- Anatomic Systems Associated with Pain Processing 10
- Primary Afferents 10
- Fiber Classes 10
- Properties of Primary Afferent Function 10
- Afferents with High Thresholds and Pain Behavior 12
- Spinal Dorsal Horn 12
- Dorsal Horn Neurons 12
- Anatomic Localization 12
- Marginal Zone (Lamina I) 12
- Substantia Gelatinosa (Lamina II) 13
- Nucleus Proprius (Laminae III, IV, and V) 13
- Central Canal (Lamina X) 13
- Functional Properties 14
- Ascending Spinal Tracts 14
- Ventral Funicular Projection Systems 14
- Dorsal Funicular Projection Systems 14
- Intersegmental Systems 14
- Supraspinal Projections 15
- Functional Overview of Pain Processing Systems 16
- Frequency Encoding 17
- Afferent Line Labeling 17
- Functionally Distinct Pathways 17
- Plasticity of Ascending Projections 17
- Pharmacology of Afferent Transmitter Systems in Nociception 17
Anatomic Systems Associated with Pain Processing *
* For a more detailed discussion of the material in this section,
Extreme mechanical distortion, thermal stimuli (>42° C [108°F]), or changes in the chemical milieu (plasma products, pH, potassium) at the peripheral sensory terminal will evoke the verbal report of pain in humans and efforts to escape in animals, as well as the elicitation of activity in the adrenal-pituitary axis. This chapter provides a broad overview of the circuitry that serves in the transduction and encoding of this information. First, the stimuli already mentioned evoke activity in specific groups of small myelinated or unmyelinated primary afferents of ganglionic sensory neurons, which make their synaptic contact with several distinct populations of dorsal horn neurons. By long spinal tracts and through a variety of intersegmental systems, the information gains access to supraspinal centers that lie in the brainstem and in the thalamus. These rostrally projecting systems represent the substrate by which unconditioned, high-intensity somatic and visceral stimuli give rise to escape behavior and verbal report of pain. This circuitry constitutes the afferent limb of the pain pathway.
Primary Afferents †
† For more detailed discussions of the material in this section,
Fiber Classes
Sensory neurons in dorsal root ganglia have a single process (glomerulus) that bifurcates into a peripheral (nerve) and central (root) axon. The peripheral axon collects sensory input originating from the environment of the innervated tissue. The central axon relays sensory input to the spinal cord or brainstem. Sensory axons are classified according to their diameter, state of myelination, and conduction velocity, as outlined in Table 2.1 . In general, conduction velocity varies directly with axon diameter and the presence of myelination. Thus, Aß axons are large and myelinated, and they conduct rapidly; A∂ axons are smaller in diameter and myelinated, and they conduct more slowly; and C fibers are small and unmyelinated, and they conduct very slowly.
Table 2.1
Classification of Primary Afferents by Physical Characteristics, Conduction Velocity, and Effective Stimuli
| Fiber Class* | Velocity Group * | Effective Stimuli |
|---|---|---|
| A-beta | Group II (>40–50 m/sec) | Low-threshold Specialized nerve endings (pacinian corpuscles) |
| A-delta | Group III (>10 and <40 m="" sec="" td=""> | Low-threshold mechanical or thermal High-threshold mechanical or thermal Specialized nerve endings |
| C | Group IV (<2 m="" sec="" td=""> | High-threshold thermal, mechanical, or chemicalFree nerve endings |
Properties of Primary Afferent Function
Recording from single peripheral afferent fibers reveals three important characteristics. First, in the absence of stimulation, minimal, if any, “spontaneous” afferent traffic occurs. Accordingly, the system operates on a very high signal-to-noise ratio. Second, regardless of the fiber type examined, with increasing intensities of the appropriate stimulus, a monotonic increase in the discharge frequency for that axon is observed ( Fig. 2.1 ). This finding reflects the fact that the more intense the stimulus, the greater is the depolarization of the terminal and the more frequently will the axon discharge. Third, different axons may respond most efficiently to a particular stimulus modality. This modality specificity reflects the nature of the terminal properties of the particular afferent axon that transduces the physical or chemical stimulus into a depolarization of the axon. These nerve endings may be morphologically specialized, as with the pacinian corpuscle that is found on the terminals of large afferents. The specialized structure translates the mechanical distortion of the structure into a transient opening of sodium channels in that axon, thus generating a brief burst of action potential.
Top: Schema of C fiber with peripheral free nerve ending (FNE; a region of normal axon and a local injury [neuroma] and the dorsal root ganglion [DRG]). In this schema, a pressure stimulus is applied to the axon at the four sites (FNE, normal axon, neuroma, and DRG), and the characteristic response is displayed in the lower left drawing. The normal axon does not transduce the continued mechanical distortion, whereas such transduction does occur at sites 1, 3, and 4. On the lower right , low-threshold A-delta (Aδ) and high-threshold A-delta/C fibers typically show little if any spontaneous activity; both will show a monotonic increase in response to increasing stimulus intensities. The low-threshold axon shows a monotonic increase over a range of intensities that are not aversive. This would be a “warmth” detector. The C fiber, however, does not begin to discharge until a temperature is reached that would correspond with the behavioral report of increasing pain. This response pattern would describe that of a nociceptor.
At the other extreme, the axon terminal may display no evident physical structure and be classified as a “free nerve ending.” Such endings are commonly associated with small, unmyelinated C fibers. The simplicity of the nerve ending as implied by this name is misleading. Such a terminal is often able to transduce a variety of stimuli including mechanical, thermal, and chemical. As indicated in Table 2.1 , A-beta (group II) fibers are activated by low-threshold mechanical stimuli (i.e., mechanoreceptors). Fibers that conduct at A-delta velocity (group III fibers) may belong to populations that are low or high threshold, and mechanical or thermal. Low-threshold afferents may begin firing at temperatures that are not noxious (30° C [86°F]) and increase their firing rate monotonically, although in this range, we perceive the stimulus as warm but not noxious. Other populations of A-delta fibers may begin to show activation at temperatures that are mildly noxious and increase their firing rates up to very high temperatures (52° C to 55° C [126°F to 131°F]). Slowly conducting afferents constitute the largest population of afferent axons. Most of these afferents are activated by high-threshold thermal, mechanical, and chemical stimuli and are called C-polymodal nociceptors (see Fig. 2.1 ). For these axons, the nature of the stimuli, which will evoke activity, is endowed by the nature of the specialized transduction proteins that are present in these terminals. Many of these transducer proteins are particularly sensitive to a range of hot or cold, but in addition they may respond to particular chemicals. One such well-characterized channel is TRPV1, which responds to noxious temperatures and to the molecule capsaicin (which evokes a sensation of intense heat when it is applied to the skin) ( Fig. 2.2 ).
Schematic showing transducer channels on a C-fiber terminal. The range of optimal temperature activation and agents that can activate these channels are shown. Different terminals may express different combinations of transducers, and this would define the thermal response properties of that sensory axon. Channel activation depolarizes voltage sensitive sodium (NaV) channels in the axon. Nav1.8 channels are often found in C fibers.
An important characteristic of these polymodal nociceptors is that they are also readily activated in a concentration-dependent fashion by specific agents released into the chemical milieu. Such agents, released from local injured cells or inflammatory cells, include a variety of amines (5-hydroxytryptamine, histamine), lipid mediators (prostaglandins), kinins (bradykinin), acidic pH, cytokines (interleukin-1ß) and enzymes (trypsin). Such products can evoke direct activation of the fibers and facilitate their activity though their eponymous receptors located on the terminals of these C fibers. This process probably represents the principal mechanism of activating afferents after the acute injury. The nature of these products and their effects on the sensory terminals are discussed in Chapter 3 .
Afferents with High Thresholds and Pain Behavior
Electrophysiologic and correlated behavioral evidence indicates that information that can generate a pain event enters the central nervous system by the activation of small-diameter, myelinated (group III-A or A-delta) or unmyelinated (group IV or C) afferents. Thus, single-unit recording in nerve fascicles in humans reveals a close correlation between the dull pain induced by a focal high-intensity thermal stimulus (second pain) and activity in fibers conducting at velocities of less than 1 m/second. Similarly, local anesthetics at low concentrations transiently block conduction in small, but not large, afferents, thus blocking the sensation evoked by high-threshold stimuli and leaving light touch intact. The afferent axons, particularly those derived from unmyelinated fibers, show extensive branching as they proceed distally, and most peripheral terminals of small afferents show little evidence of specialization and terminate as “free” nerve endings. Ample evidence indicates that these “free” nerve endings, commonly designated polymodal nociceptors, are characteristically activated only by high-intensity physical stimuli, and this property accounts for the peripheral specificity associating A-delta/C-fiber activity with pain. This transduction specificity is best exemplified in tooth pulp and cornea, in which “free” nerve endings predominate, and local stimulation is painful.
Under certain conditions, low-intensity tactile or thermal stimuli may, in fact, generate a pain state. This anomalous linkage between noninjurious stimuli and pain is referred to as hyperalgesia . More specifically, when it involves light mechanical stimuli, it is referred to as tactile allodynia . Three practical examples may be cited: (1) local tissue injury such as after a local sunburn leading to increased thermal and tactile sensitivity; (2) inflammation such as in rheumatoid arthritis leading to a state in which normal joint movement is painful; and (3) injury to the peripheral nerve leading to states in which light touch is aversive.
Spinal Dorsal Horn *
* For a more detailed discussion of the material in this section, see .
Afferent Projections
In the peripheral nerve, large and small afferents are anatomically intermixed in collections of fascicles. As the nerve root approaches the spinal cord, the tendency is for the large myelinated afferents to move medially and to displace the small, unmyelinated afferents laterally. Thus, although this pattern is not absolute, large and small afferent axons enter the dorsal horn by the medial and lateral aspects of the dorsal root entry zone (DREZ), respectively. Some unmyelinated afferent fibers that arise from dorsal root ganglion cells also pass into the spinal cord by the ventral roots, and these ventral root afferents likely account for pain reports evoked by ventral root stimulation in classic clinical studies.
The sensory innervation of the body projects in a rostrocaudal distribution to the ipsilateral spinal dorsal horn. Innervation of the head and neck is mediated by a variety of cranial nerves that project into the brainstem.
Anatomy of the Dorsal Horn
In the rostrocaudal axis, the spinal cord is broadly divided into the sacral, lumbar, thoracic, and cervical segments. At each spinal level, in the transverse plane, the spinal cord is further divided on the basis of descriptive anatomy into several laminae ( Rexed laminae ) ( Table 2.2 and Fig. 2.3 ).
Table 2.2
Principal Aspects of Dorsal Horn Organization
| Anatomic Region | Rexed Lamina(e) | Afferent Terminals | Nociceptive Cells |
|---|---|---|---|
| Marginal layer | I | A-delta/CA-beta | Marginal |
| Substantia gelatinosa | II | A-beta/A-delta/C | SG |
| Nucleus proprius | III/IV/V/VI | A-beta/A-delta | WDR |
| Central canal | X | A-delta/C | SG-type |
| Motor horn | VII/VIII/IX | A-beta |
SG, substantia gelatinosa; WDR, wide dynamic range.
Schematic showing the Rexed lamination (right) and the approximate organization of the afferents to the spinal cord (left) as they enter at the dorsal root entry zone and then penetrate into the dorsal horn to terminate in the laminae I and II (A-delta [Aδ]/C) or penetrate more deeply to loop upward and terminate as high as lamina III (A-beta [Aβ]). Photo inset shows a left dorsal horn with the root entry zone.
On entering the spinal cord, the central processes of the primary afferents send their projections into the dorsal horn. In general, terminals from the small myelinated fibers (A-delta) terminate in the marginal zone or lamina I of Rexed, the ventral portion of lamina II (II inner), and throughout lamina V. Larger myelinated fibers (A-beta) terminate in lamina IV and the deep dorsal horn (laminae V to VI). Fine-caliber, unmyelinated C fibers generally terminate throughout laminae I and II and in lamina X around the central canal.
In addition to sending their axons into the dorsal horn at the segment of entry, primary afferents also collateralize sending axons rostrally and caudally into the tract of Lissauer (small unmyelinated fibers) and into the dorsal columns (large myelinated axons). These afferents collateralize at intervals to send projections into increasingly distal segments. This organizational property emphasizes that input from a single root may primarily activate cells in the segment of entry but can also influence the excitability of neurons in segments distal to the segment of entry ( Fig. 2.4 ).
Schematic displaying the ramification of C fibers (left) into the dorsal horn and collateralization into the tract of Lissauer(stippled area) and of A fibers (right) into the dorsal columns (striped area) and into the dorsal horn. The most dense terminations are within the segment of entry, and collateralizations into the dorsal horns at the more distal spinal segments are less dense. This density of collateralization corresponds to the potency of the excitatory drive into these distal segments.
Dorsal Horn Neurons †
† For more detailed discussions of the material in this section, see .
Although exceedingly complex, the second-order noci-responsive elements in the dorsal horn may be considered in several principal classes on the basis of their approximate anatomic location and their response properties.
Anatomic Localization
Marginal Zone (Lamina I)
These large neurons are oriented transversely across the cap of the dorsal gray matter ( Fig. 2.5 ). Consistent with their locations, they receive input from mainly A-delta and C fibers and respond to intense cutaneous and muscle stimulation. Marginal neurons project to the contralateral thalamus and to the parabrachial region through the contralateral ventrolateral tracts (see later) of ascending pathways. Other marginal neurons project intrasegmentally and intersegmentally along the dorsal and dorsolateral white matter.
Firing patterns of a dorsal horn wide dynamic range (WDR) neuron and a high-threshold spinothalamic neuron. Graphs present the neuronal responses to graded intensities of mechanical stimulation applied to the receptive fields.
Substantia Gelatinosa (Lamina II)
The substantia gelatinosa contains numerous cell types. Many cells are local interneurons and likely play an important role as inhibitory and excitatory interneurons that regulate local excitability; however, some of these cells clearly project rostrally. Significant proportions of the substantia gelatinosa neurons receive direct input from C fibers and indirect input from A-delta fibers from lamina I and deep dorsal horn. These neurons are frequently excited by activation of thermal receptive or mechanical nociceptive afferents. Many of these cells exhibit complex response patterns with prolonged periods of excitation and inhibition following afferent activation and reflect the complicated network that regulates local excitability by local interneurons.
Nucleus Proprius (Laminae III, IV, and V)
These magnocellular neurons send their dendritic tree up into the overlying laminae (see Fig. 2.5 ). Consistent with this organization, many cells in this region receive large afferent (Aß) input onto its cell body and dendrites. In addition, these neurons receive input either directly or through excitatory interneurons, from small afferents (Aδ and C), which terminate in the superficial dorsal horn.
Central Canal (Lamina X)
Branches of small primary afferent fibers enter the region. This area is a peptide-rich area, and cells respond primarily to high-threshold temperature stimuli and noxious pinch with small receptive fields. Cells in this region also receive significant visceral input.
Functional Properties
Two important functional classes of neurons are frequently described: nociceptive specific and wide dynamic range (WDR).
Nociceptive Specific
Lamina I neurons tend to receive primarily high-threshold (small afferent) input. Accordingly, starting at relatively high stimulus intensities, these cells begin to show a threshold increase in discharge that is increased over the increasingly aversive range of stimulus intensities (see Fig. 2.5 ). In that manner, many of these cells are nociceptive specific.
Wide Dynamic Range Neurons
Many cells in the nucleus proprius have three interesting functional characteristics:
- 1. Given their connectivity (high threshold small afferents on the distal terminals and low threshold large afferents on their ascending dendrites and soma), these neurons display excitation driven by low- and high-threshold afferent input. This gives the WDR neurons the property of responding with increased frequency as the stimulus intensity is elevated from a very low intensity to a very high intensity (e.g., they have a wide dynamic response range). Thus, stimuli ranging from light innocuous touch evoke activity that increases as the intensity of pressure or pinch is increased (see Fig. 2.5 ). In addition to this property, the WDR neurons have two other characteristics.
- 2. Organ convergence: Depending on the spinal level, a neuron in the nucleus proprius may be activated by both somatic stimuli and activation of visceral afferent. This convergence results in a comingling of excitation for a visceral organ and a specific area of the body surface and leads to referral of input from that visceral organ to that area of the body surface. A given population of WDR neurons is excited by cutaneous or deep (muscle and joint) input applied within the dermatome coinciding with the segmental location of the cell. Thus, T1 and T5 root stimulation activates WDR neurons that are also excited by coronary artery occlusion. These viscerosomatic and musculosomatic convergences onto dorsal horn neurons underlie the phenomenon of referred visceral or deep muscle or bone pain to particular body surfaces ( Fig. 2.6 ).
Fig. 2.6 Example of organ convergence: T1 and T5 root stimulation activates wide dynamic range (WDR) neurons that are also excited by coronary artery occlusion. These results indicate that the phenomenon of referred visceral pain has its substrate in the viscerosomatic and musculosomatic convergence onto dorsal horn neurons. - 3. Low-frequency (>≈0.33 Hz) repetitive stimulation of C fibers, but not A fibers, produces a gradual increase in the frequency discharge until the neuron is in a state of virtually continuous discharge (“wind-up”). This property is discussed later.
Ascending Spinal Tracts *
* For more detailed discussions of the material in this section, see and .
Activity evoked in the spinal cord by high-threshold stimuli reaches supraspinal sites by several long and intersegmental tract systems that travel within the ventrolateral cord and to a lesser degree in the dorsal quadrant.
Ventral Funicular Projection Systems
Within the ventrolateral quadrant of the spinal cord, several systems have been identified, on the basis of their supraspinal projections. These include the spinoreticular, spinomesencephalic, spinoparabrachial, and spinothalamic tracts, which constitute the anterolateral system. These systems originate primarily from the dorsal horn neurons that are postsynaptic to primary afferents. These cells may project either ipsilaterally or contralaterally in the spinal cord. Classic studies showed that unilateral section of the ventrolateral quadrant yields a contralateral loss in pain and temperature sense in dermatomes below the spinal level of the section, a finding indicating that the ascending tracts may travel rostrally several segments before crossing. These findings led to the surgical ventrolateral cordotomy that was used in the early 20th century as an important method of pain control. Conversely, stimulation of the ventrolateral tracts in awake subjects undergoing percutaneous cordotomies results in reports of contralateral warmth and pain. Midline myelotomies that destroy fibers crossing the midline at the levels of the cut (as well as the cells in lamina X) produce bilateral pain deficits. As first described by William Gower in the 1890s, these observations suggest that predominantly crossed pathways in the ventrolateral quadrant are important for nociception.
Dorsal Funicular Projection Systems
The dorsal column medial lemniscal system is a major ascending pathway transmitting sensory information. This system is mainly composed of the collaterals of larger-diameter primary afferents transmitting tactile sensation and limb proprioception, Most fibers in the medial lemniscal system ascend from the spinal cord ipsilaterally to the medulla, where they synapse on neurons in the caudal brainstem dorsal column nuclei, which send axons across the medulla to form the medial lemniscus.
Intersegmental Systems
Early studies showed that alternating hemisections poorly modify the behavioral or the autonomic responses to strong stimuli. Systems that project for short distances ipsilaterally may contribute to the rostrad transmission of nociceptive information. Several segmental pathways relevant to the rostrad transmission of nociceptive information are the lateral tract of Lissauer, the dorsolateral propriospinal system, and the dorsal intracornual tract. Selective destruction of the dorsal gray matter (e.g., in the vicinity of the DREZ) has proved to be a possible method of pain management. This finding suggests the relevance of nonfunicular pathways traveling in the spinal gray matter.
Supraspinal Projections *
* For more detailed discussions of the material in this section, see and .
Spinofugal tracts traveling in the ventrolateral quadrant project principally into three brainstem regions: the medulla, the mesencephalon, and the diencephalon. Neurons in these regions then project further rostrally to the diencephalon and cortex or directly to cortical structures.
Spinoreticulothalamic Projections
This tract represents axons that are largely ipsilateral to the cell of origin. The tract terminates throughout the brainstem reticular formation. Spinomedullary input is believed to play an important role in initiating cardiovascular reflexes. The medullary reticular formation also performs as a relay station for the rostrad transmission of nociceptive information. These medullary neurons project into the intralaminar thalamic nucleus. This nucleus forms a shell around the medial dorsal aspects of the thalamus ( Fig. 2.7 ). The intralaminar nucleus projects diffusely to wide areas of the cerebral cortex, including the frontal, parietal, and limbic regions. This forms part of the classic ascending reticular activating system and relates to mechanisms leading to increased global cortical activation ( Fig. 2.8 ).
Schematic demonstrating the brainstem projections of spinal neurons into the medulla and mesencephalon. Third-order projections arising from the medullary and mesencephalic neurons project into the intralaminar and ventrobasal thalamus.
Schematic displaying projections from thalamic neurons to various cortical regions. See text for further discussion. VMPo, posterior portion of the ventral medial nucleus.
Spinomesencephalic Projections
Ipsilateral projections to this region terminate in periaqueductal gray and mesencephalic reticular formation. Stimulation of the mesencephalic central gray and adjacent mesencephalic reticular formation can evoke signs of intense discomfort in animals, whereas in humans autonomic responses are elicited along with reports of dysphoria. As with more caudal medullary sites, periaqueductal gray and reticular neurons project rostrally into the lateral thalamus (see Figs. 2.7 and 2.8; Fig. 2.9 ).
Schematic demonstrating the spinal neuron projections into the parabrachial region and third-order parabrachial neurons projecting into the thalamus and amygdala. VMPo, posterior portion of the ventral medial nucleus.
Spinoparabrachial Projections
These ascending nociceptive fibers originate predominantly from neurons in contralateral laminae. Projections of these neurons terminate in a group of neurons in the parabrachial area that send out axons to the central nucleus of the amygdala and the posterior portion of the ventral medial nucleus (VMpo) in the thalamus. The VMpo projects primarily to the insula ( Fig. 2.10 ).
Schematic demonstrating spinal lamina V wide dynamic range neurons projecting into the ventrobasal thalamus and lamina I neurons (high threshold) projecting into the posterior ventral medial nucleus (VMpo) and medial dorsalis neurons.
Spinothalamic Projections
This predominantly crossed system displays the following three principal targets of termination ( Fig. 2.11 ):
- 1. The ventrobasal thalamus represents the classic somatosensory thalamic nucleus. Input is distributed in a strict somatotopic pattern. This region projects in a strict somatotopic organization to the somatosensory cortex (see Fig. 2.8 ).
- 2. The VMpo then projects into the insula.
- 3. The media thalamus receives primary input from lamina I (high-threshold nociceptive specific cells). Cells in this region then project to the anterior cingulate cortex ( Fig. 2.12 ).
Fig. 2.12 Schematic of an overview of the characteristics of the projections of wide dynamic range (WDR) lamina V (Lam V) neurons in to the somatotopically mapped ventrobasal (VBL) thalamus and from there to the somatosensory (SS) cortex. As described in the text, this organization suggests the properties that would mediate the sensory-discriminative aspects of pain. VLT, ventrolateral tract.
Schematic demonstrating mediodorsalis neurons projecting into the anterior cingulate gyrus.
Functional Overview of Pain Processing Systems *
* For more detailed discussions of the material in this section, see .
The preceding discussion considers various elements that constitute linkages whereby information generated by a high-intensity stimulus activates small high-threshold afferents and activates brainstem and cortical systems. With a broad perspective, several salient features of this system activated by high-threshold input can be emphasized.
Frequency Encoding
It appears evident that stimulus intensity in a given system is encoded in terms of frequency of discharge. This holds true for any given link at the level of the primary afferent for both high- and low-threshold axons, in the spinal dorsal horn for WDR, marginal neurons, and at brainstem and cortical loci. The relationship between stimulus intensity and the neuronal response is in the form of a monotonic increase in discharge frequency.
Afferent Line Labeling
Although frequency of discharge covaries with intensity, it is evident that the nature of the connectivity also defines the content of the afferent activity. As indicated, the biologic significance of a high-frequency burst of an Aß versus a high-threshold A-delta or C fiber for pain is evident.
Functionally Distinct Pathways
At the spinal level, it is possible to characterize two functionally distinct families of response. In one spinofugal projection system (see Fig. 2.11 ), WDR neurons encode information over a wide range of non-noxious to severely aversive intensities consistent with the convergence of low- and high-threshold afferent neurons (either directly or through interneurons) onto their dendrites and soma. These cells project heavily into a variety of brainstem and diencephalic sites to the somatosensory cortex. At every level, the map of the body surface is precisely preserved, as is the broad range of intensity-frequency encoding. In the second spinofugal projection system (seeFig. 2.12 ), populations of superficial marginal cells display a strong nociceptive-specific encoding property, as defined by the high-threshold afferent input that they receive. These marginal cells project heavily to the parabrachial nuclei, to the amygdala, to the VMpo, the insula, medial thalamic nuclei, and then to the anterior cingulate cortex.
The WDR system is uniquely able to preserve spatial localization information and information regarding the stimulus over a range of intensities from modest to extreme, as initially provided by the frequency response characteristics of the WDR neurons. This type of system is able to provide the information needed for mapping the “sensory-discriminative” dimension of pain. The nociceptive-specific pathway arising from the marginal cells appears less well organized in terms of its ability to encode precise place and response intensity until it is, by definition, potentially tissue injuring. These systems project heavily through the medial thalamic region and VMpo to the anterior cingulate and the insula/amygdala, respectively. These regions are classically appreciated to be associated with emotionality and affect. Accordingly, this type of circuitry would provide an important substrate for systems underlying the affective-motivational components of the pain experience. Functional magnetic resonance imaging and positron emission tomography have demonstrated that although non-noxious stimuli often have little effect, strong somatic and visceral stimuli initiate activation within the anterior cingulate cortex. This substrate involving a precise somatosensory map represents a system capable of mapping a sensory-discriminative dimension of pain. In contrast, the other system involving the limbic forebrain suggests a circuit that can mediate an “affective-motivational” component of the pain pathway. These dimensions were first formally described by Ronald Melzack and Ken Casey.
Plasticity of Ascending Projections
Whereas the pathways outlined are clearly pertinent to the nature of the message generated by a high-intensity stimulus, the encoding of a pain message depends not only on the physical characteristics of the otherwise effective stimulus but also on the properties of associated systems that can modulate (either up or down) the excitability of each of these synaptic linkages. Thus, local interneurons releasing γ-aminobutyric acid and glycine at the level of the spinal dorsal horn commonly regulate the frequency of discharge of second-order neurons excited by large afferent input. Pharmacologically blocking that local spinal inhibition can profoundly change the nature of the sensory experience to become highly aversive. This afferent plasticity is further considered inChapter 3 . In another dimension, such plasticity may also be seen at supraspinal levels. Thus, the potential role of this plasticity is reflected by the finding, in work by Pierre Rainville et al, hypnotic suggestions leading to an enhanced pain report in response to a given experimental stimulus resulted in greater activity in the anterior cingulate. Numerous lesions in humans and animals have been shown to dissociate the reported stimulus intensity psychophysically from its affective component. Such disconnection syndromes are produced by prefrontal lobectomies, cingulotomies, and temporal lobe–amygdala lesions.
Pharmacology of Afferent Transmitter Systems in Nociception *
* For more detailed discussions of the material in this section, see and .
An important question relates to the nature of the neurotransmitters and receptors that link the afferent projection systems. Such transmitter-receptor systems have several defining characteristics. First, the linkages between the primary afferent and second-order spinal neurons, the linkages between the spinofugal axon and the third-order axon, and so on, have as a common property that the interaction leads to the excitation of the proximate neurons. Thus, the neurotransmitters mediating that synaptic transmission are excitatory. For example, at the spinal level, no “monosynaptic inhibition driven by primary afferents” occurs. Although powerful inhibitory events occur in the dorsal horn (and at every synaptic link), such inhibition must take place because of the excitation of a second neuron that releases an inhibitory transmitter. Second, it is increasingly evident that neurotransmission at any given synaptic link may consist not of one transmitter but of several cocontained and coreleased transmitters. At the small primary afferent, an excitatory amino acid (glutamate) and a peptide (e.g., substance P [sP]) are typically released. Third, although not discussed further here, each synaptic link is subject to modifications because of a dynamic regulation of the presynaptic transmitter content and the postsynaptic receptor and its linkages (e.g., with repetitive stimulation, the glutamate receptor undergoes phosphorylation, which serves to accentuate its excitatory response to a given amount of glutamate).
Primary Afferent Transmitters
Considerable effort has been directed at establishing the identity of the excitatory transmitters in the primary afferent transmitters. Currently, excitatory amino acids, such as glutamate and certain peptides, including sP, vasoactive intestinal peptide (VIP), somatostatin, calcitonin gene–related peptide (CGRP), bombesin, and related peptides have been observed. C fibers possess the following characteristics ( Figs. 2.13 and 2.14 ):
- ▪ Peptides have been shown to exist within subpopulations of small type B dorsal root ganglion cells.
- ▪ Peptides are in the dorsal horn of the spinal cord (where most primary afferent terminals are found), and these levels in the dorsal horn are reduced by rhizotomy or ganglionectomy or by treatment with the small afferent neurotoxin capsaicin (acting on the TRPV1 receptor).
- ▪ Many peptides are cocontained (e.g., sP and CGRP in the same C-fiber terminal) as well as contained with excitatory amino acids (e.g., sP and glutamate).
- ▪ Release of peptides is reduced by the spinal action of agents known to be analgesic, such as opiates (see later).
- ▪ Iontophoretic application onto the dorsal horn of the several amino acids and peptides found in primary afferents has been shown to produce excitatory effects. Amino acids produce very rapid, short-lasting depolarization. The peptides tend to produce delayed and long-lasting discharge.
- ▪ Local spinal administration of several agents such as sP and glutamate does yield pain behavior, a finding suggesting the possible role of these agents as transmitters in the pain process.
Schematic of an overview of the characteristics of the projections of nociceptive-specific lamina I (Lam I) neurons into the mediodorsalis and from there to the anterior cingulate (Ant cingulate) cortex. As described in the text, this organization suggests the properties that would mediate the affective-motivational aspects of pain. VLT, ventrolateral tract.
Schematic displays the general characteristics of the primary afferent transmitters released from small, capsaicin-sensitive, primary afferents: C fibers. A, Small afferents terminate in laminae I and II of the dorsal horn and make synaptic contact with second-order spinal neurons. B, Peptides and excitatory amino acids are cocontained in small primary afferent ganglion cells (type B) and in dorsal horn terminals in dense core and clear core vesicles, respectively. C, On release, the excitatory amino acids are able to produce a rapid, early depolarization, whereas the peptides tend to evoke a long and prolonged depolarization of the second-order membrane. mV: transmembrane potential.
Receptor antagonists exist for the receptors acted on by many of these agents (sP, VIP, glutamate). By using such agents, it has been possible to demonstrate that the primary charge carrier for depolarization of the second-order neurons is the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) subtype of the glutamate receptor. Block of other glutamate receptors (e.g., the N -methyl-D-aspartate [NMDA] receptor) or the peptidergic transmitter receptors such as for sP (neurokinin-1) typically have a modest effect on the acute excitability of the second-order neuron and appear to reflect their role in augmenting the excitability of the neuron. Given the plethora of excitatory transmitter receptors that decorate the second-order neuron, nociceptive-evoked excitation of the second-order neuron may be poorly modified by the block of a single receptor type.
Ascending Projection System Transmitters
Dorsal horn neurons projecting to brainstem sites have been shown to contain numerous peptides (including cholecystokinin, dynorphin, somatostatin, bombesin, VIPs, and sP). Glutamate has also been identified in spinothalamic projections, a finding suggesting the probable role of that excitatory amino acid. sP-containing fibers arising from brainstem sites have been shown to project to the parafascicular and central medial nuclei of the thalamus. In unanesthetized animals, the microinjection of glutamate in the vicinity of the terminals of ascending pathways, notably within the mesencephalic central gray area, evokes spontaneous painlike behavior with vocalization and vigorous efforts to escape, a finding emphasizing the presence of at least an NMDA site mediating the behavioral effects produced by NMDA in this region. Other systems will no doubt be identified as these supraspinal systems are studied in detail.
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