Afferent pain pathways: a neuroanatomical review
Transcript of Afferent pain pathways: a neuroanatomical review
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Brain Research 1000 (2004) 40–56
Review
Afferent pain pathways: a neuroanatomical review
Tatiana F. Almeida*, Suely Roizenblatt, Sergio Tufik
Department of Psychobiology, Universidade Federal de Sao Paulo, Rua Napoleao de Barros, 925. Vila Clementino, 04024-002, Sao Paulo, SP, Brazil
Accepted 23 October 2003
Abstract
Painful experience is a complex entity made up of sensory, affective, motivational and cognitive dimensions. The neural mechanisms
involved in pain perception acts in a serial and a parallel way, discriminating and locating the original stimulus and also integrating the
affective feeling, involved in a special situation, with previous memories. This review examines the concepts of nociception, acute and
chronic pain, and also describes the afferent pathways involved in reception, segmental processing and encephalic projection of pain
stimulus. The interaction model of the cerebral cortex areas and their functional characteristics are also discussed.
D 2004 Elsevier B.V. All rights reserved.
Theme: Sensory systems
Topic: Pain pathways
Keywords: Nociception; Afferent pain pathway; Tract; Supraspinal projection; Cortical structure
1. Introduction
In 1986, the International Association for the Study of
Pain (IASP) defined pain as a sensory and emotional expe-
rience associated with real or potential injuries, or described
in terms of such injuries. Pain has an individual connotation
and suffers the influence of previous experiences [75]. This
definition takes into consideration the subjectivity of the
painful phenomenon and permits the understanding of im-
portant concepts concerning this subject.
Painful manifestations can be explained on the basis of
neural substrates mediating the sensory, affective, and
nociceptive functions, as well as neurovegetative responses.
While the sensory, discriminative–perceptive component
permits the spatial and temporal localization, physical
qualification and the intensity quantification of the noxious
stimulus, the cognitive–affective component attributes emo-
tional coloring to the experience, being responsible for the
behavioral response to pain [22].
A noxious stimulus is capable of provoking a real or
potential injury, not necessarily causing pain. In this context,
pain experienced by virtue of this type of stimulus is
0006-8993/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainres.2003.10.073
* Corresponding author. R. Vieira de Morais 601, ap: 116, Campo
Belo, 04617-011, Sao Paulo, SP, Brazil. Tel: +55-11-5539-0155; fax: +55-
11-5572-5092.
E-mail address: [email protected] (T.F. Almeida).
characterized as nociceptive pain. However, it is known that
the painful phenomenon can occur spontaneously, as is the
case for nonnociceptive pain represented by the reduction of
the receptor thresholds due to alterations of the central
nervous system (CNS) [22]. There is a difference between
the terms nociception and pain; the first refers to the neuro-
physiologic manifestations generated by noxious stimulus,
while the second involves the perception of an aversive
stimulus, which requires the capacity of abstraction and the
elaboration of sensory impulses [76].
According to the IASP definition, the relation between
pain and degree of injury is not obligatory. Thus, the alert
function applies only to an acute manifestation, i.e., the one
that follows damage to the tissue. Acute pain is character-
ized by the fact of being delimited in time and disappearing
with the resolution of the pathological process. Chronic pain
that persists for an extended period of time is associated
with chronic pathological processes and causes suffering in
multiple systems [75,79].
Knowing that pain represents a complex sensory modality
accompanied by affective, motivational and cognitive
aspects, and also, associated with neurovegetative responses,
this review provides neuroanatomical evidences of the neural
pathways involved in the reception, processing, and trans-
mission of the afferent nociceptive input because these
aspects are considered of fundamental importance for pain
perception.
T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 41
2. Peripheral receptors
The propagation of pain is initiated with the activation of
physiological receptors, called nociceptors, widely found in
the skin, mucosa, membranes, deep fascias, connective
tissues of visceral organs, ligaments and articular capsules,
periosteum, muscles, tendons, and arterial vessels. The
receptors correspond to free nervous endings and represent
the more distal part of a first-order afferent neuron consist-
ing of small-diameter fibers, with little or unmyelinated, of
the A-Delta or C type, respectively. Their receptor fields can
consist of areas ranging from punctiform regions to regions
measuring several millimeters in diameter, or even of more
than one site in distant territories [69,74].
The nociceptors found in the skin originate from small
nervous stems that, when approaching the epidermis, lose
their myelin, ramifying into extensive plexuses. Two types
of free nervous endings exist: the ramified ones originating
from 1 or 2 myelinated fibers forming intraepithelial termi-
nations and the nonencapsulated glomerular bodies, deriv-
ing from a single unmyelinated fiber and organized in a
densely spiral manner below the epidermis or the mucosa. In
other organs, this organization may vary because the type of
propagated stimulation, the form of propagation, and the
quality of the painful sensation depend on the receptor
nervous fiber complex and the innerved organ [76,102].
Normally, the painful sensation results from specific
activation of the nociceptors by mechanical, thermal, or
chemical stimulus, and not by the hyperactivity of other
sensory modality receptors. They present higher thresholds
than the other receptors and respond progressively accord-
ing to the intensity of the stimulus. However, the sensitiza-
tion of the nociceptors causes reduction of the thresholds
and, in some cases, spontaneous activity [74,76,102].
3. Peripheral afferent fibers
First-order afferent fibers are classified in terms of
structure, diameter, and conduction velocity. C-type fibers
are unmyelinated, ranging in diameter from 0.4 to 1.2 Amand have a velocity of 0.5–2.0 m/s; A-Delta fibers are
barely myelinated, ranging in diameter from 2.0 to 6.0 Amand have a velocity of 12–30 m/s. The A-Beta fibers are
myelinated, with a diameter of more than 10 Am and a
velocity of 30–100 m/s, and do not propagate noxious
potentials in normal situations; however, they are funda-
mental in the painful circuitry because they participate in the
mechanisms of segmental suppression [76,95].
In the presence of a noxious stimulus, the primary
nociceptive afferents show differentiated patterns of propa-
gation. The A-Delta fibers propagate modally specific
information, with marked intensity and short latency. They
promote a quick sensation of first phase or acute pain,
triggering withdrawal actions. The C-type fibers propagate
information in a slower way, at times secondary to the action
of the A-Delta afferents. Their prolonged potentials undergo
summation along time and induce the manifestations of dull
pain. Although widely used, this differentiation does not
apply to all organs, being more evident in the skin [22].
The C-type fibers present thermosensitive receptors
reacting to heating and cooling, mechanoreceptors of low
threshold and specific receptors for algogenic substances
such as potassium ions, acetylcholine, proteolytic enzymes,
serotonin, prostaglandin, substance P, and histamine. Many
C fibers with high-threshold receptors respond equally to
thermal and mechanical stimuli, or are sensitive to mechan-
ical, thermal and chemical stimuli, and for this reason are
called, polymodal. A special type of C fiber respond to high
intensity thermal stimuli and, in association with polymodal
fibers, seem to be responsible for the mediation of the flare
response after tissue damage. Another type of C fiber of
slow conduction, mechanoinsensitive, and mediated by
histamine is also recognized and is probably involved in
the burning sensation. Finally, a new class of fibers is
described having receptors that do not respond to noxious
stimuli in general, called silent receptors, which are activat-
ed only in the presence of inflammation [76,102].
The A-Delta fibers are classified into two groups. The
first one, type I, corresponds to fibers with high-threshold
mechanoreceptors that primarily respond to mechanical
stimuli of high intensity and respond weakly to thermal or
chemical stimuli and, after being sensitized, to harmful heat.
Group II presents fibers with mechanothermal receptors for
high temperatures (45–53 jC) and some receptors for
intense cold (� 15 jC) and later sensitized to vigorous
mechanical stimuli at nonnoxious thresholds [76].
In the muscle, the stimulus in both A-Delta and C fibers
produces an aching sensation, without differentiation, which
is less localized than cutaneous pain. The A-Delta fibers
propagate innocuous mechanical, thermal and chemical
stimuli, noxious stimuli typical of ischemia/hypoxia, and
painful pressure, being recognized as polymodal type fibers.
About one-third of these fibers present special receptors that
signal the amount of effort performed by a muscle group,
inducing alterations in the blood flow and in respiration
process. The C-type fibers present the same polymodal
characteristics as the A-Delta fibers, but with a 50% higher
proportion of fibers for ischemia/hypoxia and noxious
pressure [76,102].
In visceral organs, the noxious and nonnoxious informa-
tion is propagated by A-Delta and C fibers, and not by
genuine A-Beta fibers [76]. Because electric stimuli of low
intensity elicit vagal sensations of fullness and nauseas,
while electric stimuli of high intensity cause pain, it is
believed that the visceral painful perception is dependent on
the intensity of the stimulus. Additionally, the sparse orga-
nization of the receptors and their poor differentiation
suggest that this perception also depends on spatial summa-
tion. The sensations originating from the chest and abdomen
are propagated to the CNS by means of the sympathetic and
parasympathetic chains. The sensations of the abdominal
T.F. Almeida et al. / Brain Research 1000 (2004) 40–5642
organs are poorly localized and are referred to distant
regions from the affected area, different from those origi-
nating from the chest, which can be directly located on the
affected region because they are conducted directly by local
spinal nerves [76,95].
4. Spinal cord
The primary afferents reach the spinal cord and the brain
stem, through the cranial nerve pairs V, VII, IX and X.
When approaching these structures, they detach from
thicker fibers, organizing themselves in the ventrolateral
bundle of roots. They are part of the Lissauer Tract and form
synapses with second-order neurons distributed along the
dorsal horn of the spinal cord, organized according to the
Rexed laminae [75]. About one-third of the ventral roots are
sensitive and predominantly painful, although their cell
bodies are located in the dorsal root ganglion. The integra-
tion with the neurons of the dorsal horn of the spinal cord
occurs after the passage through the anterior horn or by the
fibers that, before penetrating in the ipsilateral anterior horn,
are directed to the dorsal horn [75,76].
Intrinsic neurons of the dorsal horn promote the interac-
tion of the afferent and efferent nociceptive stimuli, and are
also responsible for their transfer to supraspinal structures. In
view of the reception and integration of the afferent stimulus,
they can be classified as projection neurons (PN) that directly
transmit the information to supraspinal centers, intersegmen-
tal propriospinal neurons (IPN), that integrate several spinal
levels, and also to the ipsilateral and contralateral regions,
initiating and mediating the descending inhibition with im-
plication in reverbatory mechanisms of sensitization; inter-
neurons, that can be divided into interlaminar and
intrasegmental intralaminar types, the latter also having
inhibitory (INI) or excitatory (INE) characteristics [76].
The neurons of the dorsal horn of the spinal cord present
differentiations with respect to the type of sensitive conver-
gence, i.e., the type of afference they receive. They are
classified into three distinct groups and the organization of
the ascending pathways of the spinal cord and the response
pattern in the presence of the nociceptive impulse depend on
them. The specific nociceptive neurons respond exclusively
to noxious stimuli and they are found in laminae I, II
(external), V and VI. The sources of input for these neurons
are A-Delta nociceptive fibers of high threshold and heat
nociceptive and C polymodal nociceptive fibers. Their
receptive fields are punctiform and show somatotropic
organization, mainly in lamina I. The specific nociceptive
neurons present a limitation for the gradual response to
different stimulus intensities but are involved in the codify-
ing of the localization and physical quality of this stimulus
[76,92,101].
The Wide Dynamic Range (WDR) neurons respond to
mechanical, thermal and chemical stimuli coming from the
A-Delta, C and A-Beta fibers. Because of the convergence
of noxious and nonnoxious fibers, this group plays a
fundamental role in the mechanisms of segmental suppres-
sion of pain involved in the Gate Control Theory [70]. They
are found in laminae I, II (external), IV, V, VI, X and in the
anterior horn. Their main characteristic is the capacity of
coding for the stimulus intensity because they show increas-
ing frequencies of response from innocuous to noxious
stimulation. Their receptor fields are extensively organized
in the more central regions of the dorsal horn and demon-
strate variation of the activated area depending on stimulus
intensity [76,92,101].
The NonNociceptive (N-NOC) neurons respond to in-
nocuous stimuli such as low intensity mechanical, thermal
and proprioceptive ones, propagated by A-Delta and A-Beta
fibers. They are localized in laminae I, II (internal), II and
IV, and act indirectly in segmental suppression mechanisms
[76,92].
The interaction model of the afferent information in the
dorsal horn of the spinal cord (DHSC) proposes several
pathways for the nociceptive impulses to reach the projec-
tion neurons and from there, the supraspinal structures. The
WDR and SN in the superficial layers can be directly
activated by A-Delta or C fibers or through the activation
of the excitatory neurons that are located in lamina II
(external). The afference of nonnoxious potentials propa-
gated by A-Beta fibers that reach the WDR and N-NOC
neurons in layers I and II (external) is provided by excit-
atory neurons originating in deeper layers because these
fibers do not innervate the superficial layers. In layer V, the
projection neurons receive direct afferences from C-type
fibers. However, they show dendrites that reach the super-
ficial layers, being indirectly stimulated by excitatory neu-
rons of lamina II (external) [76,92].
Moreover, the WDR and N-NOC neurons are activated
by A-Beta fibers and, in this case, they are important as
relays for interaction of the noxious and nonnoxious stimuli.
This model also takes into consideration the role of inhib-
itory neurons in the modulation of the afferent impulses for
the projection neurons. The inhibitory neurons are activated
by A-Delta, C and A-Beta fibers and regulate the nocicep-
tive activity by interacting with the projection neurons and
the primary afferents by presynaptic and postsynaptic inhib-
itions, respectively [76].
5. Afferent nociceptive pathways of the spinal cord
After the direct or indirect interactions with the projec-
tion neurons in the DHSC, the axons of second-order
neurons become part of the constitution of the anterolateral
fascicle or posterior fascicle, forming afferent bundles that
transmit the nociceptive impulses to structures of the brain
stem and diencephalon including the thalamus, periaque-
ductal substance, parabrachial region, reticular formation of
the medulla, amygdaloid complex, septal nucleus, and
hypothalamus, among others [76,102].
T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 43
The different ascending bundles form two phylogenetic
different systems. The first, older one, runs through the
medial region of the brain stem, and is formed by the
paleospinothalamic, spinoreticular, spinomesencephalic, spi-
noparabrachio-amygdaloid, spinoparabrachio-hypothalamic,
and spinohypothalamic bundles. The other system, more
recent, occupies the lateral region of the brain stem and
consists of the neospinothalamic bundle, spinocervical bun-
dle, and postsynaptic beam of the dorsal horn [76].
5.1. Spinothalamic tract
This tract originates from neurons of the WDR, SN
and N-NOC types propagating innocuous and noxious
potentials that are related to pain, temperature, touch and
itching [5,6,31,69,74,104]. In the medulla, the bodies of
these neurons are located in larger numbers in laminae I and
V, but are also found in laminae II, IV, VI, VII, VIII and X
(Fig. 1) [27,31,76,114].
The lamina I neurons have been the subject of many
studies. According to the morphology of the soma and the
orientation of the dendrites, there are distinct fusiform,
pyramidal and multipolar cellular types, which probably
form distinct physiological systems for the propagation of
pain and temperature [111]. This concept is supported by the
description of modally differentiated fibers in this lamina,
exclusively activated by noxious cooling, and others with
specific nociceptive characteristic, which present different
arrangements in the midbrain and project to distinct regions
of the thalamus [28,41,46].
Still in lamina I, SN neurons receive inputs from A-Delta
fibers of high threshold for mechanical and thermal stimuli.
The WDR neurons receive afferences from fibers of non-
noxious high threshold in general and also inputs from C-
type fibers [76,78]. With respect to noxious mechanical
stimuli, SN neurons are classified as maintenance cells
because they exhibit a prolonged response time in relation
to the initial stimulation. In contrast, the WDR are classified
as adaptive neurons because their time response ends right
after the end of the initial stimulus. Only the SN have the
ability to code the intensity of the stimulus and are possibly
responsible for the sensation of pain caused by sustained
mechanical stimuli, also contributing to the acute sensation
of pain [7,102].
Based on the origin and the model of projection of these
fibers, some authors have described three forms of affer-
ences of the spinothalamic tract. One is the monosynaptic
neospinothalamic pathway or ventral spinothalamic tract,
that directly projects to nuclei of the lateral complex of the
thalamus, involved in the sensory–discriminative compo-
nent of pain. Another is the multisynaptic paleospinothala-
mic pathway, or dorsal spinothalamic tract, that projects to
nuclei of the posterior medial and intralaminar complex of
the thalamus, involved in the motivational–affective aspects
of pain. Finally, a monosynaptic spinothalamic pathway
projecting directly to the medial central nucleus of the
thalamus involved in the affective component of the painful
experience [95,112].
5.2. Spinoreticular tract
This tract originates mainly in laminae V, VII and
VIII, and also in laminae I and X, mostly from SN and
WDR, although also involving N-NOC neurons, which
propagate noxious and innocuous stimuli (Fig. 2) [50,60,
71,76,102].
The spinoreticular tract presents two projection compo-
nents in the brain stem; one of them directed at the
precerebellar nucleus in the lateral reticular formation,
involved in motor control, and the other directed to the
medial pontobulbar reticular formation involved in the
mechanisms of nociception [76]. Some fibers originating
from lamina I reach the dorsal and ventral subceruleus
nuclei, from which projections to the intralaminar nuclei
of the thalamus, ventral thalamus and hypothalamus
[11,47,52,59,60,64,86,95,103]. However, the real functional
importance of this tract is believed to be due to the
connections established in the brain stem because the
projections to the intralaminar nuclei of the thalamus are
sparse and probably occur by means of collateral branches
of the spinothalamic tract [50,70].
The afferences of spinoreticular tract are involved in the
motivational–affective characteristic, as well as the neuro-
vegetative responses to pain [25,74,76,112]. This tract is an
important pathway for the modulation of the nociceptive
segmental pathways by activating brain stem structures
responsible for descending suppression [35,50,70,112].
5.3. Spinomesencephalic tract
The neurons that give origin to this tract are WDR, SN
and N-NOC and are arranged in the spinal cord in a manner
similar to the neurons of spinothalamic tract, obeying a
somatotopic organization, mainly in laminae I, II, IV, V, VI,
but also observed in laminae VII, X, and in the ventral horn
(Fig. 3) [26,54,72,76,100,102,108–110]. Fibers originating
in lamina I, in the region of the cervical intumescence, and
at some thoracic levels show two distinct afferent systems,
ipsilateral and bilateral, occupying the dorsolateral funiculus
[54,71,100,109,110]. According to the site of their projec-
tions, two systems of different afferences are considered.
The spinoannular bundle, that projects to the periaqueductal
gray (PAG) matter, and the spinotectal bundle that reaches
the deep layers of the superior colliculus [72,76].
The projections to the midbrain periaqueductal gray
(PAG) matter originate from WDR and SN, and are func-
tionally distinct. Those that reach the PAG in the portion
more dorsal to the limiting sulcus have an excitatory
characteristic in afferent nociceptive transmission and those
that project more ventral to the limiting sulcus activate
inhibitory mechanisms responsible for the inhibition of the
afference of this same pathway. A pattern of excitation
Fig. 1. Spinothalamic tract. Most of the axons decussate transversely through the anterior white comissure of the spinal cord and ascend through the lateral
contralateral funiculus; some of them show an ipsilateral course [49,76,80,98,114]. During its passage through the brain stem, the spinothalamic tract originates
collateral branches destined to the reticular formation of the medulla, pons and midbrain, including the gigantocellularis and parogigantocellularis nuclei and
periaqueductal gray matter, probably responsible for the activation of the descending suppressor system, the behavioral response and also the neurovegetative
responses to pain [76,112].
T.F. Almeida et al. / Brain Research 1000 (2004) 40–5644
Fig. 2. Spinoreticular tract. Along the tract, most of the fibers run through the anterolateral funiculus, together with the ventral spinothalamic tract. The
afference originating in the laminae from the lumbar intumescence is mainly contralateral; although a portion originating in laminae I and V ascends in an
ipsilateral manner. The afferences originating in the cervical intumescences and sacral segments are arranged bilaterally in the direction of the brain stem
[40,50,60,72,76,102,110]. The main structures innervated by this tract are: nucleus raphe magnus, retroambiguous nucleus, supraspinal nucleus, medulla
central nucleus, lateral reticular nucleus, gigantocellularis nucleus, parogigantocellularis nucleus, pontine caudal and oral nucleus, in addition to the
parabrachial region.
T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 45
followed by inhibition is commonly observed when stimu-
lating the PAG, as well as other regions of the midbrain.
This suggests an autoregulatory medullary/midbrain activity
with different connections and velocities of propagation
[42,106,107].
The activity of spinomesencephalic tract, as well as the
spinothalamic tract and the postsynaptic route of the dorsal
column, suffers inhibitory or excitatory influence from
interneurons activated by collateral neurons of the spinocer-
vical tract [38,39]. A model of collateralized afference
between the spinomesencephalic tract and spinothalamic
tract has also been described in cervical, thoracic and
lumbar segments that activate one another in the direction
of the PAG and of the ventroposterolateral nucleus of the
thalamus [103].
In addition to the characteristics of somatosensory pro-
cessing and activation of the mechanisms of descending
analgesia, the stimulation of regions innervated by the
spinomesencephalic tract produces different responses impli-
cated in nociceptive processing. Thus, stimulation of these
regions is capable of provoking aversive behaviors in the
presence of noxious stimuli and motor responses of the visual
Fig. 3. Spinomesencephalic tract. Most of the fibers ascend through the anterolateral contralateral funiculus of the spinal cord, together with the ventral and
spinoreticular spinothalamic tract, although some have been detected in the dorsolateral funiculus. Studies with anterograde tracers and techniques of neuronal
degeneration have indicated that the main structures of projection of spinomesencephalic tract are the lateral and ventrolateral region of the PAG, the posterior
pretectal nucleus and the Darkschewitsch nucleus. Moderate projections to the medial region of the PAG, cuneiform nucleus and midbrain reticular formation,
the lateral region of the deep laminae of the superior colliculus and the medical magnocellular nucleus. Lesser projections to the most dorsal region of the PAG,
nucleus of inferior colliculus, the intermediate lamina of the superior colliculus, the lateral region of the red nucleus and in the Edinger–Westphal region of the
oculomotor nucleus, besides scarce fibers projecting to the interstitial nucleus of Cajal and anterior pretectal nucleus [100,106,107]. Projections from neurons
of lamina I occur solely towards the medial region of the thalamus or towards the thalamus and midbrain [110].
T.F. Almeida et al. / Brain Research 1000 (2004) 40–5646
desertion type, besides autonomic, cardiovascular, motiva-
tional, and affective responses [42,54,55,76,106,108,110].
5.4. Spinoparabrachial tract
The parabrachial nucleus (PN) receives direct and indi-
rect afferences from nociceptive pathways. The neurons of
laminae I and II of the SN neurons participate in the direct
afferences, representing a genuine nociceptive pathway
(Fig. 4) [9,10,76,92,101].
The collaterals of other afferent tracts that converge to the
PNconstitute the indirect nociceptive pathways [112]. Studies
have demonstrated that these two pathways are involved in the
propagation of visceral pain due to the inflammatory process
and thermal stimuli at noxious levels [9,17,56,101,111].
The PN receives afferences from the spinomesencephalic
tract, the sacral parasympathetic nucleus and collaterals of
the spinoreticular tract. It projects to the thalamus and to the
spinal cord, in addition to the structures described above
[76,86]. However, the afferences to the amygdala and other
limbic structures do not occur exclusively through the PN.
Direct tracts from the spinal cord to the amygdala, lenticular
nucleus, nucleus accumbens, septum, cingular, frontal and
infralimbic cortex have been described. For this reason, they
are considered spinal–limbic pathways by some authors
(Fig. 4) [37,48,92,102,111].
Fig. 4. Spinoparabrachial tract. The axons of these neurons ascend through the contralateral dorsolateral funiculus up to the brain stem where, after reaching the
NPB in its mesencephalic and pontine portions, give origin to two differentiated systems: the spinoparabrachial amygdaloid pathway and the spinoparabrachial
hypothalamic pathway [76,92,101,111]. The spinoparabrachial amygdaloid pathway projects to the amygdala and stria terminalis from the NPB. The
spinoparabrachial hypothalamic pathway projects to the ventromedial nucleus of the hypothalamus.
T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 47
In view of the projection towards the first relay in the PN
and the formation of the two systems of afference to the
amygdala and hypothalamus, the function of autonomic,
motivational and affective regulation is attributed to the
spinoparabrachial tract, as well as the neuroendocrine
responses to pain [76,92].
5.5. Spinohypothalamic tract
This structure originates from laminae I, V, X, the lateral
spinal nucleus, nucleus caudalis and some regions around
the central medullary canal, and is composed of SN, WDR
and N-NOC neurons. These neurons respond to noxious and
innocuous stimulation coming from muscles, tendons,
joints, skin and viscera (Fig. 5) [56,58,76].
The pathway of its fibers constitutes an exception when
compared to other tracts. Projections to the lateral, preforn-
ical, dorsomedial, suprachiasmatic and supraoptic nuclei
have been described in the hypothalamus. It has been sug-
gested that integration with the autonomic nervous system
occurs starting from these regions by means of afferences to
the vagal dorsal nucleus and preganglionic neurons of the
intermediolateral column. During the afference to the brain
stem and diencephalon, collateral projections to the superior
Fig. 5. Spinohypothalamic tract. Many of these fibers travel along the contralateral anterolateral funiculus. After projection to nuclei of the lateral
hypothalamus, approximately half of its fibers become part of the constitution of the supraoptic decussation, reach the ipsilateral hypothalamus and are directed
caudally to innervate the thalamus, amygdala, septum, and striatum [33,66,107,108]. Current studies demonstrate that the activation of the thalamus precedes
the projection of the spinothalamic tract to the hypothalamus [113].
T.F. Almeida et al. / Brain Research 1000 (2004) 40–5648
colliculus, substantia nigra, red nucleus, pretectal nucleus,
globus pallidus, caudate–putamen and substantia innominata
have been described (Fig. 5) [18,32,33,66]. The afferences to
the hypothalamus are organized in different manners, the
nonnociceptive potentials are propagated directly through the
trigeminal–hypothalamic tract and the nociceptive signals
travel along two parallel pathways, the trigeminal–hypotha-
lamic and reticular–hypothalamic tract [62,113].
The model of afferences of this tract suggests that its
projections can contribute to the neuroendocrine autonomic,
motivational–affective, and alert responses of somatic and
visceral origin of the painful experience [56,57,76,102,
113,115].
5.6. Spinocervical tract
This tract originates mainly from laminae III and IV, and
to a lesser extent from laminae I, II and V. Its neurons
receive afferences from peripheral A-Delta and A-Beta
fibers and mostly consists of WDR and N-NOC fibers,
T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 49
although SN have also been described (Fig. 6) [13,14,20,
27,43,76].
Studies with anterograde and retrograde markers or
neuronal degeneration have indicated that differentiated
fiber systems originate from laminae III and IV in the
spinocervical tract. Cell groups in these laminae, stimulated
by A-Delta fibers, originate projections to the lateral cervi-
cal nucleus and the solitary tract nucleus and receive
descending projections from these structures. A spinocer-
Fig. 6. Spinocervical tract. The pathway of the axons runs ipsilaterally from the dor
in the initial segment, travel over short distances in the spinal cord. Because it repr
medullary segments C1–C3, the site of the first relay, from which it crosses th
establishes second order projections with nuclei of the posterior and medial compl
the PAG and superior colliculus, as well as with nuclei of the spine, medial spin
[54,76,102,106,109,110].
vical tract/spinal solitary tract system has been proposed,
with a function in the integration of somatic and visceral
stimuli. Similarly, neurons originating in laminae III, IV and
V, stimulated by A-Beta and A-Delta primary afferents,
form the spinocervical afferent system, the postsynaptic
pathway of the spinal column, from collaterals that at the
level of the cervical–thoracic junction project towards the
lateral spinal nucleus and the nucleus of the spinal column
by means of the dorsolateral funiculus and the spinal
solateral funiculus adjacent to the spinocerebellar tract. Collaterals originate
esents a multisynaptic pathway, it reaches the lateral cervical nucleus in the
e midline, becomes part of the constitution of the medial lemniscus and
ex of the thalamus. Collaterals have also been described for the midbrain in
al nucleus and from the lateral cervical nucleus directly to the spinal cord
Fig. 7. Postsynaptic pathway of the spinal column. It is organized into a multisynaptic pathway running along an ipsilateral course in the spinal cord up to the
first relay in the nucleus of the spinal column, projecting through the medial lemniscus towards the lateral complex of the thalamus and the superior colliculus,
in addition to originating collaterals in the spinal cord itself [51,79,98].
T.F. Almeida et al. / Brain Research 1000 (2004) 40–5650
column, which are modulated at these levels by descend-
ing inhibitory projections and by the action of local
interneurons [29,44,45,65,68,83,100,113]. Other collaterals
have also been described, suggesting the activation of the
spinomesencephalic, spinothalamic, spinocervical and spi-
noreticular tracts from the stimulation of the spinocervical
tract [20,38,39,45,46,54,115].
Apparently, the medial spinal nucleus exerts an inhibitory
modulation by means of collaterals on the lateral spinal
nucleus. Afferent fibers of the spinocervical tract originating
from laminae I, III, IV and V in the cervical and lumbar
segments reach differentiated neurons in the medial region
that serve as the basis for the inhibition of the lateral spinal
nucleus [29,50]. The functions related to this tract concern the
sensory–discriminative, motivational–affective and auto-
nomic characteristics of pain, as well as a role as sensory
integrator and modulator of afferent inputs in the spinal cord
[46,67,76,110].
T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 51
5.7. Postsynaptic pathway of the spinal column
This structure originates mainly from laminae III and V,
also occurring in laminae VI and VII. It consists of neurons
of the WDR, SN and N-NOC, from which groups of fibers
are organized along two distinct pathways, close to the
midline of the spinal cord and at the junction of the gracile
and cuneiform bundles originating from the lumbar–sacral
region and the thoracic column, respectively (Fig. 7)
[2,51,76,79,98].
Extensive direct and indirect projections are described for
the gracile nucleus, which plays an important role of sensory
integration of the projections from abdominal organs and
from the skin, and then projecting to the thalamus [1,3,23,76].
The postsynaptic pathway of the dorsal column represents
the largest afferent pathway for information of visceral origin,
as determined in studies that demonstrated the control of
visceral cancer pain by means of myelotomy techniques,
limited myelotomy to the midline [51] and corroborated by
similar findings after injuries or administration of morphine
to rats and monkeys into the pathway of the spinal column
[2]. Injuries in this region have proved to be more effective in
the control of visceral pain than interruption in the pathway of
the anterolateral quadrant [1,4,76,79]. This pathway also
presents functions related to kinesthesia, discrimination be-
tween two points, and graphesthesia. In view of the regions of
thalamic projection, the postsynaptic pathway of the dorsal
column is considered to be involved in the sensory–discrim-
inative and motivational–affective components of pain
[1,76].
6. Afferent supraspinal projections of the nociceptive
pathway
From the interaction of the sensory impulses in the spinal
cord, the nociceptive afferent pathways give origin to the
different models of projection to subcortical and cortical
structures. In this stage, the sensory–discriminative and
affective–cognitive components referring to the painful ex-
perience are attributed to the nociceptive impulse. Studies
have indicated that the midbrain, thalamus, hypothalamus,
lentiform nucleus, somatosensory cortices, insular, prefron-
tal, anterior and parietal cingulum are basic structures in this
circuitry [19,34,36,59,78,85,91,103].
6.1. Thalamus
The thalamus represents the main relay structure for sen-
sory information destined to the cortex and, involved in the
reception, integration, and transfer of the nociceptive poten-
tial. The different projections to its nuclei and from them to the
cortex define the functional circuitry of pain processing [76].
The lateral nuclear complex consists of the ventropostero-
lateral (VPL), ventroposteromedial (VPM) and ventroposter-
oinferior (VPI) nuclei. Studies have shown that the
convergence of fibers and the function of these nuclei occur
from the projections of spinothalamic tract. Thus, it was
demonstrated that neurons of the WDR type predominate in
the VPL and VPM nuclei, and that SN neurons are found in
the VPI nucleus. They all respond to the thermal and
mechanical stimuli, and some also respond to freezing.
Although they show a somatotopic organization, the receptor
fields in VPI nuclei are larger than those in the VPL and VPM
nuclei, and are characterized by a punctiform aspect. More-
over, their projections to the SII cortex suggest different
forms of processing with respect to the sensory–discrimina-
tive and affective–cognitive aspects of pain [8,73,76,83,97].
The VPL nucleus is recognized as themain somatosensory
relay. The convergence of noxious and innocuous stimuli of
cutaneous, muscular, and articular origin has been demon-
strated in several studies [24,55,63,82,99] as well as inter-
connections with the primary somatosensory (SI) cortex,
responsible for the aspects of pain localization and intensity
[53,89,99,101,104]. However, neurons have been described
which equally respond to the somatic and visceral stimuli in
addition to specific visceral neurons, showing that this
nucleus also participates in the processing of visceral pain
[15,114] which occurs through the postsynaptic pathway of
the dorsal column with projections for the gracile nucleus
[1,76,79]. Visceral afferences of the spinothalamic tract have
also been described, although their main noxious conver-
gence originates from the skin [22,81]. These two systems
seem to contribute discriminative aspects of visceral pain
[16,98]. The VPM nucleus presents cell types and organiza-
tion similar to the VPL nucleus, being similarly involved in
the sensory–discriminative [104] aspects of thermal, me-
chanical and tactile information [14,66,104]. However, its
contribution to the painful experience is differentiated. By
virtue of its projections to the prefrontal cortex, the conver-
gence of fibers originating from the parabrachial region and
the paratrigeminal nucleus, together with the interconnec-
tions with the amygdala, hypothalamus and PAG, suggests an
involvement in the emotional aspects, psychomotor and
autonomic responses of pain [21,48,66,77].
The existence of inhibitory interactions involving VPL
and VPM nuclei, which form a modulatory system similar
to that presented in the Gate Control Theory [70] in the
propagation of pain to superior centers is well known
[94,97,98]. Other afferences to the lateral complex of the
thalamus include fibers of the spinocervical tract [13],
spinoparabrachial tract [48], and spinoreticular tract [60,93].
The posterior complex of the thalamus consists of the
pulvinar oralis nucleus, posterior nucleus (PO), and the
posterior division of the ventromedial nucleus (VmPO). It
presents sparse receptor fields without a somatotopic orga-
nization and is organized in a reverberating cortical–tha-
lamic–cortical circuitry, which strengthens the activation of
thalamic and cortical neurons in the presence of the noxious
stimulation [76,90].
The VmPO and PO nuclei are an integral part of the
medial nociceptive system, establishing connections with
Fig. 8. Nociceptive thalamic efferences to cortical and subcortical regions. Lateral nuclear complex: ventroposterolateral (VPL), ventroposteromedial (VPM),
ventroposteroinferior (VPI) nuclei. Posterior nuclear complex: posterior nuclei (PO), posterior division of the ventromedial nucleus (VmPO). Medial nuclear
complex: ventral region of the dorsal medial nucleus (MDvc), centromedial nucleus (CM), lateral central nucleus (LC).
T.F. Almeida et al. / Brain Research 1000 (2004) 40–5652
the insular and cingular cortex and are involved in the
affective–cognitive aspects of pain [84,97]. Specific pro-
jections of the spinothalamic tract originating from lamina I
indicate that these nuclei are centers of integration of painful
and thermal noxious information, mainly in the presence of
freezing and visceral sensations [12,46,61,108]. Spinotha-
lamic projections to the PO nucleus have been described
from the superficial and also from the deeper laminas of the
dorsal horn, in the region of the cervical intumescence.
Neurons in this region respond to the noxious and innocu-
ous mechanical stimuli, showing representations of some
corporal regions [107].
In addition to the spinothalamic tract, the posterior
complex of the thalamus receives afferences from the
spinohypothalamic tract [107] spinoparabrachial tract [12],
and postsynaptic pathway of the dorsal column [76]. The
medial complex of the thalamus is composed by the ventral
region of the dorsal medial nucleus (MDvc) and by the
intralaminar nuclei, among them, the lateral central nucleus
(LC) and the centromedial nucleus (CM). Extensive recep-
tor fields are described—bilaterally activated and projecting
to the cingular cortex [82] suggesting a contribution to the
motivational–affective aspects of pain [74,101,102,110].
Like the VmPO nucleus, it receives afferences from laminae
I and V of the spinothalamic tract [30,60,82,97,105] and
interconnects with structures responsible for the control of
attention and motor response, such as the striatum and the
cerebellum, probably involved in the escape behavior in the
presence of a harmful stimulus [76].
Fig. 9. The interconnection model of lateral and medial
Spinoreticular projections have been described for this
nucleus [60,74,101]. However, the subject remains contro-
versial [11]. Similarly, projections of the spinomesence-
phalic tract [110] and spinohypothalamic tract have been
described (Fig. 8) [107].
6.2. Cortical projections
Considering the multiple aspects of the painful experi-
ence, the models of afference to thalamic nuclei and their
cortical projections, two systems of nociceptive projection
acting in a parallel and complementary manner are distin-
guished, i.e., the lateral and medial systems. Within this
perspective there are three important cortical regions which
have been studied on the basis of functional criteria by
means of single neuron recordings: primary somatosensory
cortex (SI), secondary somatosensory cortex (SII), and the
anterior cingulated cortex [8,76,83,96,97,105].
The lateral system participates directly in the sensory–
discriminative attribution of nociception and involves spe-
cific thalamic nuclei, which project to SN and WDR neurons
of the SI and SII cortices. The ability to code topographically
noxious stimuli of different intensities is a predominant
function of the nociceptive neurons present in SI
[89,99,101,104]. Although SN and WDR neurons are able
to code the intensity of these stimuli, this function seems to be
related more to the WDR type whereas SN neurons mainly
act on the topographic localization of peripheral stimuli. This
characteristic may indicate that both the localization of the
systems with cortical and subcortical structures.
T.F. Almeida et al. / Brain Research 1000 (2004) 40–56 53
stimulus and the discrimination of its intensity are performed
by two different channels of the nociceptive system [97]. In
addition, nociceptive neurons located in the SII have been
reported to code the painful stimulus in temporal terms
[96,97]. The SI and SII cortices are interconnected with the
posteroparietal area and with the insula through a cortico–
limbic somatosensory pathway, and at this level the somato-
sensory input is associated to other sensory modalities and
with learning and memory. This model of interaction is
critical for an evaluation of the stimuli characteristics and
further behavioral decision, the latter, in relation to the
prefrontal cortex function [74,88,101,110].
In contrast, the medial nociceptive system has less defined
projections from the medial region of the thalamus to exten-
sive cortical areas (SI and SII), including limbic structures
such as the insula and the anterior cingulated cortex [87]. For
this reason, it mainly contributes to the motivational–affec-
tive component of pain, although it also participates in the
sensory–discriminative circuitry [87,96,97].
The insula receives impulses from the lateral system and
its projection pathway is directed at the limbic system, mainly
amygdala and some regions of the prefrontal cortex related to
the emotional and affective component and to memory
inherent to the painful experience. It is also considered to
be a somatomotor visceral area because it acts as a sensory
component of integration between visceral, vestibular, and
tactile sensations [87,88].
The anterior cingulated cortex plays a pivotal role
bringing the attentional and emotional mechanisms to pain
experience. Its coordinate inputs from parietal areas with
frontal cortical regions which integrate the perception of
bodily threat with the strategies and response priorities of
pain behavior (Fig. 9) [48,66,77,84,88,97].
7. Conclusion
Neuroanatomical evidences have contributed to the no-
tion that pain is a complex entity involving multiple
ascending pathways, different functional projections to
thalamus, and a cortical circuit comprising areas, which
although playing a specific functional role, participate in
pain processing in serial and parallel manner. Questions
related to the affective–motivational and cognitive–evalu-
ative components of pain experience and furthermore, the
variability of pain expression among healthy subjects, and
also among different chronic pain conditions, still remain.
New experimental paradigms are needed for the understand-
ing of the neuronal interaction involved in pain perception.
Acknowledgements
The authors thank Klecio R. Antunes for the figure
production. This research was supported by AFIP and
FAPESP/CEPID (98/14303 3).
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