I

Chapter
2
Anatomy of the Pain
Processing System
Tony L. Yaksh and Z. David Luo

CHAPTER OUTLINE
Anatomic Systems Associated with Pain Ascending Spinal Tracts  14
Processing  10 Ventral Funicular Projection Systems  14
Primary Afferents  10 Dorsal Funicular Projection Systems  14
Fiber Classes  10 Intersegmental Systems  14
Properties of Primary Afferent Function  10 Supraspinal Projections  15
Afferents with High Thresholds and Pain Spinoreticulothalamic Projections  15
Behavior  12 Spinomesencephalic Projections  15
Spinal Dorsal Horn  12 Spinoparabrachial Projections  15
Afferent Projections  12 Spinothalamic Projections  16
Anatomy of the Dorsal Horn  12 Functional Overview of Pain Processing
Dorsal Horn Neurons  12 Systems  16
Anatomic Localization  12 Frequency Encoding  17
Marginal Zone (Lamina I)  12 Afferent Line Labeling  17
Substantia Gelatinosa (Lamina II)  13 Functionally Distinct Pathways  17
Nucleus Proprius (Laminae III, IV, and V)  13 Plasticity of Ascending Projections  17
Central Canal (Lamina X)  13 Pharmacology of Afferent Transmitter
Functional Properties  14 Systems in Nociception  17
Nociceptive Specific  14 Primary Afferent Transmitters  17
Wide Dynamic Range Neurons  14 Ascending Projection System Transmitters  18

Anatomic Systems Associated Primary Afferents†

with Pain Processing*
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 unmyeli-
nated 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.
*For a more detailed discussion of the material in this section, see Reference 1.
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 tis-
sue. 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 unmy-
elinated, and they conduct very slowly.
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,
For more detailed discussions of the material in this section, see References 2 to 4.
†

10
 Chapter 2—Anatomy of the Pain Processing System 11

the system operates on a very high ­signal-to-noise ratio. Second, into a transient opening of sodium channels in that axon, thus
regardless of the fiber type examined, with increasing intensi- ­generating a brief burst of action potential.
ties of the appropriate stimulus, a monotonic increase in the dis- At the other extreme, the axon terminal may display no
charge frequency for that axon is observed (Fig. 2.1). This finding evident physical structure and be classified as a “free nerve
reflects the fact that the more intense the stimulus, the greater is ending.” Such endings are commonly associated with small,
the depolarization of the terminal and the more frequently will unmyelinated C fibers. The simplicity of the nerve ending as
the axon discharge. Third, different axons may respond most effi- implied by this name is misleading. Such a terminal is often
ciently to a particular stimulus modality. This modality specific- able to transduce a variety of stimuli including mechanical,
ity reflects the nature of the terminal properties of the particular thermal, and chemical. As indicated in Table 2.1, A-beta (group
afferent axon that transduces the physical or chemical stimu- II) fibers are activated by low-threshold mechanical stimuli
lus into a depolarization of the axon. These nerve endings may (i.e., mechanoreceptors). Fibers that conduct at A-delta veloc-
be morphologically specialized, as with the pacinian corpuscle ity (group III fibers) may belong to populations that are low
that is found on the terminals of large afferents. The specialized or high threshold, and mechanical or thermal. Low-threshold
structure translates the mechanical distortion of the structure 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
Table 2.1  Classification of Primary Afferents increase their firing rates up to very high temperatures (52°C
by Physical Characteristics, Conduction to 55°C [126°F to 131°F]). Slowly conducting afferents con-
Velocity, and Effective Stimuli stitute the largest population of afferent axons. Most of these
Fiber Class* Velocity Group* Effective Stimuli afferents are activated by high-threshold thermal, mechanical,
and chemical stimuli and are called C-polymodal nociceptors
A-beta Group II Low-threshold
(>40–50 m/sec) Specialized nerve endings
(see Fig. 2.1). For these axons, the nature of the stimuli, which
(pacinian corpuscles) will evoke activity, is endowed by the nature of the special-
A-delta Group III (>10 Low-threshold
ized transduction proteins that are present in these terminals.
and <40 m/sec) mechanical or thermal Many of these transducer proteins are particularly sensitive to
High-threshold a range of hot or cold, but in ­addition they may respond to
mechanical or thermal particular ­chemicals. One such well-characterized channel is
Specialized nerve endings TRPV1, which responds to noxious temperatures and to the
C Group IV High-threshold thermal, molecule capsaicin (which evokes a sensation of intense heat
(<2 m/sec) mechanical, or chemical when it is applied to the skin) (Fig. 2.2).
Free nerve endings
An important characteristic of these polymodal nociceptors is
*The Erlanger-Gasser A-beta/A-delta/C classification scheme is based on that they are also readily activated in a concentration-­dependent
anatomic characteristics. The Lloyd-Hunt group II/III/IV classification scheme is fashion by specific agents released into the chemical milieu. Such
based on conduction velocity in muscle afferents.
agents, released from local injured cells or ­inflammatory cells,
include a variety of amines (5-hydroxytryptamine, histamine),
lipid mediators ­(prostaglandins), kinins (bradykinin), acidic
FNE Neuroma DRG pH, cytokines (interleukin-1ß) and enzymes (trypsin). Such
products can evoke direct activation of the fibers and ­facilitate
Normal Axon
1 2 3 4

Site 1 Na+
Site 2 TRPV1 >43C Capsaicin*/lipids/H+
Site 3 Hz
Site 4 Low threshold Aδ TRPV2 >52C
High threshold Aδ/C NaV 1.8
TRPV3 >34–38C
30 34 38 42 46 50 54 58 TRPV4 >27–35C
Thermal Stimulus (°C)
TRPM8 <25–28C Menthol
Fig. 2.1 Top: Schema of C fiber with peripheral free nerve ending (FNE; TRPA1 <17C Mustard oil
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 ASIC H+
axon at the four sites (FNE, normal axon, neuroma, and DRG), and the
characteristic response is displayed in the lower left drawing. The normal FNE
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 Fig. 2.2 Schematic showing transducer channels on a C-fiber terminal.
increase in response to increasing stimulus intensities. The low-threshold The range of optimal temperature activation and agents that can activate
axon shows a monotonic increase over a range of intensities that are these channels are shown. Different terminals may express different
not aversive. This would be a “warmth” detector. The C fiber, however, combinations of transducers, and this would define the thermal response
does not begin to discharge until a temperature is reached that would properties of that sensory axon. Channel activation depolarizes voltage
correspond with the behavioral report of increasing pain. This response sensitive sodium (NaV) channels in the axon. Nav1.8 channels are often
pattern would describe that of a nociceptor. found in C fibers.
12 Section I—The Basic Science of Pain
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) affer-
ents. 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 activ-
ity 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 end-
ings, commonly designated polymodal nociceptors, are charac-
teristically 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 specific-
ity 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 ther-
mal stimuli may, in fact, generate a pain state. This anoma-
lous 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 pain-
ful; and (3) injury to the peripheral nerve leading to states in
which light touch is aversive.
Spinal Dorsal Horn*
Afferent Projections
In the peripheral nerve, large and small afferents are anatomi-
cally intermixed in collections of fascicles. As the nerve root
approaches the spinal cord, the tendency is for the large myeli-
nated 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 affer-
ents 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.
*For a more detailed discussion of the material in this section, see Reference 5.
Table 2.2  Principal Aspects of Dorsal Horn
Organization
Anatomic Rexed Afferent Nociceptive
Region Lamina(e) Terminals Cells
Marginal layer I A-delta/ Marginal
CA-beta
Substantia II A-beta/A- SG
gelatinosa delta/C
Nucleus III/IV/V/VI A-beta/A-delta WDR
proprius
Central canal X A-delta/C SG-type
Motor horn VII/VIII/IX A-beta
SG, substantia gelatinosa; WDR, wide dynamic range.
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).
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 ven-
tral 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, unmyeli-
nated 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 send-
ing 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 orga-
nizational 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).
Dorsal Horn Neurons†
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 ana-
tomic 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
For more detailed discussions of the material in this section, see References 4 and 6.
†
 Chapter 2—Anatomy of the Pain Processing System 13

Aβ
Aδ
C
I (Marginal zone)
II (Substantia gelatinosa)
III
IV (Nucleus proprius)
Fig. 2.3 Schematic showing the Rexed
V
lamination (right) and the approximate
VI organization of the afferents to
VII the spinal cord (left) as they enter
(Motor horn) at the dorsal root entry zone and
VIII
then penetrate into the dorsal
IX 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
X (Central canal) zone.

Distribution of Afferent Terminals Horizontal Wide Dynamic Range

50 Squeeze
Aß
L1 Pinch
A Fiber: Laminae III-V C
Trifurcate: Segment of entry Press
HZ Brush
Dorsal column
C Fiber: Laminae I-II
Trifurcate: Segment of entry
Lissauer tract 0
L5 50
High Threshold Squeeze
C Fiber A Fiber
• Projections up to  4-6 segments
• Density of projections diminish distally C HZ
Press
Brush Pinch

Transverse
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.
t­ halamus and to the parabrachial region through the
­contralateral ­ventrolateral tracts (see later) of ascending
pathways. Other marginal ­neurons project intrasegmen-
tally and intersegmentally along the dorsal and dorsolateral
white matter.
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 recep-
tive or mechanical nociceptive afferents. Many of these cells
exhibit complex response patterns with prolonged periods
0
0 50 100 sec
Fig. 2.5 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.
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 orga-
nization, 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.
14 Section I—The Basic Science of Pain
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 prop-
erty, 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).
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*
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
*For more detailed discussions of the material in this section, see References 5 and 7.
Visceral Afferent (Coronary)
Coronary
ischemia
(Left arm)
Somatic Afferent
Viscerosomatic convergence onto a
single thoracic WDR neuron
“Referred pain”
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.
s­ upraspinal projections. These include the spinoreticu-
lar, spinomesencephalic, spinoparabrachial, and spinotha-
lamic 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 cross-
ing. These findings led to the surgical ventrolateral cordo-
tomy that was used in the early 20th century as an important
method of pain control. Conversely, stimulation of the ven-
trolateral tracts in awake subjects ­undergoing percutane-
ous 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 ascend-
ing pathway transmitting sensory information. This system is
mainly composed of the collaterals of larger-diameter primary
afferents transmitting tactile sensation and limb propriocep-
tion, 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
 Chapter 2—Anatomy of the Pain Processing System 15

Periaqueductal gray Cortical

matter All regions
Somatosensory
Mesencephalon
Diencephalon
Reticular formation
of pons
Intralaminar
Parabrachial nuclei
VMPo
Medial lemniscus
Pons Lateral

Insula

Fig. 2.8 Schematic displaying projections from thalamic neurons to

Reticular formation of various cortical regions. See text for further discussion. VMPo, posterior
medulla portion of the ventral medial nucleus.
Medulla

Supraspinal Projections
Dorsal column Anterolateral system Spinoparabrachial
Spinoreticular tract projection systems
Spinomesencephalic
tract Cortical
Spinal cord Spinothalamic tract

Fig. 2.7 Schematic demonstrating the brainstem projections of spinal Diencephalon

neurons into the medulla and mesencephalon. ­Third-order projections VMPo
arising from the medullary and mesencephalic neurons project into the Amygdala
intralaminar and ventrobasal thalamus.
Mesencephalon

tract of Lissauer, the dorsolateral propriospinal system, and the Parabrachial

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. Medulla

Supraspinal Projections*
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.
Spinal Cord
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.

Spinoreticulothalamic Projections Spinomesencephalic Projections

This tract represents axons that are largely ipsilateral to the cell
of origin. The tract terminates throughout the brainstem retic-
ular formation. Spinomedullary input is believed to play an
important role in initiating cardiovascular reflexes. The med-
ullary 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, includ-
ing 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).
*For more detailed discussions of the material in this section, see References 8 and 9.
Ipsilateral projections to this region terminate in periaqueductal
gray and mesencephalic reticular formation. Stimulation of the
mesencephalic central gray and adjacent ­mesencephalic reticu-
lar 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).
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).
16 Section I—The Basic Science of Pain

Cortical

Ant cingulate
Diencephalon

Medial dorsalis Diencephalon

Mediodorsalis
Posterior ventral medial
(VMpo)

Ventrobasal thalamus

Fig. 2.11 Schematic demonstrating mediodorsalis neurons projecting

into the anterior cingulate gyrus.
Spinal Cord

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.

Somatosensory cortex

Cortical
Diencephalon
SS cortex: Precise map
(place/intensity/modality)
Ventrobasal
thalamus
Thalamocortical projections
VBL -> Somatosensory cortex

Ascending thalamic projections

Lam V-> Ventrobasal (VBL)
Fig. 2.12 Schematic of an overview of the Precise anatomical mapping Spinothalamic tract
characteristics of the projections of wide
dynamic range (WDR) lamina V (Lam V) neurons Ascending axons in VLT
in to the somatotopically mapped ventrobasal
Spinothalamic
(VBL) thalamus and from there to the
somatosensory (SS) cortex. As described in the Spinal Cord
text, this organization suggests the properties Spinofugal projections
that would mediate the sensory-discriminative Lam V: WDR-intensity encoded
aspects of pain. VLT, ventrolateral tract. High degree of localization Ventrolateral tracts

Spinothalamic Projections Functional Overview of Pain

This predominantly crossed system displays the following
three principal targets of termination (Fig. 2.11):
1. The ventrobasal thalamus represents the classic soma-
tosensory 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).
Processing Systems*
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.
*For more detailed discussions of the material in this section, see References 10 to 12.
 Chapter 2—Anatomy of the Pain Processing System 17
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 rela-
tionship 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 sig-
nificance 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 function-
ally 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 soma-
tosensory 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 (see Fig.
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 localiza-
tion 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 pre-
cise place and response intensity until it is, by definition, poten-
tially 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 classi-
cally appreciated to be associated with emotionality and affect.
Accordingly, this type of circuitry would provide an impor-
tant substrate for systems underlying the affective-­motivational
components of the pain experience. Functional magnetic reso-
nance imaging and positron ­emission tomography have dem-
onstrated 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 con-
trast, the other system ­involving the limbic forebrain suggests
a circuit that can ­mediate an ­“affective-motivational” compo-
nent 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 stimu-
lus, 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 com-
monly 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 aver-
sive. This afferent plasticity is further considered in Chapter 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 disconnec-
tion syndromes are produced by prefrontal lobectomies, cingu-
lotomies, and temporal lobe–amygdala lesions.
Pharmacology of Afferent
Transmitter Systems in Nociception*
An important question relates to the nature of the neurotrans-
mitters and receptors that link the afferent projection systems.
Such transmitter-receptor systems have several defining character-
istics. 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 trans-
mission are excitatory. For example, at the spinal level, no “mono-
synaptic 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 exci-
tation of a ­second neuron that releases an inhibitory transmit-
ter. 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 pep-
tide (e.g., substance P [sP]) are typically released. Third, although
not discussed ­further here, each synaptic link is subject to mod-
ifications because of a dynamic regulation of the ­presynaptic
transmitter content and the postsynaptic receptor and its
­linkages (e.g., with repetitive stimulation, the glutamate recep-
tor 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 transmit-
ters. Currently, excitatory amino acids, such as ­glutamate and cer-
tain peptides, including sP, vasoactive ­intestinal peptide (VIP),
*For more detailed discussions of the material in this section, see References 3 and 13
to 17.
18 Section I—The Basic Science of Pain

Anterior Cigulate

Cortical
Diencephalon
Anterior Cingulate: Limbic-emotion

Thalamocortical projections Ventrobasal

Thalamus
Submedius -> Anterior Cingulate

Mediodorsalis
Ascending thalamic projections
Lam I -> mediodorsalis (?)

Fig. 2.13 Schematic of an overview of the Ascending axons in VLT Spinothalamic Tract
characteristics of the projections of nociceptive- Spinothalamic
specific lamina I (Lam I) neurons into the
mediodorsalis and from there to the anterior
Spinofugal projections
cingulate (Ant cingulate) cortex. As described
in the text, this organization suggests the Lam I: Marginal-nociceptive specific
Spinal Cord
properties that would mediate the affective- Poor spatial encoding
motivational aspects of pain. VLT, ventrolateral
tract. Ventrolateral Tracts

Excitation n Local spinal administration of several agents such as sP

Recording
Primary afferent Sensory
C terminal afferent
Receptor Dorsal horn
neuron
mV
Dorsal horn Intracellular recording
Membrane neuron
Time (msec)
A B C is the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
Fig. 2.14 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.
somatostatin, calcitonin gene–related peptide (CGRP), bomb-
esin, and related peptides have been observed. C fibers possess
the following characteristics (Figs. 2.13 and 2.14):
n Peptides have been shown to exist within subpopula-
tions of small type B dorsal root ganglion cells.
n 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).
n 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).
n Release of peptides is reduced by the spinal action of
agents known to be analgesic, such as opiates (see later).
n 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 depo-
larization. The peptides tend to produce delayed and
long-lasting discharge.
and glutamate does yield pain behavior, a finding sug-
gesting the possible role of these agents as transmitters
in the pain process.
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
(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 cholecys-
tokinin, 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 path-
ways, 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.
References
Full references for this chapter can be found on www.expertconsult.com.