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1 Neural Basis of Pain

1 Neural Basis of Pain
The Massachusetts General Hospital Handbook of Pain Management

1
Neural Basis of Pain

Gary J. Brenner

Severe pain is world destroying.
—Elaine Scarry from The Body in Pain

I. Nociceptors

1. Definitions

2. Primary afferent fibers

3. Dorsal horn synapses and biochemical mediators

4. Peripheral sensitization
II. Ascending nociceptive pathways

1. Topographical arrangement of the dorsal horn (Rexed laminae)

2. Dorsal horn projection neurons

3. Spinothalamic tract

4. Spinohypothalamic tract

5. Cranial nerves

6. Central sensitization
III. Supraspinal systems: integration and higher processing

1. Thalamus

2. Hypothalamus

3. Limbic system

4. Cerebral cortex

5. Cingulate cortex
IV. Pain modulation

1. Descending systems

2. “On” and “off” cells: a component of descending analgesia

3. Projections to the dorsal horn
V. Conclusion
Selected Reading

One of the most important functions of the nervous system is to provide information about potential bodily injury. Pain is defined by the International Association for Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” The body’s perception of pain is termed nociception. The pain system may be grossly divided into the following components:

1.
Nociceptors are the specialized receptors in the peripheral nervous system that detect noxious stimuli. Primary nociceptive afferent fibers, normally Adelta (Ad) and C fibers, transmit information regarding noxious stimuli to the dorsal horn of the spinal cord.

2.
Ascending nociceptive tracts, for example the spinothalamic and spinohypothalamic tracts, convey nociceptive stimuli from the dorsal horn of the spinal cord to higher centers in the central nervous system (CNS).

3.
Higher centers in the CNS are involved in pain discrimination, including affective components of pain, memory components of pain, and motor control related to the immediate aversive response to painful stimuli.

4.
Descending systems allow higher centers of the CNS to modify nociceptive information at multiple levels.
I. NOCICEPTORS
1. Definitions
Although it is somewhat confusing, the term nociceptor is used to refer to the free nerve terminals of primary afferent fibers that respond to painful, potentially injurious stimuli, as well as to the entire apparatus (sensory neuron including free terminals) capable of transducing and transmitting information regarding noxious stimuli. In this chapter, the term nociceptor will be used to refer to the entire nociceptive primary afferent.
Free nerve terminals contain receptors capable of transducing chemical, mechanical, and thermal signals. Recently, for example, a membrane receptor that responds to heat has been discovered, and, interestingly, this receptor is also stimulated by capsaicin, the molecule responsible for the “hot” sensation associated with hot peppers. Nociceptive terminals innervate a wide variety of tissues and are present in both somatic and visceral structures including the cornea, tooth pulp, muscles, joints, the respiratory system, the cardiovascular system, the digestive system, the urogenital system, and the meninges, as well as the skin.
Nociceptors may be divided according to three criteria: degree of myelination, type(s) of stimulation that evokes a response, and response characteristics. Using the criterion of degree of myelination (which is related to conduction velocity), nociceptors can be divided into two classes: Ad fibers are thinly myelinated and conduct at a velocity of 2 to 30 meters per second. C fibers are unmyelinated and conduct at less than 2 m/sec (Table 1).

Table 1. Classification of fibers in peripheral nerves

Ad and C nociceptors can be further divided according to the stimuli that they sense. They may respond to mechanical, chemical, or thermal (heat and cold) stimuli, or to a combination of these (polymodal). For example, C-fiber mechano-heat receptors respond to noxious mechanical stimuli and intermediate heat stimuli (41° to 49°C), have a slow conduction velocity, and constitute the majority of nociceptive afferent fibers. Ad-fiber mechano-heat receptors can be divided into two subtypes. Type I receptors have a high heat threshold (>53°C) and conduct at relatively fast velocities (30 to 55 m/sec). These receptors detect pain sensation during high-intensity heat responses. Type II receptors have a lower heat threshold and conduct at a slower velocity (15 m/sec). Some receptors respond to both warmth and thermal pain. There are also both C and Ad fibers that are mechanically insensitive but respond to heat, cold, and a variety of chemicals, such as bradykinin, hydrogen ions, serotonin, histamine, arachidonic acid, and prostacyclin.
2. Primary afferent fibers
The neural impulses originating from the free endings of nociceptors are transmitted via primary afferent nerves to the spinal cord, or via cranial nerves to the brainstem if they come from the head or neck. Most primary afferent fibers innervating tissues below the level of the head have cell bodies located in the dorsal root ganglion (DRG) of spinal nerves. Primary afferent fibers of cranial nerves V, VII, IX, and X (the sensory cranial nerves) have cell bodies in their respective sensory ganglia.
The majority of nociceptors are C fibers, and 80% to 90% of C fibers respond to nociceptive input. The differences in conduction velocities and response characteristics of Ad and C fibers may explain the typical subjective pain experience associated with a noxious stimulus: a first pain (called epicritic pain) that is rapid, well localized, and pricking in character (Ad), followed by a second pain (called protopathic pain) that is burning and diffuse (C). Visceral afferent nociceptive fibers (Ad and C) travel with sympathetic and parasympathetic fibers; their cell bodies are also found in the DRG. Muscle is also innervated by both Ad and C fibers and, interestingly, muscle pain appears to be limited in quality to that of a cramp.
3. Dorsal horn synapses and biochemical mediators
Primary afferent nociceptors enter the spinal cord via Lissauer’s tract and synapse on neurons in the dorsal horn (Fig. 1). Lissauer’s tract is a bundle of predominately (80%) primary afferent fibers, consisting mainly of Ad and C fibers that penetrate the spinal cord en route to the dorsal horn. After entering the spinal cord, Ad and C fibers run up or down one or two segments before synapsing with second-order neurons in the dorsal horn.

Figure 1. Diagrammatic cross section of the spinal cord.

The dorsal horn synapse is an important site of further processing and integration of the incoming nociceptive information. The dorsal horn may be a point at which nociceptive information is conducted to higher centers, or it may be a point at which nociceptive information is inhibited by descending systems. The responsiveness of dorsal horn neurons may change in response to prior noxious afferent input, particularly repetitive input (central sensitization).
Biochemical mediators
Numerous neurotransmitters and other biochemical mediators are released in the dorsal horn. These substances are derived from three main sources:

a.
Primary afferent fibers

b.
Interneurons

c.
Descending fiber systems
The neurochemistry of the dorsal horn is complicated and there are qualitative differences between the pharmacology of acute pain and that of the facilitated pain states associated with chronic noxious stimulation. Some of the neurochemical mediators can be categorized as excitatory or inhibitory, although many serve complex and mixed functions. For example, the endogenous opioid dynorphin may be inhibitory or excitatory depending on the state of the nervous system. The following are examples of excitatory and inhibitory substances active in the dorsal horn.
Excitatory neuromediators:

Excitatory amino acids—glutamate and aspartate

Neuropeptides—substance P (SP) and calcitonin gene-related peptide (CGRP)

Growth factor—brain-derived neurotrophic factor (BDNF)
Inhibitory neuromediators:

Endogenous opioids, such as enkephalin and b-endorphin

Gamma-aminobutyric acid (GABA)

Glycine
Cells of the dorsal horn possess specific receptors for the substances just listed, as well as receptors for a multitude of other neurochemicals (some probably undiscovered). Of particular note is one of the glutamate receptors, the N-methyl-D-aspartate (NMDA) receptor, which is widely distributed in the dorsal horn. Extensive experimental data now implicate the NMDA receptor in the generation and maintenance of facilitated pain states.
4. Peripheral sensitization
Prolonged noxious stimulation can sensitize nociceptors. Sensitization refers to a decreased threshold as well as to an increased response to suprathreshold stimulation. It is observed following direct nerve injury and inflammation, and it is the result of a complex set of transcriptional and post-translational changes in the primary nociceptive afferents. Sensitization of the entire nociceptive pathway can arise secondary to changes in the CNS (central sensitization) or the periphery (peripheral sensitization). Once sensitization is established, it may be impossible to separate central contributions from peripheral contributions to the process of sensitization. The related topics of hyperalgesia, allodynia, inflammation, and nerve injury are briefly discussed next.
Hyperalgesia
Tissue damage results in activation of nociceptors, and if the damage is prolonged and intense it can generate a state in which there is a lowered threshold to painful stimuli. This state is known as hyperalgesia. In areas of hyperalgesia it is also possible to observe an increased response to noxious stimuli. There are alterations in both the subjective and the neurophysiologic responses to stimuli. The subjective response is characterized by a lowered pain threshold and an increase in pain response, while nociceptors demonstrate a corresponding decreased threshold and increased response. Primary hyperalgesia is hyperalgesia at the site of injury, and secondary hyperalgesia refers to hyperalgesia in the surrounding skin. Neural changes producing hyperalgesia can also occur in the CNS (central sensitization).
Allodynia
In addition to the development of a lowered threshold for noxious stimuli following tissue damage (hyperalgesia), it is possible to observe a post-injury state in which normally innocuous stimuli are perceived as painful. This phenomenon is termed allodynia. For example, very light touch in the area of a burn or associated with post-herpetic neuralgia can generate excruciating pain. Like hyperalgesia, allodynia is most likely caused by plastic changes in both primary sensory fibers and spinal cord neurons.
Inflammation
Inflammation, the characteristic reaction to injury, results in rubor, calor, dolor, tumor, and functio laesa (i.e., redness, heat, pain, swelling, and loss of function). During an inflammatory response, activation of nociceptive pathways can lead to sensitization resulting clinically in spontaneous and increased stimulation-induced pain (i.e., hyperalgesia and allodynia). Release of prostaglandins, cytokines, growth factors, and other mediators by inflammatory cells can directly stimulate nociceptors. The precise nature of this interaction between the immune and nervous systems and the manner in which this can lead to pathologic pain states, however, remains to be clarified. The critical observation is that inflammation is an important cause of both acute and chronic alterations in pain processing and sensation.
Nerve injury
Direct neural trauma can also lead to pathologic pain states characterized by spontaneous pain (i.e., pain occurring in the absence of any stimulus), hyperalgesia, and allodynia. Such neuropathic pain can arise following injury to peripheral or central elements of the pain system. A clinical example of this is complex regional pain syndrome type I (CRPS-I), formerly called reflex sympathetic dystrophy (RSD), in which an apparently minor injury can lead to sensitization of pain processing in a region including but not limited to that involved in the injury.
II. ASCENDING NOCICEPTIVE PATHWAYS
1. Topographical arrangement of the dorsal horn (rexed laminae)
The gray matter of the spinal cord can be divided into 10 laminae (the Rexed laminae I through X) on the basis of the histologic organization of the numerous types of cell bodies and dendrites. The dorsal horn is composed of laminae I through VI (Fig. 2). The majority of nociceptive input converges on lamina I (the marginal zone), lamina II (the substantia gelatinosa), and lamina V in the dorsal horn. However, some primary visceral and somatic nociceptive afferent fibers synapse in other laminae. Cutaneous mechanoreceptor Ad afferent fibers synapse in laminae I, II, and V; visceral mechanoreceptor Ad fibers synapse in laminae I and V; cutaneous nociceptor C fibers synapse in laminae I and II; and visceral nociceptive C fibers synapse in many laminae including I, II, IV, V, and X. The ascending spinal pathways involved with nociceptive transmission arise mainly from laminae I, II, and V (Fig. 3). These pathways include the spinothalamic tract, the spinohypothalamic tract, the spinoreticular tract, and the spinopontoamygdala tract.

Figure 2. Rexed laminae I through X of the spinal cord.

Figure 3. Ascending pain pathways. (Reproduced with permission from Bonica JJ, ed. The Management of Pain, vol. 1. Philadelphia: Lea and Febiger, 1990:29.)

2. Dorsal horn projection neurons
The second-order neurons in the pain pathway are the dorsal horn projection neurons (or their equivalent in cranial pathways). Their cell bodies are in the spinal cord (or in cranial nerve nuclei in the head and neck), and they are classified according to their response characteristics. High-threshold [HT; also called nociceptivespecific (NS)] cells respond exclusively to noxious stimuli; these cells receive input only from nociceptors (i.e., Ad and C fibers). Their receptive fields are small and organized somatotopically, being most abundant in lamina I.
Other cells, called wide dynamic range (WDR) cells, respond to a range of stimuli from innocuous to noxious. They integrate information from A-beta (Ab; transmitters of information about nonnoxious stimuli), Ad , and C fibers. These cells have larger receptive fields, are the most prevalent cells in the dorsal horn, and are found in all laminae, with a concentration in lamina V. The convergence of sensory information onto a single dorsal horn neuron is critical for the coding of stimulus intensity in terms of output frequency by these second-order neurons.
3. Spinothalamic tract
The spinothalamic tract (STT) (Fig. 3) is the most important of the ascending pathways for the transmission of nociceptive stimuli. It is located in the anterolateral quadrant of the spinal cord. The cell bodies of STT neurons reside in the dorsal horn; most of their axons cross at the midline in the ventral white commissure of the spinal cord and ascend in the opposite anterolateral quadrant, although some do remain ipsilateral. Neurons from more distal regions of the body (e.g., the sacral region) are found more laterally, and neurons from more proximal regions (e.g., the cervical region) are found more medially within the spinothalamic tract as it ascends. STT neurons segregate into medial and lateral projections to the thalamus (see Limbic System, later).
Neurons that project to the lateral thalamus arise from laminae I, II, and V, and from there they synapse with fibers that project to the somatosensory cortex. The fibers are thought to be involved in sensory and discriminative aspects of pain.
Neurons that project to the medial thalamus originate from the deeper laminae VI and IX. The neurons send collateral projections to the reticular formation of the brainstem and midbrain, the periaqueductal gray matter (PAG), and the hypothalamus, or directly to other areas of the basal forebrain and somatosensory cortex. They are thought to be involved with autonomic reflex responses, state of arousal, and emotional aspects of pain.
4. Spinohypothalamic tract
Nociceptive and non-nociceptive information from neurons within the dorsal horn is conveyed directly to diencephalic structures, such as the hypothalamus, by a recently discovered pathway—the spinohypothalamic tract. This pathway projects to the region of the brain (the hypothalamus) that is involved in autonomic functions such as sleep, appetite, temperature regulation, and stress response. In fact, the majority (60%) of SHT neurons project to the contralateral medial or lateral hypothalamus and, therefore, are presumed to have a significant role in autonomic and neuroendocrine responses to painful stimuli. Thus, the SHT appears to form the anatomic substrate that coordinates reflex autonomic reactions to painful stimuli. Some of its connections (e.g., to the suprachiasmatic nucleus, which partly controls the sleep/wake pattern) may account for behaviors such as difficulty in sleeping with painful conditions, particularly chronic pain. The majority of SHT neurons respond preferentially to mechanical nociceptive stimulation, and a smaller number respond to noxious thermal stimulation. The fibers of the SHT cross midline in the supraoptic decussation. The spinoreticular tract (SRT) and the spinopontoamygdala tract are also probably involved with state of arousal and emotional aspects of pain.
5. Cranial nerves
The transmission of pain in the head and neck has many of the same characteristics as the nociceptive system, which has firstorder synapses in the dorsal horn of the spinal cord. The face and oral cavity are richly innervated with nociceptors. The primary nociceptive afferent fibers for the head originate mainly from cranial nerve V but also from cranial nerves VII, IX, and X, and from the upper cervical spinal nerves. The primary afferent fibers of the cranial nerves project mainly to nuclei of the trigeminal system, whereas the upper cervical nerves project to second-order neurons in the dorsal horn of the spinal cord. From there, projections continue to the supraspinal systems.
Trigeminal System
The trigeminal system (V) receives afferent input from the three divisions of the trigeminal nerve (ophthalmic, maxillary, and mandibular), which serve the entire face as well as the dura and the vessels from a large portion of the anterior two thirds of the brain. The trigeminal has three sensory nuclei, all of which receive projections from cells that have cell bodies located within the trigeminal ganglion, a structure similar to the DRG. The three nuclei are the mesencephalic, the main sensory, and the spinal trigeminal. The latter is further divided into the subnucleus oralis, the subnucleus interpolaris, and the subnucleus caudalis. The sub-nucleus caudalis (also known as the medullary dorsal horn) extends caudally from the medulla to the level of the upper cervical segments of the spinal cord (C3 to C4).
The trigeminal nuclei give rise to several ascending pathways. The axons of cell bodies in the main sensory nucleus and the subnucleus oralis project either ipsilaterally, forming the dorsal trigeminothalamic tract, or contralaterally, in the ventral trigeminothalamic tract. Both tracts terminate in the thalamus. The subnucleus caudalis contributes as well to the trigeminothalamic tracts, but it also has direct projections to the thalamus, the reticular formation, and the hypothalamus.
Glossopharyngeal nerve
The glossopharyngeal nerve (IX) conveys impulses associated with tactile sense, thermal sense, and pain from the mucous membranes of the posterior third of the tongue, tonsil, posterior pharyngeal wall, and eustachian tubes.
Vagus nerve
The vagus nerve (X) conveys impulses associated with tactile sense from the posterior auricular skin and external auditory meatus, and those associated with visceral sensation from the pharynx, larynx, trachea, esophagus, and thoracic and abdominal viscera, via the spinal trigeminal tract and the fasciculus solitarius (the sensory tract of VII, IX, and X).
6. Central Sensitization
Just as prolonged noxious stimulation of nociceptors can result in altered pain states (peripheral sensitization), so repetitive stimulation of second-order (and higher-order) neurons can alter pain processing (central sensitization). Hyperalgesia and allodynia are manifestations of central as well as peripheral sensitization (see Peripheral Sensitization, earlier). The ability of the neural tissue to change in response to various incoming stimuli is a key function of the nervous system, and it is termed neural plasticity. Presumably, this function has some evolutionary or protective advantage, although in clinical pain practice, a disadvantage is often seen—the development of chronic pain. Both short-term and long-term plastic changes occur in the dorsal horn. Wind-up is an increase in the ratio of outgoing to incoming action potentials of a dorsal horn neuron with each successive nociceptive stimulus. It occurs in response to repetitive C-fiber stimulation, and it is reversed as soon as the stimulation ceases. This is an example of a short-term plastic change. Central sensitization (including windup) is associated with NMDA receptor activation. In the case of long-term sensitization, various mechanisms produce the changes and there may be associated new gene expression (e.g., C-fos).
III. SUPRASPINAL SYSTEMS: INTEGRATION AND HIGHER PROCESSING
Integration of pain in higher centers is complex and poorly understood. At a basic level, the integration and processing of painful stimuli may fall into the following broad categories:
Discriminative component: This somatotopically specific component involves the primary (SI) and secondary (SII) sensory cortex. The level of integration allows the brain to define the location of the painful stimulus. Integration of somatic pain, as opposed to visceral pain, takes place at this level. The primary and secondary cortices receive input predominantly from the ventrobasal complex of the thalamus, which is also somatotopically organized.
Affective component: The integration of the affective component of pain is very complex and involves various limbic structures. In particular, the cingulate cortex is involved in the affective components of pain (it receives input from the parafascicular thalamic nuclei and projects to various limbic regions). The amygdala is also involved in the integration of noxious stimuli.
Memory components of pain: Recent evidence has demonstrated that painful stimuli activate CNS regions such as the anterior insula.
Motor control and pain: The supplemental motor area is thought to be involved in the integration of the motor response to pain.
1. Thalamus
The thalamus is a complex structure that acts as the relaying center for incoming nociceptive stimuli, and it has two important divisions that receive nociceptive input. First is the lateral division, formed by the ventrobasal complex in which nociceptive specific input from NS and WDR neurons synapses. It is somatotopically organized and projects to the somatosensory cortex. Second is the medial division, which consists of the posterior nucleus and the centrolateral nucleus. It is thought that these nuclei project to limbic structures involved in the affective component of pain, because there is no nociceptive-specific information conveyed by them to higher cortical regions.
The medial and intralaminar nuclei receive input from many ascending tracts, in particular the STT, and the reticular formation. There is little evidence of somatotopic organization of these nuclei. The ventrobasal thalamus is organized somatotopically and can be further subdivided into (a) the ventral posterior lateral nucleus, which receives input mainly from the STT but also from the dorsal column system and the somatosensory cortex, to which it projects, and (b) the ventral posterior medial nucleus, which receives input from the face via the trigeminothalamic tract and projects to the somatosensory cortical regions of the face. Input to the posterior thalamus comes mainly from the STT, the spinocortical tract, and the dorsal column nuclei. The receptive fields are large and bilateral and lack somatotopic organization. The posterior nuclei project to the somatosensory cortex and appear to have a role in the sensory experience of pain. The STT also sends projections to the centrolateral nucleus, which is involved in motor activity (e.g., the cerebellar and cerebral cortex).
2. Hypothalamus
The hypothalamus receives innocuous and noxious stimuli from all over the body, including deep tissues such as the viscera (see Spinohypothalamic Tract, earlier). The hypothalamic neurons are not somatotopically organized and therefore do not provide discriminatory aspects and localization of pain. Some hypothalamic nuclei send projections to the pituitary gland via the hypophyseal stalk, the brainstem, and the spinal cord. The gland regulates both the autonomic nervous system and neuroendocrine response to stress, including pain.
3. Limbic system
The limbic system consists of subcortical regions of the telencephalon, mesencephalon, and diencephalon. It receives input from the STT, the thalamus, and the reticular formation, and it projects to various parts of the cerebral cortex, particularly the frontal and temporal cortex. It is involved in the motivational and emotional aspects of pain, including mood and experience.
4. Cerebral cortex
The somatosensory cortex and the cingulate cortex are involved in pain. The somatosensory cortex is the most important area for nociception. It is located posterior to the central sulcus of the brain, and it receives input from the various nuclei of the thalamus, particularly the ventral posterior lateral and medial nuclei and the posterior thalamus. The somatosensory cortex is cytoarchitecturally organized and therefore has an important role in the discriminatory aspect and localization of pain. Efferent fibers from the somatosensory cortex travel back to the thalamus and contribute to the descending nociceptive system.
5. Cingulate cortex
The cingulate cortex is a component of the limbic system. The limbic system receives sensory and cortical impulses and activates visceral and somatic effectors; it contributes to the physiologic expression of behavior and emotion. The limbic system includes the subcallosal, cingulate, and parahippocampal gyri and hippocampal formation as well as the following subcortical nuclei: the amygdala, the septal nuclei, the hypothalamus, the anterior thalamic nuclei, and the nuclei in the basal ganglia. Recent work has demonstrated that the cingulate gyrus is activated in humans by painful stimuli. Cingulate cortex lesions have been used in an attempt to alleviate pain and suffering.
IV. PAIN MODULATION
Figure 4 and Figure 5 illustrate pathways involved in the modulation of nociceptive information. The evidence for descending controls came from two basic observations. The first observation, in the late 1960s, was that neurons in the dorsal horn of decerebrate animals are more responsive to painful stimuli with spinal cord blockade. The second observation, in the late 1980s, was that electrical stimulation of the PAG profoundly relieved pain in animals. So great was the stimulation-produced analgesia that surgery could be performed on these animals without apparent pain. Furthermore, the animals behaved normally in every other way and there was no observed effect on other sensory modalities. These studies were pivotal in demonstrating an anatomic basis for the “natural equivalent” of stimulation-produced analgesia. Furthermore, subsequent studies demonstrated that small concentrations of morphine, when injected into regions such as the PAG, produced significant analgesia. Interestingly, both stress-induced analgesia and stimulation-induced analgesia can be reversed by opioid antagonists. A number of brain centers are involved in the intrinsic modulation of noxious stimuli. These include the somatosensory cortex, the hypothalamus (paraventricular nucleus, lateral hypothalamus), the midbrain PAG, areas in the pons including the lateral tegmental area, and the raphe magnus. Electrical stimulation of these regions in humans (in some cases) and in animals produces analgesia.

Figure 4. Descending pain pathways. 5-HT, serotonin; NE, noradrenergic input; ALF, anterolateral fasciculus; STT, spinothalamic tract; SRT, spinoreticular tract; SMT, spinomesencephalic tract. (Reproduced with permission from Bonica JJ, ed. The Management of Pain, vol. 1. Philadelphia: Lea and Febiger, 1990:108.)

Figure 5. Cross section of the spinal cord showing the location of the ascending pain pathways (e.g., the spinothalamic tract). The descending pain pathways are in the dorsolateral funiculus (not shown) of the spinal cord.

Fibers from these central structures descend directly or indirectly (e.g., PAG to raphe magnus) via the dorsolateral funiculus to the spinal cord and send projections to laminae I and V. Activation of the descending analgesic system has a direct effect on the integration and passage of nociceptive information at the level of the dorsal horn. Blockade of the dorsolateral funiculus (with cold or sectioning) increases the response of nociceptive second-order neurons following activation by painful stimuli.
1. Descending systems
The descending system appears to have three major functionally interrelated components: the opioid, the noradrenergic, and the serotonergic systems.
Opioid system
The opioid system is involved in descending analgesia. Opioid precursors (pro-opiomelanocortin, proenkephalin, and prodynorphin) and their respective peptides (beta-endorphin, met- and leuenkephalin, and dynorphin) are present in the amygdala, the hypothalamus, the PAG, the raphe magnus, and the dorsal horn. With the recent advent of opioid receptor cloning, knowledge is steadily increasing about the action sites of the various opioids (i.e., on mu, delta, and kappa receptors).
Noradrenergic System
Noradrenergic neurons project from the locus caeruleus and other noradrenergic cell groups in the medulla and pons. These projections are found in the dorsolateral funiculus. Stimulation of these areas produces analgesia, as does the administration (direct or intrathecal) of an alpha-2-receptor agonist such as clonidine.
Serotonergic System
Many neurons in the raphe magnus are known to contain serotonin [5-hydroxytryptamine (5-HT)], and they send projections to the spinal cord via the dorsolateral funiculus. Pharmacologic blockade, or lesioning, of the raphe magnus can reduce the effects of morphine, and administration of 5-HT to the spinal cord produces analgesia.
2. “On” and “off” cells: a component of descending analgesia
Nociceptive cells in the dorsal horn can be activated or inhibited following stimulation of the PAG. Therefore, it is reasonable to posit the existence of brain centers that provide both excitatory and inhibitory descending output. The raphe magnus, and other brain regions known to be involved in descending modulation (e.g., the PAG), appears to generate such output. Several types of neurons involved in the control of nociceptive information reside in the raphe magnus: in particular, there are neurons named “on” cells and “off” cells based on apparent function.
“On” cells are active prior to a nocifensive withdrawal reflex (e.g., tailflick). These cells are stimulated by nociceptive input; they are excited by stimulation and are inhibited by morphine. “On” cells facilitate nociceptive transmission in the dorsal horn. “Off” cells shut off prior to a nocifensive withdrawal reflex. These cells are inhibited by noxious stimuli, whereas they are excited by electrical stimulation and by morphine. It has been postulated that opioids act to inhibit inhibitory interneurons (GABAergic) that act on “off” cells and that, in this way, they produce a net excitatory effect on these cells. “Off” cells inhibit nociceptive transmission in the dorsal horn.
3. Projections to the dorsal horn
The nerve fibers that originate in nuclei that are involved in pain modulation terminate in the dorsal horn predominately in laminae I and II but also in other laminae, including IV, V, VI, and X. Thus there is a circuitry of projecting neurons acting directly or indirectly via interneurons on afferent fibers as well as projecting neurons such as the spinothalamic tract neurons.
V. CONCLUSION
The neuroanatomy and neurochemistry of the pain system is extremely complex. Neuroanatomic techniques have taught us a great deal about the “connectivity” of the system. Newer techniques have enabled the study of individual cells and specific cell populations in an attempt to elucidate roles in both ascending and descending systems. Sophisticated imaging—for example, functional magnetic resonance imaging and positron emission tomography—have allowed investigation of in vivo brain activity in the presence of acute and chronic pain. Thus, the nociceptive system continues to be investigated using reductionistic and holistic approaches to better understand its resting and pathologic states.
SELECTED READING

1.
Fields HL. Pain. New York: McGraw-Hill, 1999.

2.
Kruger L, ed. Pain and touch. San Diego: Academic Press, 1996.

3.
Scarry E. The body in pain: The making and unmaking of the world. Oxford: Oxford University Press, 1985.

4.
Simone DA. Peripheral mechanisms of pain perception. In: Abram SE, ed. The atlas of anesthesia: Pain management. Philadelphia: Churchill-Livingstone, 1998:1.1–1.11.

5.
Waldman SD, Winnie AP, eds. Part I. Anatomy and physiology of pain: Clinical correlates. In: Interventional pain management, 4th ed. Philadelphia: WB Saunders, 1996:1–72.

6.
Wall PD, Melzack R, eds. Textbook of pain, 4th ed. Philadelphia: Churchill-Livingstone, 1999.

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