induce a change in affect caused an increased metabolism in the primary somatosensory cortex, whereas stimuli that elicited motivational-affective responses activated a larger portion of the cortex. This showed that the pathway to the primary somatosensory cortex is responsible for the discriminative aspect of pain. In contrast, the pathway that includes synapses in the brain stem reticular formation and centrolateral thalamic nucleus projects to the frontal lobe, limbic system, and insular cortex. This pathway mediates the motivational-affective component of pain.
Visceral sensation travels along the same central pathways as somatic sensation in the spinothalamic tracts and thalamic radiations, and the cortical receiving areas for visceral sensation are intermixed with the somatic receiving areas.
It is now clear that the extensive neuronal connections described above are not innate and immutable but can be changed relatively rapidly by experience to reflect the use of the represented area. Clinical Box 8–4 describes remarkable changes in cortical and thalamic organization that occur in response to limb amputation to lead to the phenomenon of phantom limb pain.
CLINICAL BOX 8–4
Phantom Limb Pain
In 1551, a military surgeon, Ambroise Pare, wrote “…the patients, long after the amputation is made, say they still feel pain in the amputated part. Of this they complain strongly, a thing worthy of wonder and almost incredible to people who have not experienced this.” This is perhaps the earliest description of phantom limb pain. Between 50 and 80% of amputees experience phantom sensations, usually pain, in the region of their amputated limb. Phantom sensations may also occur after the removal of body parts other than the limbs, for example, after amputation of the breast, extraction of a tooth (phantom tooth pain), or removal of an eye (phantom eye syndrome). Numerous theories have been evoked to explain this phenomenon. The current theory is based on evidence that the brain can reorganize if sensory input is cut off. The ventral posterior thalamic nucleus is one example where this change can occur. In patients who have had their leg amputated, single neuron recordings show that the thalamic region that once received input from the leg and foot now respond to stimulation of the stump (thigh). Others have demonstrated remapping of the somatosensory cortex. For example, in some individuals who have had an arm amputated, stroking different parts of the face can lead to the feeling of being touched in the area of the missing limb.
There is some evidence that the use of epidural anesthesia during the amputation surgery can prevent the acute pain associated with the surgery, thereby reducing the need for opioid therapy in the immediate postoperative period. They also reported a reduced incidence of phantom pain following this anesthetic procedure. Spinal cord stimulation has been shown to be an effective therapy for phantom pain. Electric current is passed through an electrode that is placed next to the spinal cord to stimulate spinal pathways. This interferes with the impulses ascending to the brain and lessens the pain felt in the phantom limb. Instead, amputees feel a tingling sensation in the phantom limb.
Numerous animal studies point to dramatic reorganization of cortical structures. If a digit is amputated in a monkey, the cortical representation of the neighboring digits spreads into the cortical area that was formerly occupied by the representation of the amputated digit. Conversely, if the cortical area representing a digit is removed, the somatosensory map of the digit moves to the surrounding cortex. Extensive, long-term deafferentation of limbs leads to even more dramatic shifts in somatosensory representation in the cortex, with, for example, the hand cortical area responding to touching the face. The explanation of these shifts appears to be that cortical connections of sensory units to the cortex have extensive convergence and divergence, with connections that can become weak with disuse and strong with use.
Plasticity of this type occurs not only with input from cutaneous receptors but also with input in other sensory systems. For example, in cats with small lesions of the retina, the cortical area for the blind spot begins to respond to light striking other areas of the retina. Development of the adult pattern of retinal projections to the visual cortex is another example of this plasticity. At a more extreme level, experimentally routing visual input to the auditory cortex during development creates visual receptive fields in the auditory system.
PET scanning in humans also documents plastic changes, sometimes from one sensory modality to another. Thus, for example, tactile and auditory stimuli increase metabolic activity in the visual cortex in blind individuals. Conversely, deaf individuals respond faster and more accurately than normal individuals to moving stimuli in the visual periphery. Plasticity also occurs in the motor cortex. These findings illustrate the malleability of the brain and its ability to adapt.
EFFECTS OF CNS LESIONS
Clinical Box 8–2 describes some of the deficits noted after damage within the somatosensory pathways. Clinical Box 8–5 describes the characteristic changes in sensory and motor functions that occur in response to spinal hemisection.
CLINICAL BOX 8–5
A functional hemisection of the spinal cord causes a characteristic and easily recognized clinical picture that reflects damage to ascending sensory (dorsal-column pathway, ventrolateral spinothalamic tract) and descending motor (corticospinal tract) pathways, which is called the Brown-Séquard syndrome. The lesion to fasciculus gracilus or fasciculus cuneatus leads to ipsilateral loss of discriminative touch, vibration, and proprioception below the level of the lesion. The loss of the spinothalamic tract leads to contralateral loss of pain and temperature sensation beginning one or two segments below the lesion. Damage to the corticospinal tract produces weakness and spasticity in certain muscle groups on the same side of the body. Although a precise spinal hemisection is rare, the syndrome is fairly common because it can be caused by a spinal cord tumor, spinal cord trauma, degenerative disc disease, and ischemia.
Drug treatments for Brown-Séquard syndrome are based on the etiology and time since onset. High doses of corticosteriods have been shown to be of value particularly if administered soon after the onset of such a spinal cord injury. Steroids decrease the inflammation by suppressing polymorphonuclear leukocytes and reverse the increase in capillary permeability.
Damage to the dorsal columns leads to ipsilateral loss of the ability to detect light touch, vibration, and proprioception from body structures represented caudal to the level of damage. Damage to the ventrolateral spinothalamic pathway leads to contralateral loss of pain and temperature sensation below the level of the lesion. Such spinal damage could occur with a penetrating wound or a tumor.
Lesions of the primary somatosensory cortex do not abolish somatic sensation. Irritation of this region causes paresthesia or an abnormal sensation of numbness and tingling on the contralateral side of the body. Destructive lesions impair the ability to localize noxious stimuli in time, space, and intensity. Damage to the cingulate cortex impairs the recognition of the aversive nature of a noxious stimulus.
An infarct in the thalamus can lead to a loss of sensation. Thalamic pain syndrome is sometimes seen during recovery from a thalamic infarct. The syndrome is characterized by chronic pain on the side of the body contralateral to the stroke.
MODULATION OF PAIN TRANSMISSION
PROCESSING INFORMATION IN THE DORSAL HORN
Transmission in nociceptive pathways can be interrupted by actions within the dorsal horn of the spinal cord at the site of sensory afferent termination. Many people have learned from practical experience that rubbing or shaking an injured area decreases the pain due to the injury. The relief may be due to the simultaneous activation of innocuous cutaneous mechanoreceptors whose afferents emit collaterals that terminate in the dorsal horn. The activity of these cutaneous mechanosensitive afferents may reduce the responsiveness of dorsal horn neurons to their input from nociceptive afferent terminals. This is called the gate-control mechanism of pain modulation and it serves as the rationale behind the use of transcutaneous electrical nerve stimulation (TENS) for pain relief. This method uses electrodes to activate Aα and Aβ fibers in the vicinity of the injury.
Opioids are a commonly used analgesic that can exert their effects at various places in the CNS, including in the spinal cord and dorsal root ganglia. Figure 8–10 shows some of the various modes of action of opioids to decrease nociceptive transmission. There are interneurons in the superficial regions of the dorsal horn that contain endogenous opioid peptides (enkephalin and dynorphin). These interneurons terminate in the region of the dorsal horn where nociceptive afferents terminate. Opioid receptors (OR) are located on the terminals of nociceptive fibers and on dendrites of dorsal horn neurons, allowing for both presynaptic and postsynaptic sites of actions for opioids. Activation of the postsynaptic OR hyperpolarizes the dorsal horn interneuron by causing an increase in K+ conductance. Activation of the presynaptic OR leads to a decrease in Ca2+ influx, resulting in a decrease in release of glutamate and substance P. Together these actions reduce the duration of the EPSP in the dorsal horn neuron. Activation of OR on dorsal root ganglia cell bodies also contributes to reduced transmission from nociceptive afferents.
FIGURE 8–10 Local-circuit interneurons in the superficial dorsal horn of the spinal cord integrate descending and afferent pathways. A) Interactions of nociceptive afferent fibers, interneurons, and descending fibers in the dorsal horn. Nociceptive fibers terminate on spinothalamic projection neurons. Enkephalin (ENK)-containing interneurons exert both presynaptic and postsynaptic inhibitory actions. Serotonergic and noradrenergic neurons in the brainstem activate ENK interneurons and suppress the activity of spinothalamic projection neurons. B1) Activation of nociceptors releases glutamate and neuropeptides from sensory terminals, depolarizing, and activating projection neurons. B2) Opioids decrease Ca2+ influx leading to a decrease in the duration of nociceptor action potentials and a decreased release of transmitter. Also, opioids hyperpolarize the membrane of dorsal horn neurons by activating K+conductance and decrease the amplitude of the EPSP produced by stimulation of nociceptors. (From Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)
Chronic use of morphine to relieve pain can cause patients to develop resistance to the drug, requiring progressively higher doses for pain relief. This acquired tolerance is different from addiction, which refers to a psychological craving. Psychological addiction rarely occurs when morphine is used to treat chronic pain, provided the patient does not have a history of drug abuse. Clinical Box 8–6 describes mechanisms involved in motivation and addiction.
CLINICAL BOX 8–6
Motivation & Addiction
Neurons in the forebrain ventral tegmental area and nucleus acumbens are involved in motivated behaviors such as reward, laughter, pleasure, addiction, and fear. These areas have been referred to as the brain’s reward center or pleasure center. The mesocortical dopaminergic neurons that project from the midbrain to the nucleus accumbens and the frontal cortex are also involved. Addiction, defined as the repeated compulsive use of a substance despite negative health consequences, can be produced by a variety of different drugs. According to the World Health Organization, over 76 million people worldwide suffer from alcohol abuse, and over 15 million suffer from drug abuse. Not surprisingly, alcohol and drug addiction are associated with the reward system. The best studied addictive drugs are opioids (eg, morphine and heroin); others include cocaine, amphetamine, alcohol, cannabinoids, and nicotine. These drugs affect the brain in different ways, but all have in common the fact that they increase the amount of dopamine available to act on D3 receptors in the nucleus accumbens. Thus, acutely they stimulate the reward system of the brain. Long-term addiction involves the development of tolerance, which is the need for increasing amounts of a drug to produce a high. Also, withdrawal produces psychologic and physical symptoms. One of the characteristics of addiction is the tendency of addicts to relapse after treatment. For opioid addicts, the relapse rate in the first year is about 80%. Relapse often occurs on exposure to sights, sounds, and situations that were previously associated with drug use. Even a single dose of an addictive drug facilitates release of excitatory neurotransmitters in brain areas concerned with memory. The medial frontal cortex, hippocampus, and amygdala are concerned with memory, and they all project via excitatory glutamatergic pathways to the nucleus accumbens. Despite intensive study, relatively little is known about the brain mechanisms that cause tolerance and dependence. However, the two can be separated. Absence of β-arrestin-2 blocks tolerance but has no effect on dependence. β-Arrestin-2 is a member of a family of proteins that inhibit heterotrimeric G proteins by phosphorylating them.
Withdrawal symptoms and cravings associated with addiction to opioids can be reversed by treatment with various drugs that act on the same CNS receptors as morphine and heroin. These include methadone and buprenorphine.The U.S. Federal Drug Administration has approved the use of three drugs for treatment of alcohol abuse: naltrexone, acamprosate, and disulfiram. Naltrexone is an opioid receptor antagonist that blocks the reward system and the craving for alcohol. Acamprosate may reduce the withdrawal effects associated with alcohol abuse. Disulfiram causes an accumulation of acetaldehyde by preventing the full degradation of alcohol. This leads to an unpleasant reaction to alcohol ingestion (eg, flushing, nausea, and palpitations). Topiramate, a Na+ channel blocker, is showing promise in clinical trials of alcohol addiction. This is the same drug that has shown to be effective in treatment of migraine headaches.
ROLES OF PERIAQUEDUCTAL GRAY & BRAINSTEM
Another site of action for morphine and endogenous opioid peptides is the mesencephalic periaqueductal gray (PAG). An injection of opioids into the PAG induces analgesia. The PAG is a part of a descending pathway that modulates pain transmission by inhibition of primary afferent transmission in the dorsal horn (Figure 8–6). These PAG neurons project directly to and activate two groups of neurons in the brainstem: serotonergic neurons in the nucleus raphé magnus and catecholaminergic neurons in the rostral ventromedial medulla. Neurons in both of these regions project to the dorsal horn of the spinal cord where the released serotonin and norepinephrine inhibit the activity of dorsal horn neurons that receive input from nociceptive afferent fibers (Figure 8–10). This inhibition occurs, at least in part, due to the activation of the dorsal horn enkephalin-containing interneurons. There is also a group of brainstem catecholaminergic neurons in the locus coeruleus that are elements of this descending pain modulating pathway. These pontine neurons also exert their analgesic effect by the release of norepinephrine in the dorsal horn.
The analgesic effect of electroacupuncture may involve the release of endogenous opioids and activation of this descending pain modulatory pathway. Electroacupuncture activates ascending sensory pathways that emit collaterals in the PAG and in the brainstem serotonergic and catecholaminergic regions. The analgesic effect of electroacupuncture is prevented by administration of naloxone, an OR antagonist.
It is well known that soldiers wounded in the heat of battle often feel no pain until the battle is over. This is an example of stress-induced analgesia that can also be exemplified by reduced pain sensitivity when being attacked by a predator or other stressful events. Release of norepinephrine, perhaps from brainstem catecholaminergic neurons, in the amygdala may contribute to this phenomenon. As described above, the amygdala is a part of the limbic system that is involved in mediating the motivational-affective responses to pain.
The release of endogenous cannabinoids such as 2-arachidonoylglycerol (2AG) and anandamide may also contribute to stress-induced analgesia. These chemicals can act on at least two types of G protein-coupled receptors (CB1and CB2). CB1 receptors are located in many brain regions, and activation of these receptors accounts for the euphoric actions of cannabinoids. CB2 receptors are expressed in activated microglia under various pathologies that are associated with chronic neuropathic pain (see Clinical Box 8–3). Binding of an agonist to CB2 receptors on microglia reduces the inflammatory response and has an analgesic effect. Work is underway to develop selective CB2agonists for therapeutic treatment of neuropathic pain.
Touch and pressure are sensed by four types of mechanoreceptors that are innervated by rapidly conducting Aα and Aβ sensory afferents. They are rapidly adapting Meissner’s corpuscles (respond to changes in texture and slow vibrations), slowly adapting Merkel’s cells (respond to sustained pressure and touch), slowly adapting Ruffini corpuscles (respond to sustained pressure), and rapidly adapting Pacinian corpuscles (respond to deep pressure and fast vibrations).
Nociceptors and thermoreceptors are free nerve endings on unmyelinated C fibers or lightly myelinated Aδ fibers in hairy and glaborous skin and deep tissues. These nerve endings have various types of receptors that are activated by noxious chemical (eg, TRPV1, ASIC), mechanical (eg, P2X, P2Y, TRPA1), and thermal (eg, TRPV1) stimuli. In addition, chemical mediators (eg, bradykinin, prostaglandin, serotonin, histamine) released in response to tissue injury directly activate or sensitize nociceptors.
The generator or receptor potential is the nonpropagated depolarizing potential recorded in a sensory organ after an adequate stimulus is applied. As the stimulus is increased, the magnitude of the receptor potential is also increased. When it reaches a critical threshold, an action potential is generated in the sensory nerve.
Converting a receptor stimulus to a recognizable sensation is termed sensory coding. All sensory systems code for four elementary attributes of a stimulus: modality, location, intensity, and duration.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage, whereas nociception is the unconscious activity induced by a harmful stimulus applied to sense receptors. First pain is mediated by Aδ fibers and causes a sharp, localized sensation. Second pain is mediated by C fibers and causes a dull, intense, diffuse, and unpleasant feeling. Acute pain has a sudden onset, recedes during the healing process, and serves as an important protective mechanism. Chronic pain is persistent and caused by nerve damage; it is often associated with hyperalgesia (an exaggerated response to a noxious stimulus) and allodynia (a sensation of pain in response to an innocuous stimulus). Chronic pain is often refractory to NSAIDs and opioids.
Visceral pain is poorly localized, unpleasant, and associated with nausea and autonomic symptoms. It often radiates (or is referred) to other somatic structures perhaps due to convergence of somatic and visceral nociceptive afferent fibers on the same second-order neurons in the spinal dorsal horn that project to the thalamus and then to the primary somatosensory cortex.
Discriminative touch, proprioception, and vibratory sensations are relayed via the dorsal column (medial lemniscus) pathway to the VPL in the thalamus and then to the primary somatosensory cortex. Pain and temperature sensations are mediated via the ventrolateral spinothalamic tract, which projects to the VPL and then to cortex. The discriminative aspect of pain results from activation of the primary somatosensory cortex; the motivational-affective component of pain is from activation of the frontal lobe, limbic system, and insular cortex.
Transmission in pain pathways is modulated by endogenous opioids that can act in the PAG, brainstem, spinal cord, and dorsal root ganglia. Descending pain modulating pathways include neurons in the PAG, nucleus raphé magnus, rostral ventromedial medulla, and locus coeruleus.
New pain therapies focus on synaptic transmission in nociception and peripheral sensory transduction. Capsaicin transdermal patches or creams reduce pain by exhausting the supply of substance P in nerves and by acting on TRPV1 receptors in the skin. Lidocaine and mexiletine are useful in some cases of chronic pain and act by blocking Nav1.8, which is uniquely associated with nociceptive neurons in dorsal root ganglia. Ziconotide, a voltage-gated N-type Ca2+ channel blocker, is used for intrathecal analgesia in patients with refractory chronic pain. Gabapentin, an anticonvulsant drug, is effective in treatment of neuropathic and inflammatory pain by acting on voltage-gated Ca2+ channels. Topiramate, a Na+ channel blocker, is another anticonvulsant drug that can be used to treat migraines. NMDA receptor antagonists can be co-administered with an opioid to reduce tolerance to an opioid.
For all questions, select the single best answer unless otherwise directed.
1. A 28-year-old male was seen by a neurologist because he had experienced prolonged episodes of tingling and numbness in his right arm. He underwent a neurological exam to evaluate his sensory nervous system. Which of the following receptors is correctly paired with the type of stimulus to which it is most apt to respond?
A. Pacinian corpuscle and motion.
B. Meissner’s corpuscle and deep pressure.
C. Merkel cells and warmth.
D. Ruffini corpuscles and sustained pressure.
E. Muscle spindle and tension.
A. are activated by strong pressure, severe cold, severe heat, and chemicals.
B. are absent in visceral organs.
C. are specialized structures located in the skin and joints.
D. are innervated by group II afferents.
E. are involved in acute but not chronic pain.
3. A generator potential
A. always leads to an action potential.
B. increases in amplitude as a more intense stimulus is applied.
C. is an all-or-none phenomenon.
D. is unchanged when a given stimulus is applied repeatedly over time.
E. all of the above.
4. Sensory systems code for the following attributes of a stimulus:
A. modality, location, intensity, and duration
B. threshold, receptive field, adaptation, and discrimination
C. touch, taste, hearing, and smell
D. threshold, laterality, sensation, and duration
E. sensitization, discrimination, energy, and projection
5. Which of the following are correctly paired?
A. Neuropathic pain and withdrawal reflex
B. First pain and dull, intense, diffuse, and unpleasant feeling
C. Physiological pain and allodynia
D. Second pain and C fibers
E. Nociceptive pain and nerve damage
6. A 32-year-old female experienced the sudden onset of a severe cramping pain in the abdominal region. She also became nauseated. Visceral pain
A. shows relatively rapid adaptation.
B. is mediated by B fibers in the dorsal roots of the spinal nerves.
C. is poorly localized.
D. resembles “fast pain” produced by noxious stimulation of the skin.
E. causes relaxation of nearby skeletal muscles.
7. A ventrolateral cordotomy is performed that produces relief of pain in the right leg. It is effective because it interrupts the
A. left dorsal column.
B. left ventrolateral spinothalamic tract.
C. right ventrolateral spinothalamic tract.
D. right medial lemniscal pathway.
E. a direct projection to the primary somatosensory cortex.
8. Which of the following CNS regions is not correctly paired with a neurotransmitter or a chemical involved in pain modulation?
A. Periaqueductal gray matter and morphine
B. Nucleus raphé magnus and norepinephrine
C. Spinal dorsal horn and enkephalin
D. Dorsal root ganglion and opioids
E. Spinal dorsal horn and serotonin
9. A 47-year-old female experienced migraine headaches that were not relived by her current pain medications. Her doctor prescribed one of the newer analgesic agents that exert their effects by targeting synaptic transmission in nociception and peripheral sensory transduction. Which of the following drugs is correctly paired with the type of receptor it acts on to exert its antinociceptive effects?
A. Topiramate and Na+ channel
B. Ziconotide and NMDA receptors
C. Naloxone and opioid receptors
D. Lidocaine and TRPVI channels
E. Gabapentin and Nav1.8
10. A 40-year-old man loses his right hand in a farm accident. Four years later, he has episodes of severe pain in the missing hand (phantom limb pain). A detailed PET scan study of his cerebral cortex might be expected to show
A. expansion of the right hand area in his right primary somatosensory cortex.
B. expansion of the right-hand area in his left primary somatosensory cortex.
C. a metabolically inactive spot where his hand area in his left primary somatosensory cortex would normally be.
D. projection of fibers from neighboring sensory areas into the right-hand area of his right primary somatosensory cortex.
E. projection of fibers from neighboring sensory areas into the right-hand area of his left primary somatosensory cortex.
11. A 50-year-old woman undergoes a neurological exam that indicates loss of pain and temperature sensitivity, vibratory sense, and proprioception in the left leg. These symptoms could be explained by
A. a tumor on the right medial lemniscal pathway in the sacral spinal cord.
B. a peripheral neuropathy.
C. a tumor on the left medial lemniscal pathway in the sacral spinal cord.
D. a tumor affecting the right posterior paracentral gyrus.
E. a large tumor in the right lumbar ventrolateral spinal cord.
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