Chapter 2. Anatomy and Physiology of Pain

Understanding the anatomy and physiology of pain transmission systems is important for the pain management specialist. Injuries to these areas may cause the common pain syndromes for which patients seek help (e.g., diabetic neuropathy, postherpetic neuralgia). Interventions at distinct anatomic sites may provide the relief the patient seeks (nerve blocks, implantable devices). And ongoing research may reveal new modalities or pharmaceutical agents to provide relief, such as the cyclooxygenase-2 (COX-2) inhibitors. This chapter is designed as an overview for the clinician and not as a comprehensive review of the anatomy and physiology of the nervous system, about which textbooks have been written.

This chapter reviews the transmission of a nociceptive or pain impulse from the site of stimulus in the periphery to the central nervous system. The basic anatomic pathways of nociceptive transmission and of descending nociceptive modulations are described. Some of the basics of physiology also are discussed, with the assumption that the reader is knowledgeable about the fundamentals of neuronal transduction, such as action potential propagation and the relationship of the cell body to the dendrites and axon. Although some mention of pathophysiology and disease states is made, for further discussion, please see the specific chapters in this book.

This chapter focuses on the ability of the nervous system to transmit and modulate nociceptive stimuli. The studies reviewed here likely apply more to acute pain than to chronic pain. Although there is intense interest in developing an animal model of chronic pain, most of the experimental paradigms used are more closely analogous to the injury of acute pain than chronic pain. The latter is both a physical and emotional entity and may result from plasticity in the nervous system.1 The complexities of chronic pain syndromes, including such theories as chronic pain as a variant of depressive disorders,2 are discussed elsewhere.

Knowledge of nociceptive transmission has advanced considerably since Descartes outlined his concept of the nerve as tubes with delicate threads to convey a painful impulse.3 It is now widely believed that stimulation of a primary afferent neuron in the peripheral nervous system results in activation of neurons in the dorsal horn of the spinal cord and then in transmission rostrally to the brain.

Sensory neurons, called primary afferents, have a cell body in the dorsal root ganglia (DRG) of the spinal cord or in the ganglia of the cranial nerves. Cranial nerves V, VII, IX, and X receive inputs from primary afferents and, thus, sensory information from the head, face, and throat. Cells in the DRG are a heterogenous population of size and function; a reflection of the heterogeneity of the sensory inputs processed by the central nervous system.4

This heterogeneity is reflective of the multiple functions of the peripheral sensory nervous systems, as well as the supportive function of the glial system. The classic nomenclature of peripheral neurons relies on the size of the axon and presence or absence of myelin as distinguishing characteristics. This taxonomy is referred to as the Erlanger-Gasser classification.5 There are three major groups, A, B, and C, in order of diminishing axonal diameter. Group A is further divided into four subgroups: Aα, or primary muscle spindle and motor to skeletal muscles; Aβ, which are cutaneous touch and pressure afferents; Aγ, motor to muscle spindle; and Aδ, which are mechanoreceptors, nociceptors, thermoreceptors, and sympathetic postganglionic fibers. Group B is sympathetic preganglionic fibers. Group C refers to mechanoreceptors, nociceptors, and thermoreceptors, as well as sympathetic postganglionic fibers.

Classification of primary afferents on the basis of size and morphology is convenient for scientific experimentation, and thus there has been interest in refining the Erlanger-Gasser classification.4 Most pain management practitioners are familiar with the traditional classification and are acquainted with the terms Aδ and C fibers as pain transmission fibers. Neuronal fibers have also been classified, again on the basis of the size of the cross-section of the axon, as type Ia/b, II, III, and IV, from large myelinated to smaller and more slowly conducting fibers. Because this more recent terminology is used less often by clinicians, in this chapter the terminology more familiar to clinicians is used.

Thus, the sensory neurons of greatest interest to the pain clinician are the Aδ and C fibers, which have cell bodies in the DRG and which project from the periphery to the dorsal horn of the spinal cord (or the equivalent area for the cranial nerves).6 The morphology of the peripheral termination of the axon is a reflection of the neuron’s function: mechanoreceptors end in specialized structures, whereas nociceptors have free endings. Although the majority of Aδ fibers respond to low-intensity mechanical, chemical, or thermal stimuli, the free nerve endings of the Aδ and C-type neurons likely allow the specialized response to hazardous, potentially dangerous, and damaging stimuli.7 It may be an evolutionary protective mechanism to have fibers respond to the threat of damage and thus avoid the possibility of permanent injury.8 There is evidence that chronic pain may be related to central nervous system changes.9 This chapter focuses primarily on the anatomy and physiology of acute pain in the undamaged nervous system.

The nociceptive primary afferents supply all the areas of the body: skin and subcutaneous tissue; muscle, joints, and periosteum; and the viscera. The skin, subcutaneous tissue, and fascia are supplied by mechanical nociceptors (Aδ high-threshold mechanoreceptors,) polymodal nociceptors (C-fiber nociceptors), and myelinated mechanothermal nociceptors (Aδ heat nociceptors).10 The latter respond to both noxious heat and intense mechanical stimuli. It is likely that these Aδ fibers are responsible for the first pain perceived after heat stimulation.4,6,7 This is in contrast to the high-threshold Aδ mechanoreceptors, which respond to repeated stimuli and not to the initial noxious stimulus of heat or cold. These fibers are likely responsible for sensitization.11 The C-polymodal nociceptors, which also respond to high-intensity stimuli, whether mechanical or heat, respond by sensitizing to heat but, interestingly, the response to mechanical stimuli is fatigue.9,12

The unique properties of these neurons account for the variety of responses seen to noxious stimuli, both clinically and experimentally. Brief noxious input results in an immediate but transient sensation that is mediated by Aδ fibers. The same stimulus also evokes a slow-onset burning pain sensation that is C-fiber dependent.9,13 Following injury, endogenous nerve growth factor and impulse-sensitive neuronal mechanisms are needed to regulate collateral sprouting of sensory axons in rats.14 Microneurography allows studies to be conducted in humans.15 Thus, the properties postulated from animal studies are now being shown experimentally in humans, and the potential for further diagnostic applications is intriguing.16

Muscle, fascia, and tendons are innervated by Aδ and C fibers. Activation of these neurons by noxious stimulation produces diffuse, aching pain that is poorly localized. Ischemic contraction of muscle may result in C-fiber activation. The muscle nociceptors are also activated by chemical stimulation.17 Joints are innervated by Aδ and C fibers, which, when activated in a normal joint, result in deep aching pain. In an arthritic joint or during acute inflammation, however, even normal and minimal activities result in pain. There is significant interest in the pathogenesis of arthritis and the interaction between inflammatory changes and the development of chronic pain.18

The periosteum of bone is acutely sensitive to noxious stimuli, whereas the marrow and cortex of the bone are not pain responsive under normal conditions.16 Teeth are innervated by nociceptive and mechanical afferents. Both the inner and outer aspects of the tooth are innervated. The tooth pulp has a mixed population of afferents and responds to chemical, thermal, and mechanical stimuli.19,20

The viscera are innervated by nociceptors as well as parasympathetic and sympathetic fibers. In contrast to cutaneous innervation, visceral structures are sparsely innervated so that few fibers respond to stimuli over a large area.21 Whether specific organs have specifics nociceptors is still controversial.7 Clinically, patients are likely to complain of diffuse discomfort or poorly localized pain except under conditions of extremes (e.g., appendicitis, pleurisy). Very often, even extreme perturbations are interpreted as discomfort rather than pain (e.g., acute myocardial infarction). There is evidence of convergence of deep somatic (muscle, joints) and visceral nociceptive information at higher midbrain structures.22 This finding may also contribute to the poor localization of noxious stimuli.

The heart has Aδ fibers (and some C fibers), which appear to be responsive to stretch but function primarily as part of the cardiovascular reflex responsiveness, more than as an early warning sign of potential damage. The classic pain of myocardial ischemia, angina, is postulated to be mediated via chemical sensitization of afferents by substances released by the damaged cells (potassium, hydrogen ions) as well as humoral factors (bradykinin and prostaglandins).10,12

The lungs and bronchi are also innervated by Aδ and C fibers. These fibers play a diverse role, serving to warn of irritants in the airway that are either mechanical or chemical. Furthermore, such distinct stimuli as pulmonary edema, embolism, and changes in oxygen tension may give rise to the sensation of dyspnea.

The abdominal viscera include such diverse structures as the stomach and intestines, gallbladder, and urinary bladder. These structures have sympathetic and parasympathetic innervation. Mechanoreceptors also innervate these hollow viscera. The mechanoreceptors transmit changes such as distention and contractions associated with pain. There is currently a great deal of interest in understanding visceral nociception.21,22 Controversy abounds in the clinical realm of pain management as to the etiology of visceral pain states. For example, the innervation of the viscera includes sympathetic and parasympathetic fibers, but whether certain chronic abdominal pain syndromes are sympathetically maintained pain syndromes is not proven. (See Chapters 34 and 39.)

Chronic pelvic pain and interstitial cystitis are two common clinical manifestations of visceral pain states. Both syndromes may be disabling to patients and are frustratingly difficult to treat. The urinary system has both nociceptive and sympathetic innervation. Distention may lead to C-fiber activation as well as Aδ involvement.23 These stimuli, such as with a renal stone entering a ureter, may lead to intense cramping and pain. The reproductive system is highly innervated with slowly adapting mechanoreceptors and more sparsely innervated by Aδ and C fibers.23 Mechanisms do exist, however, so that repeated noxious stimuli may result in sensitization. (See subsequent chapters for more details and for discussion of clinical pain states and therapies.)

The primary afferents, which have their cell bodies in the DRG, extend from the periphery to terminate centrally in the dorsal horn. The fibers that enter the dorsal horn are segregated by size as they form small bands or rootlets and approach the dorsal horn. Lissauer observed that the smaller fibers are segregated laterally and then terminate in the first layers of the dorsal horn. This area has come to be known as Lissauer’s tract. There are clinical applications of knowledge of the anatomy of the dorsal horn and dorsal root entry zone. Neurosurgeons may perform a selective posterior rhizotomy in the hopes of ablating otherwise intractable, unrelenting chronic pain. These techniques are discussed further in the chapters on clinical pain management.

It is important to note that many cells in the DRG have more than one process.24 Thus, a fiber may receive input from two distinct areas, such as the dura mater and part of the face. The connections that appear to subserve sensory processing during migraine, for example, are complex.25 The terminal connections may also branch and innervate multiple spinal levels.26 There is also evidence that sensory fibers may travel in the ventral roots, as well. There are certainly small unmyelinated fibers in ventral tracts. Thus, the anatomy is more complex than a simple schema can represent. These complexities may explain why selective posterior rhizotomy is rarely successful clinically in providing complete relief of unrelenting pain. But as understanding of the peripheral nervous system grows, so does an appreciation of its complexity. Injury to peripheral nerves may result in chronic changes. Initial injury and acute changes may develop into chronic ectopic inputs, which may induce a state of central sensitization and structural reorganization of dorsal horn synapse.11 Thus, there are profound physiologic reasons why a surgical anatomic approach to pain management may not be sufficient.

The majority of primary afferents terminate in the ipsilateral dorsal horn. The process of the spinal neurons bifurcates into an ascending and a descending branch, thus innervating the spinal cord over several spinal segments. Some processes travel dorsal to the central canal to end in the contralateral dorsal horn. The terminus of each primary afferent is the reflection of its function, as the dorsal horn neurons are segregated by physiology. Rexed divided the gray matter of the spinal cord into ten laminae.27 This classic cytoarchitectural segregation yields six subdivisions of the dorsal horn (laminae I through VI) and three subdivisions of the ventral horn (laminae VII through IX.) Lamina X describes the column of cells around the central canal.

The dorsal laminae of the spinal cord run its entire length and in the medulla become the medullary dorsal horn. The marginal layer of the dorsal horn refers to lamina I. Lamina II, or the substantia gelatinosa, is subdivided into outer and inner areas (IIo and IIi). The substantia gelatinosa is of interest to clinicians and researchers.28 Laminae III through V are referred to as the nucleus proprius or the magnocellular layer.

Dorsal horn neurons, which process nociceptive information, are a heterogenous population. Laminae I and V have nociceptive specific neurons. There are two populations of nociceptive-specific neurons. One type receives inputs from Aδ fibers, both high-threshold mechanoreceptors and temperature-sensitive receptors and from polymodal C fibers. The second type of nociceptive-specific neuron appears to receive inputs only from high-threshold Aδ mechanoreceptors. The other neuron type that processes nociceptive input is the wide-dynamic-range neuron. Found predominantly in lamina V (and to a lesser degree in lamina I,) the wide-dynamic-range neuron receives input from Aδ fibers of both high-threshold mechanoreceptors and temperature-sensitive neurons and also from polymodal C fibers as well as Aβ low-threshold mechanoreceptors.25

The physiology of the dorsal horn explains the heterogeneity of function. Lamina I cell projection pathways have been shown to be concerned with long-latency, long-duration reactions to prolonged events, rather than to brief stimuli.26 Lamina I neurons, which project via the spinothalamic tract, are an integral component of the central representation of pain and temperature. These nociceptive-specific neurons, both the high-threshold mechanoreceptors and the temperature-sensitive polymodal C fibers, are inhibited by morphine in a dose-dependent manner.29,30 This suggests that opiate-modulation of nociceptive transmission is functionally organized. Both substance P and neurokinin A are released by neurons in the substantia gelatinosa when a noxious impulse is transmitted.31 Somatostatin is released following noxious thermal but not noxious mechanical stimuli, which implies some encoding of information by the dorsal horn.11

The fibers of greatest interest to pain clinicians are Aδ and C fibers. The Aδ nociceptors terminate in laminae I and IIo and have collateral branches that terminate in laminae V and X. Similarly, the C fibers, which enter the spinal cord via the lateral aspect of Lissauer’s tract, also terminate in laminae I and IIo, as well as lamina V. The termination of the large, myelinated Aβ fibers is in laminae III and IV, as well as lamina V.27 Following an injury, however, there may be marked alterations in the cytoarchitecture of the dorsal horn. Woolf and colleagues have reported that following nerve injury, large-diameter fibers may invade laminae I and IIo.11 This may provide a mechanism to explain the clinical finding of allodynia and the physiologic alterations in neuropathic pain syndromes.32–34 This subject is discussed in detail in subsequent chapters.

The information conveyed by the primary afferents travels first to the dorsal horn and then from the dorsal horn rostral via the ascending tracts.35 A variety of neurotransmitters is used to convey noxious information.29,36 There are distinct areas of dopamine-containing neurons.37 The peptide substance P is found in the dorsal horn.38,39 There is evidence that glutaminergic neurons are also involved, as well as neurons that respond to γ-aminobutyric acid (GABA), although these neurons are not as prevalent.40 A segmental chronic pain syndrome can be induced in rats by an intrathecal infusion of N-methyl-d-aspartate (NMDA).41 The possibility of targeting a specific receptor to provide relief has generated a great deal of excitement from clinicians. And, indeed, medications that target a variety of receptors are used by clinicians to modulate pain transmission.1 Although the neurons that carry noxious stimuli are in many ways distinct and segregated from those that carry innocuous stimuli, there remains an amount of interspersion of these distinctive fibers in the ascending systems.42,43

The spinothalamic tract (STT) and the trigeminothalamic tract transmit primarily pain and temperature information.44,45 Neither tract, however, transmits exclusively noxious stimuli: the tracts are heterogenous and transmit some innocuous stimuli such as light touch, as well.43 Furthermore, it is now accepted that other ascending tracts convey noxious information, as well.46–48

The lateral and ventral STTs travel in the anterior lateral quadrant of the spinal cord. The spinomesencephalic tract (SMT) is located in the anterior lateral quadrant and in the dorsolateral funiculus.45 The dorsal column postsynaptic spinomedullary system is a second-order dorsal column pathway that is located appropriately in the dorsal column.49,50 The propriospinal multisynaptic ascending system is a more complicated network of short chains of neurons, which may play a role in nociceptive transmission.49,51

A lesion of the anterior lateral quadrant (which disrupts the STT, and the SMT) results in the abolition of pain sensation on the side contralateral to the lesion, below the spinal segment.52 There is also some mild decrease in responsiveness to noxious stimuli on the ipsilateral side. The neurons of the STT are located throughout the dorsal horn, but with the greatest concentration in lamina I.53 As it ascends, the STT widens as fibers are added along the anteromedial border. Thus, the STT has somatotropic organization, with axons originating in the sacral region lateral to those of the lumbar region and so forth, and with the cervical region representing the most medial aspect in the spinal cord but the facial area being the most medial in the medulla. As the STT travels rostrally it divides, at the mesencephalon, into a medial component that innervates the medial thalamic region and a lateral component that projects to the ventrobasal and posterior thalamus. The ventroposterolateral (VPL) nucleus of the thalamus is somatotropically organized, in contrast to the other thalamic nuclei, and receives the majority of the lamina I projections.53

The SRT conveys impulses from the spinal cord to the reticular formation. The reticular formation triggers arousal, and so the SRT likely conveys information that becomes the affective aspect of pain. The SRT may be important for the motivational and emotional aspect of pain (and of autonomic and somatic motor reflexes). The SMT projects to the midbrain reticular formation. Its function, therefore, is likely similar to that of the SRT. These tracts, the SRT and the SMT, are likely to be involved in the perpetuation of chronic pain in many individuals. White and Sweet, in their classic neurosurgery text,52 report that lesioning medial to the STT in the midbrain resulted in relief of chronic pain.

Evidence exists of alternative ascending pathways that convey nociceptive impulses. A small percentage of neurons in the dorsal column postsynaptic system respond to noxious stimuli.46 The spinocervical tract (SCT) has neurons that respond to tactile stimuli as well as noxious stimuli. Although the SCT appears to play a role in the transmission of nociceptive impulses in the cat, its role in the transduction of pain in humans is unclear.43 In cats, there is a convergence of visceral and somatic inputs in the medulla.47 The propriospinal multisynaptic ascending system is composed of neurons with short axons that make multiple synaptic contacts with other short-axon neurons. Basbaum proposed a role for this multisynaptic ascending system in the maintenance of chronic pain.49

The anatomy and physiology of the neurons that serve the head and face are similar to the systems that transmit impulses from the body.54 The nerves that transmit noxious stimuli are those of the cranial nerves; specifically, the trigeminal nerve (CN V,) the fascial nerve (CN VII,) the glossopharyngeal nerve (CN IX,) and the vagus nerve (CN X.) The area of the medulla that receives these inputs is often referred to as the medullary dorsal horn. Because the trigeminal system is the one most important to pain clinicians, it is the system reviewed here.

The trigeminal nerve system is of particular interest to pain clinicians because of a number of chronic pain states, such as tic douloureux and postherpetic neuralgia. The trigeminal ganglion divides into three branches: the ophthalmic, maxillary, and mandibular nerves. Each division carries information about proprioception, touch and pressure, and pain and temperature. The gasserian ganglion has somatotropic organization, and this is preserved as the fibers course to their unique terminations. The somatotropic laminar organization is true for both myelinated and unmyelinated fibers. The large-diameter fibers terminate in the main sensory nucleus, whereas the Aδ and C fibers terminate in the subnucleus caudalis.55

The trigeminal subnucleus caudalis can be subdivided by its cytoarchitecture into three layers. These three layers have been termed the marginal layer, the substantia gelatinosa, and the magnocellular layer. These areas correlate with their dorsal horn counterparts in both form and function.55,56 Thus, this area is appropriately called the medullary dorsal horn. This is not meant to imply that the trigeminal system is a separate entity from the dorsal horn. There is evidence that central neurons may send collateral projections to both the sensory trigeminal nuclei and the spinal cord.57

The ascending trigeminal systems that convey sensory information from the face are similar to the spinal systems. Neurons in the subnucleus caudalis (which receives the projections from the nociceptors, the A and C fibers) travel in the ventral trigeminothalamic tract to the thalamus and the cortex.58 There is also a tract that is likely analogous to the neospinothalamic tract: the neotrigeminothalamic system (nTTS.) The nTTS is somatotropically organized and conveys information about pain and temperature to the ventroposteromedial thalamic nucleus.

There is also a paleotrigeminothalamic system (pTTS.) Some fibers from the subnucleus caudalis project to a variety of terminations, thus, having both ipsilateral and contralateral connections to the brainstem reticular formation, as well as to the periaqueductal gray matter, hypothalamus, and medial and intrathalamic nuclei. As these structures project diffusely, including to the limbic system, the pTTS likely plays a role in the affective qualities of pain.56

The parabrachial region may be an important relay station for further processing of nociceptive information from trigeminal afferents.59 There is interest in the parabrachial region as an area that may modulate pain and tonic immobility.60 In certain species, analgesia may reinforce immobility as an adaptation of defense mechanisms during predator-prey confrontation.59 It is uncertain if an analogous function exists in humans.

Supraspinal Systems: Thalamus

The thalamus is both an end point and the transition area for the sensory input traveling to the sensory cortex.61,62 The medial and intralaminar nuclei of the thalamus receive input from the spinal cord and the reticular formation but are not somatotropically organized. The nuclei receive input from the ascending spinal (and trigeminal) systems and the reticular formation and innervate a wide area of the brain.63 In contrast, the ventrobasal complex of the thalamus is somatotropically organized. The ventrobasal thalamus receives input from the neospinothalamic tract and the neotrigeminothalmic tract and projects to the primary somatosensory (SI) and secondary somatosensory (SII) region of the somatosensory cortex, allowing localization and sensory discrimination.62,64

The ventrobasal complex of the thalamus refers to the region composed of the ventral and the posterior thalamic nuclei. It is subdivided in the lateral division (the ventroposterolateral nucleus) and a medial division (the ventroposteromedial nucleus). The neurons respond primarily to stimuli on the contralateral surfaces of the body or face.65 The thalamus may have a modulatory role on nociceptive transmission during varied states of arousal.66 White and Sweet52 reported that the lesions in this area of the thalamus produced transient analgesia but a marked interference of a patient’s ability to perceive spatial discrimination. In patients with spinal cord transection, somatotropic organization and spontaneous neuronal activity in thalamic nuclei has been described.67

The reticular formation is involved with the affective component of pain. The aversive response and the motivational aspect of pain are modulated via reticular activation. Similarly, the motor, autonomic, and sensory functions that are a response to noxious stimuli are mediated by the pathways through the reticular formation. It is possible that the reticular formation is involved in pain behavior.64 Casey proposes that one way in which opiates may relieve suffering without altering an individual’s ability to recognize a stimulus as noxious is via the reticular formation.68,69

Hypothalamus

The hypothalamus has a role in both the autonomic nervous system and the neuroendocrine response. The hypothalamus probably plays a role in the response both to somatic and visceral tissue damage and to pain.70 Thus, the emotional response and autonomic arousal elicited by pain is likely mediated, at least in part, by the hypothalamus. There are STT neurons that provide nociceptive input to the many areas that are involved in producing the multifaceted response to pain, which is familiar to clinicians.71

Limbic System

The limbic system refers to a wide array of structures that are part of the telencephalon, diencephalon, and mesencephalon. The parts of the telencephalon that contribute to the limbic system are the amygdala, hippocampus, nucleus accumbens, and preoptic regions. In the diencephalon, the hypothalamus and parts of the thalamus contribute to the limbic system. The limbic area also encompasses the ventral tegmental area, the dorsal tegmental nucleus, and parts of the midbrain raphe nuclei and the periaqueductal gray matter. The interconnections between these areas and wider areas of the cortex are complex and diverse.72 This organization explains the allowable diversity of response to painful stimuli.

Cerebral Cortex

The human cortex has two main areas that receive sensory inputs: SI and SII. SI, on the postcentral gyrus, receives direct somatotropically organized input from the ipsilateral ventrobasal complex of the thalamus (the ventroposterolateral and the ventroposteromedial nuclei). The SII area is smaller than the SI area and is located on the parietal lobe of the cortex. The somatosensory cortex allows the discrimination of sensation. The somatotropic organization of the somatosensory cortex was mapped in the first half of this century by Penfield and Rasmussen.73 The illustrated representation of this mapping, the homunculus, is familiar to any medical student.

The role of the sensory cortex in nociceptive processing is the subject of renewed research and debate. Although early studies revealed that many SI neurons respond to noxious stimuli, these responses were putatively only localizing in nature. Further investigation suggested that the SI neurons actually have an integrative function whereby the intensity of a stimulus is encoded and processed.74,75 The nitric oxide–cyclic guanosine monophosphate pathway appears to play a role in cortical nociceptive processing.76

Descending Pathways

The descending nociceptive modulatory system is of interest to researchers and clinicians. Melzack and Wall proposed the existence of a nociceptive modulating system in their seminal article in Science in 1965.3 The gate-control hypothesis of pain proposed that dorsal horn processing could be modified not only by stimulation that arrived from the periphery, but also from putative descending pathways. A few years later, Reynolds demonstrated the effect of electrical stimulation in the periaqueductal gray matter (PAG) on the nocifensive responses of the rat.77 It is now widely believed that descending antinociceptive mechanisms are an important part of an animal’s defense system.78

The remarkable effect of PAG electrical stimulation is to diminish or ablate the animal’s response to a noxious stimulus while preserving the sensation of light touch.79 During PAG electrical stimulation, the animal maintains normal motor control and the ability to eat. Electrical stimulation of the PAG completely inhibits the nocifensive response of an animal to a variety of noxious stimuli, not limited to somatic stimuli, but including visceral and tooth pulp stimulation. The analgesic response endures for a brief time following termination of the stimulation. Electrical stimulation of the PAG results in analgesia that is naloxone reversible, implying an opiate-mediated response.80 Stimulation of the PAG has been shown to provide pain relief to humans with a variety of pain diagnoses, although it remains an experimental therapy.81,82 There remains tremendous interest in providing some type of pain relief to patients with neuropathic pain. In animal models, PAG stimulation appears to provide an antinociceptive effect.83 The result in humans, however, is more difficult to ascertain.

The electrical stimulation and, thus, the activation of neurons in the PAG results in suppression of activity of dorsal horn neurons.84 Basbaum and Fields have published extensively both together and independently on the putative descending nociceptive modulatory systems and have elucidated the anatomic and physiologic pathways of descending inhibition of nociception.85,86 The PAG has connections to the nucleus raphe magnus in the medulla, as well as to the parabrachial nucleus, a proposed site of behavior modification.87 Subsequent studies revealed that the function of the nucleus raphe magnus was served by a group of nearby structures within the rostral ventromedial medulla (RVM). The information from these rostral areas is conveyed to the dorsal horn by way of the dorsal lateral funiculus. If any of these structures or their connections are ablated, so is the inhibition of nocifensive reflexes.88

The PAG and the RVM are also involved in opiate analgesia.89 Microinjection of morphine or of selective μ-opioid agonists into the PAG or RVM results in potent naloxone-reversible antinociception. Lesioning the dorsal lateral funiculus unilaterally diminishes the opiate analgesia produced by PAG microinjection; and bilateral lesions of the dorsal lateral funiculus ablate the opiate effect on nocifensive reflexes. Thus, a system of descending endogenous opioid analgesia can be elucidated, and a pathway from the PAG to the dorsal horn, by way of the RVM and the dorsal lateral funiculus, has been demonstrated in a variety of animal species; this pathway seems likely to exist in humans, as well.90 The connections of the neurons in the medulla are complex, but it appears as if serotonergic cell projections to brainstem sites may contribute to the integration of sensory, autonomic, and motor modulation at the brainstem level.91 There are other loci, such as the nucleus cuneiformis, which may also play a role in sensory and motor integration of responses to noxious stimuli.92

Fields and colleagues noted that the electrophysiologic responses of neurons in the RVM to microinjection or iontophoresis of opiates was mixed: some neurons became less active and others became more active.93 Electrical stimulation has the effect of activating neurons, whereas μ-opioid agonists inhibit neuronal response. Thus, the disparate responses of neurons to two stimuli that elicit the same analgesic response in animals could be rectified: a heterogenous population of neurons was described.

Certain neurons in the RVM are activated by noxious stimuli. Called “on-cells,” these neurons fire more rapidly during noxious stimuli, and if these cells are spontaneously firing and a noxious stimulus is applied, the nocifensive reflex time is shortened. μ-Opioid agonists diminish or ablate the firing of on-cells. The second cell population stops firing before a nocifensive reflex response occurs. These “off-cells” are activated by opiates, and if a noxious stimulus is applied during the spontaneous firing of an off-cell, the nocifensive reflex time is lengthened.93

The circuitry of the RVM involves excitatory amino acids, GABA and opioids, as well as serotonergic and noradrenergic neurons.94 Neurotensin microinjected into the RVM has either a facilitatory or an inhibitory effect on the response of spinal neurons to noxious thermal stimulation, depending on the dose of the neurotensin.95 During conditions of analgesia, the removal of the RVM predictably lessens the analgesic response of the animal. During conditions of hyperalgesia, the temporary blocking of the RVM with local anesthetic actually attenuates the hyperalgesic response.96 Thus, the RVM contains a heterogenous population of neurons that has the potential to either ameliorate or facilitate nociceptive transmission. This descending modulatory system occurs in a number of species and is likely to exist in humans, as well. And, whereas the electrophysiologic classification of neurons in humans is likely to remain elusive, the ability to modulate hyperalgesia and chronic pain is the goal of every pain clinician.