Afferent pain pathways: a neuroanatomical review

www.elsevier.com/locate/brainres

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].


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].


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.


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].


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.


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].


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,


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].


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].


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).


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.


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).

References

[1] E.D. Al-Chaer, N.B. Lawand, K.N. Westlund, W.D. Willis, Pelvic

visceral input into the nucleus gracilis is largely mediated by the

postsynaptic dorsal column pathway, J. Neurophysiol. 76 (1996)

2675–2690.

[2] E.D. Al-Chaer, N.B. Lawand, K.N. Westlund, Visceral nociceptive

input into the ventral posterolateral nucleus of the thalamus: a new

function for the dorsal column pathway, J. Neurophysiol. 76 (1996)

2661–2674.

[3] E.D. Al-Chaer, K.N. Westlund, W.D. Willis, Nucleus gracilis: an

integrator for visceral and somatic information, J. Neurophysiol. 78

(1997) 521–527.

[4] E.D. Al-Chaer, Y. Feng, W.D. Willis, A role for the dorsal column in

nociceptive visceral input into the thalamus of primates, J. Neuro-

physiol. 79 (1998) 3143–3150.

[5] D. Andrew, A.D. Craig, Spinothalamic lamina I neurons selectively

sensitive to histamine: a central neural pathway for itch, Nat. Neuro-

sci. 4 (2001) 9–10.

[6] D. Andrew, A.D. Craig, Spinothalamic lamina I neurons selectively

responsive to cutaneous warming in the cat, J. Physiol. 537 (2001)

489–495.

[7] V. Andrew, A.D. Craig, Responses of spinothalamic lamina I neurons

to maintained noxious mechanical stimulation in the cat, J. Neuro-

physiol. 87 (2002) 1889–1901.

[8] A.V. Apkarian, T. Shi, Squirrel monkey lateral thalamus: I. Somatic

nociresponsive neurons and their relation to spinothalamic terminals,

J. Neurosci. 14 (1994) 6779–6795.

[9] H. Bester, N. Matsumoto, J.M. Besson, J.F. Bernard, Further evidence

for the involvement of the spinoparabrachial pathway in nociceptive

processes: a c-Fos study in the rat, J. Comp. Neurol. 383 (1997)

439–458.

[10] H. Bester, V. Chapman, J.M. Besson, Physiological properties of the

lamina I spinoparabrachial neurons in the rat, J. Neurophysiol. 83

(2000) 2239–2259.

[11] A. Blomqvist, K.J. Berkeley, A re-examination of the spino-reticulo-

diencephalic pathway in the cat, Brain Res. 579 (1992) 17–31.

[12] A. Blomqvist, E.T. Zhang, A.D. Craig, Cytoarchitectonic and im-

munohistochemical characterization of a specific pain and tempera-

ture relay, the posterior portion of the ventral medial nucleus, in the

human thalamus, Brain 123 (2000) 601–619.

[13] J. Broman, O.P. Ottersin, Cervicothalamic tract terminals are enriched

in glutamate like immunoreactivity: an electron microscopic double

labeling study in the cat, J. Neurosci. 12 (1992) 204–221.

[14] A.G. Brown, D.J. Maxwell, A.D. Short, Receptive fields and in

field afferent inhibition of neurons in the cat’s lateral cervical nuc-

leus, J. Physiol. 413 (1989) 119–137.

[15] J. Bruggemann, T. Shi, A.V. Apkarian, Squirrel monkey lateral tha-

lamus: II. Viscerosomatic convergent representation of urinary blad-

der, colon, and esophagus, J. Neurosci. 14 (1994) 6796–6814.

[16] J. Bruggemann, T. Shi, A.V. Apkarian, Viscerosomatic interactions

in the thalamic ventral posterolateral nucleus (VPL) of the squirrel

monkey, Brain Res. 787 (1998) 269–276.

[17] J. Buritova, J.M. Besson, J.F. Bernard, Involvement of the spinopar-

abrachial pathway in inflammatory nociceptive processes: a c-Fos

protein study in the awake rat, J. Comp. Neurol. 397 (1998) 10–28.

[18] R. Burstein, O. Falkowsky, D. Borsook, A. Strassman, Distinct lat-

eral and medial projections of the spinohypothalamic tract of the rat,

J. Comp. Neurol. 373 (1996) 549–574.

[19] S.W. Cadden, R. Orchardson, The neural mechanisms of oral and

facial pain, Dent. Update 28 (2001) 359–367.

[20] C.Q. Cao, L. Djouhri, A.G. Brown, Lumbosacral spinal neurons in

the cat that are candidates for being activated by collaterals from the

spinocervical tract, Neuroscience 57 (1993) 153–165.

[21] C.A. Caous, B.H. De Souza, C.J. Lindsey, Neuronal connection of

the paratrigeminal nucleus: a topographic analysis of neurons pro-


jecting to bulbar, pontine and thalamic nuclei related to cardiovas-

cular, respiratory and sensor functions, Auton. Neurosci. Basic Clin.

94 (2001) 14–24.

[22] K.L. Casey, The imaging of pain: background and rationale, in: K.L.

Casey, M.C. Bushnell (Eds.), Pain Imaging, 2000, pp. 1–29.

[23] F. Cevero, Sensory innervation of the viscera: peripheral bases of

visceral pain, Physiol. Rev. 74 (1994) 95–138.

[24] M.J. Chandler, S.F. Hobbs, Q.G. Fu, D.R. Kenshalo Jr., R.W. Blair,

R.D. Foreman, Responses of neurons in ventroposterolateral nucleus

of primate thalamus to urinary bladder distension, Brain Res. 571

(1992) 26–34.

[25] C.D. Chapman, W.S. Ammons, R.D. Foreman, Raphe magnus inhi-

bition of feline T1–T4 spinoreticular tract cell responses to visceral

and somatic inputs, J. Neurophysiol. 53 (1985) 773–785.

[26] K.D. Cliffer, R. Burstein, G.J. Giesler Jr., Distributions of spino-

thalamic, spinohypothalamic and spinotelencephalic fibers revealed

by anterograde transport oPHA-L in rats, J. Neurosci. 11 (1991)

852–868.

[27] A.D. Craig, Spinal distribution of ascending lamina I axons ante-

rogradely labeled with phaseolus vulgaris leucoagglutinin (PHA-L)

in the cat, J. Comp. Neurol. 313 (1991) 377–393.

[28] A.D. Craig, J.O. Dostrovsky, Differential projections of thermore-

ceptive and nociceptive lamina I trigeminothalamic and spinothala-

mic neurons in the cat, J. Neurophysiol. 86 (2001) 856–870.

[29] A.D. Craig, J. Broman, A. Blomqvist, Lamina I spinocervical tract

terminations in the medial part of the lateral cervical nucleus in the

cat, J. Comp. Neurol. 322 (1992) 99–110.

[30] A.D. Craig, M.C. Bushnell, M.C. Zhang, A thalamic nucleus specific

for pain and temperature sensation, Nature 372 (1994) 770–773.

[31] A.D. Craig, K. Krout, D. Andrew, Quantitative responses character-

istics of thermoreceptive and nociceptive lamina I spinothalamic

neurons in the cat, J. Neurophysiol. 86 (2001) 1459–1480.

[32] R.J. Dado, J.T. Katter, G.J. Giesler Jr., Spinothalamic and spinohy-

pothalamic tract neurons in the cervical enlargement of rats: I. Loca-

tions of antidromically identified axons in the thalamus and

hypothalamus, J. Neurophysiol. 71 (1994) 959–980.

[33] R.J. Dado, J.T. Katter , G.J. Giesler Jr., Spinothalamic and spinohy-

pothalamic tract neurons in the cervical enlargement of rats: III.

Locations of antidromically identified axons in the cervical cord

white matter, J. Neurophysiol. 71 (1994) 1003–1021.

[34] A.S. Day, J.H. Lue, W.Z. Sun, J.Y. Shieh, C.Y. Wen, A beta-fiber

intensity stimulation of chronically constricted median nerve induces

c-fos expression in thalamic projection neurons of the cuneate nu-

cleus in rats with behavioral signs of neuropathic pain, Brain Res.

895 (2001) 194–203.

[35] T. De Broucker, P. Cesaro, J.C. Willer, D. Le Bars, Diffuse noxious

inhibitory controls in man. Involvement of the spinoreticular tract,

Brain 113 (1990) 1223–1234.

[36] S.W. Derbyshire, A.K. Jones, F. Creed, Cerebral responses to nox-

ious thermal stimulation in chronic low back pain patients and nor-

mal controls, NeuroImage 16 (2002) 158–168.

[37] Y.Q. Ding, B.Z. Qin, J.S. Li, N. Mizuno, Induction of c-Fos-like

protein in the spinoparabrachial tract-neurons locating within the

sacral parasympathetic nucleus in the rat, Brain Res. 659 (1994)

283–286.

[38] L. Djouhri, E. Jankowska, Indications for coupling between feline

spinocervical tract neurons and midlumbar interneurons, Exp. Brain

Res. 119 (1998) 39–46.

[39] L. Djouhri, Z. Meng, A.G. Brown, A.D. Short, Electrophysiologi-

cal evidence that spinomesencephalic neurons in the cat may be

excited via spinocervical tract collaterals, Exp. Brain Res. 116

(1997) 477–484.

[40] W.K. Dong, S.W. Harkins, B.T. Ashleman, Origins of cat somato-

sensory far-field and early near-field evoked potentials, Electroence-

phalogr. Clin. Neurophysiol. 53 (1982) 143–165.

[41] J.O. Dostrovsky, A.D. Craig, Cooling-specific spinothalamic neu-

rons in the monkey, J. Neurophysiol. 76 (1996) 3656–3665.

[42] P.M. Dougherty, A. Schwartz, F.A. Lenz, Responses of primate

spinomesencephalic tract cells intradermal capsaicin, Neuroscience

90 (1999) 1377–1392.

[43] J.W. Downie, D.G. Ferrington, L.S. Sorkin, W.D. Willis Jr., The

primate spinocervicothalamic pathway: responses of cells of the

lateral cervical nucleus and spinocervical tract to innocuous and

noxious stimuli, J. Neurophysiol. 59 (1988) 861–885.

[44] D. Dubuisson, Effect of dorsal-column stimulation on gelatinosa

and marginal neurons of cat spinal cord, J. Neurosurg. 70 (1989)

257–265.

[45] T.P. Enevoldson, G. Gordon, Spinocervical neurons and dorsal horn

neurons projecting to the dorsal column nuclei through the dorso-

lateral fascicle: a retrograde HRP study in the cat, Exp. Brain Res. 75

(1989) 621–630.

[46] A.C. Ericson, A. Blomqvist, K. Krout, Fine structural organization

of spinothalamic lamina I terminations in the nucleus submedius of

the cat, J. Comp. Neurol. 371 (1996) 497–512.

[47] R.D. Foreman, R.W. Blair, R.N. Weber, Viscerosomatic convergence

onto T2–T4 spinoreticular, spinoreticular –spinothalamic, and spino-

thalamic tract neurons in the cat, Exp. Neurol. 85 (1984) 597–619.

[48] C. Gauriau, J.F. Bernard, Pain pathways and parabrachial circuits in

the rat, Exp. Physiol. 87 (2002) 251–258.

[49] K. Grottel, D. Bukowska, J. Huber, J. Celichowski, Distribution of

the sacral neurons of origin of the ascending spinal tracts with axons

passing through the lateral funiculi of the lowermost thoracic seg-

ments: an experimental HRP study in the cat, Neurosci. Res. 34

(1999) 67–72.

[50] L.H. Haber, B.D. Moore, W.D. Willis, Electrophysiological response

properties of spinoreticular neurons in the monkey, J. Comp. Neurol.

207 (1982) 75–84.

[51] R.M. Hirshberg, E.D. Al-Chaer, N.B. Lawand, K.N. Westlund, W.D.

Willis, Is there a pathway in the posterior funiculus that signals

visceral pain? Pain 67 (1996) 291–305.

[52] J. Huber, K. Grottel, W. Mrowczynski, Spinoreticular neurons in the

second sacral segment of the feline spinal cord, Neurosci. Res. 34

(1999) 59–65.

[53] W.D. Hutchison, M.A. Luhn, R.F. Schmidt, Responses of lateral

thalamic neurons to algesic chemical stimulation of the cat knee

joint, Exp. Brain Res. 101 (1994) 452–464.

[54] J.L. Hylden, H. Hayashi, R. Dubner, Physiology and morphology of

the lamina I spinomesencephalic projection, J. Comp. Neurol. 247

(1986) 505–515.

[55] T.S. Jensen, T.L. Yaksh, Brainstem excitatory amino acid receptors

in nociception: microinjection mapping and pharmacological char-

acterization of glutamate-sensitive sites in the brainstem associated

with algogenic behavior, Neuroscience 46 (3) (1992) 535–547.

[56] J.T. Katter, R. Burstein, G.J. Giesler Jr., The cells of origin of the

spinohypothalamic tract in cats, J. Comp. Neurol. 303 (1991)

101–112.

[57] J.T. Katter, R.J. Dado, E. Kostarczyk Jr., G.J. Giesler, Spinothalamic

and spinohypothalamictract neurons in the sacral spinal cord of rats:

II. Responses to cutaneous and visceralstimuli, J. Neurophysiol. 75

(1996) 2606–2628.

[58] G. Kayalioglu, B. Robertson, K. Kristensson, Nitric oxide synthase

and interferon-gama receptor immunoreactivities in relation to as-

cending spinal pathways to thalamus, hypothalamus, and the peri-

aqueductal grey in the rat, Somatosens. Motor Res. 16 (1999)

280–290.

[59] G.A. Kevetter, W.D. Willis, Collaterals of spinothalamic cells in the

rat, J. Comp. Neurol. 215 (1983) 453–464.

[60] G.A. Kevetter, L.H. Haber, R.P. Yezierski, J.M. Chung, R.F. Martin,

W.D. Willis, Cells of origin of the spinoreticular tract in the monkey,

J. Comp. Neurol. 207 (1982) 61–74.

[61] Y. Kobayashi, Distribution and morphology of spinothalamic tract

neurons in the rat, Anat. Embryol. (Berl.) 197 (1998) 51–67.

[62] E. Kostarczyk, X. Zhang Jr., G.J. Giesler, Spinohypothalamic tract

neurons in the cervical enlargement of rats: locations of antidromi-


cally identified ascending axons and their collateral branches in the

contralateral brain, J. Neurophysiol. 77 (1997) 435–451.

[63] C.J. Labuda, T.D. Cutler, P.M. Dougherty, P.N. Fuchs, Mechanical

and thermal hypersensitivity develops following kainite lesion of the

ventral posterior lateral thalamus in rats, Neurosci. Lett. 290 (2000)

79–83.

[64] A. Levante, P. Cesaro, D. Albe-Fessard, Electrophysiological

and anatomical demonstration of a bulbar relayed pathway to-

wards the medial thalamus in the rat, Neurosci. Lett. 38 (1983)

139–144.

[65] Q.J. Li, G.W. Lu, The property of peripheral input of projection

neurons in the spinal cord dorsal horn, Sci. China, Ser B Chem. Life

Sci. Earth Sci. 32 (1989) 1224–1232.

[66] J.L. Li, T. Kaneko, R. Shigemoto, N. Mizuno, Distribution of trige-

minohypothalamic and spinohypothalamic tract neurons displaying

substance P receptor-like immunoreactivity in the rat, J. Comp. Neu-

rol. 378 (1997) 508–521.

[67] G.W. Lu, Spinocervical tract-dorsal column postsynaptic neurons: a

double-projection neuronal system, Somatosens. Motor Res. 6 (1989)

445–454.

[68] G.W. Lu, E.T. Yang, The morphology of cat spinal neurons projec-

ting to both the lateral cervical nucleus and the dorsal column nuclei,

Neurosci. Lett. 101 (1989) 29–34.

[69] R.B. Lynn, Mechanisms of esophageal pain, Am. J. Med. 92 (1992)

11s–19s.

[70] R. Melzak, P.D. Wall, Pain mechanisms: a new theory, Science 150

(1965) 971–979.

[71] D. Menetrey, A. Chaouch, J.M. Besson, Location and properties of

dorsal horn neurons at origin of spinoreticular tract in lumbar en-

largement of the rat, J. Neurophysiol. 44 (1980) 862–877.

[72] D. Menetrey, A. Chaouch, D. Binder, J.M. Besson, The origin of the

spinomesencephalic tract in the rat: an anatomical study using the

retrograde transport of horseradish peroxidase, J. Comp. Neurol. 20

(1982) 193–207.

[73] Z. Meng, G. Lu, Projection linkage from spinal neurons to both

lateral cervical nucleus and solitary tract nucleus in the cat, Biol.

Signals Recept. 9 (2000) 38–44.

[74] S. Mense, Basic neurobiologic mechanisms of pain and analgesia,

Am. J. Med. 75 (1983) 4–14.

[75] H. Merskey, N. Bogduk, Classification of Chronic Pain: Descrip-

tions of Chronic Pain Syndromes and Definitions of Pain Terms,

IASP Press, Seattle, 1994, p. 210.

[76] M.J. Millan, The induction of pain: an integrative review, Prog.

Neurobiol. 57 (1999) 1–164.

[77] L. Monconduit, L. Bourgeais, J.F. Bernard, L. Villanueva, Systemic

morphine selectively depresses a thalamic link of widespread noci-

ceptive inputs in the rat, Eur. J. Pain 6 (2002) 81–87.

[78] T.J. Morrow, P.E. Paulson, K.L. Brewer, Chronic, selective forebrain

responses to excitotoxic dorsal horn injury, Exp. Neurol. 161 (2000)

220–226.

[79] P.W. Nathan, Pain, Br. Med. Bull. 33 (1977) 149–156.

[80] P.W. Nathan, M. Smith, P. Deacon, The crossing of the spinothala-

mic tract, Brain 124 (2001) 793–803.

[81] T.J. Ness, Evidence for ascending visceral nociceptive information

in the dorsal midline and lateral spinal cord, Pain 87 (2000) 83–88.

[82] Y. Nishikawa, H. Yoshimoto, A. Mori, S. Mukunoki, K. Kakudo, Y.

Yoshida, Functional properties of nociceptive neurons in the nucleus

centralis lateralis of the cat thalamus, J. Osaka Dent. Univ. 33 (1999)

65–73.

[83] R. Noble, A.D. Short, Spatial spread of in-field afferent inhibition in

the cat’s spinocervical tract, J. Physiol. 413 (1989) 107–118.

[84] C. Ohye, Stereotactic treatment of central pain, Stereotact. Funct.

Neurosurg. 70 (1998) 71–76.

[85] P.E. Paulson, K.L. Casey, T.J. Morrow, Long-term changes in

behavior and regional cerebral blood flow associated with

painful peripheral mononeuropathy in the rat, Pain 95 (2002)

31–40.

[86] S. Pezet, B. Ont Niente, G. Grannec, Chronic pain is associated with

increased TrKA immunoreactivity in spinoreticular neurons, J. Neu-

rosci. 19 (1999) 5482–5492.

[87] N. Picard, P.L. Strick, Motor areas of the medial wall: a review of

their location and functional activation, Cereb. Cortex 6 (1996)

342–353.

[88] D.D. Price, Psychological and neural mechanisms of the affective

dimension of pain, Science 288 (2000) 1769–1772.

[89] I. Rektor, P. Kanovsky, M. Bares, J. Louvel, M. Lamarche, Event-

related potentials, CNV, readiness potential, and movement accom-

panying potential recorded form posterior thalamus in human sub-

jects, Neurophysiol. Clin. 31 (2001) 253–261.

[90] W.A. Roberts, S.A. Eaton, T.E. Salt, Widely distributed GABA-

mediated afferent inhibition processes within the ventrobasal thala-

mus of rat and their possible relevance to pathological pain states and

somatotopic plasticity, Exp. Brain Res. 89 (1992) 363–372.

[91] G. Rosen, K. Hugdahl, L. Ersland, Different brain areas activated

during imagery of painful and non-painful ‘finger movements’ in a

subject with an amputated arm, Neurocase 7 (2001) 255–260.

[92] H.G. Schaible, B.D. Grubb, Afferent and spinal mechanisms of joint

pain, Pain 55 (1993) 5–54.

[93] R.D. Skinner, R. Nelson, M. Griebel, Ascending projections of long

descending propriospinal tract (LDPT) neurons, Brain Res. Bull. 22

(1985) 253–258.

[94] M. Sun, Y. Li, J. Zhang, J. Bian, Effects of noxious stimuli on the

discharge of pain-excitation neurons and pain-inhibition neurons in

the nucleus ventralis posterolalis of thalamus in the rat and a mod-

ulating action of electroacupuncture on its electric activities, Zhenci

Yanjiu 16 (1991) 19–22.

[95] M.J. Teixeira, A Lesao do Trato de Lissauer e do Corno Posterior da

Substancia Cinzenta da Medula Espinhal e a Estimulac�ao do Sistema

Nervoso Central para o Tratamento da Dor por Desaferentacao, Tese

de doutoramento. Sao Paulo, FMUSP, 1990 pp. 1–54.

[96] L. Timmermann, M. Ploner, K. Haucke, Differential coding of pain

intensity in the human primary and secondary somatosensory cortex,

J. Neurophysiol. 86 (2001) 1499–1503.

[97] R.D. Treede, D.R. Kenshalo, R.H. Gracely, The cortical representa-

tion of pain, Pain 79 (1999) 105–111.

[98] C.C. Wang, K.N. Westlund, Responses of rat dorsal column neu-

rons to pancreatic nociceptive stimulation, NeuroReport 12 (2001)

2527–2530.

[99] H.R. Weng, J.I. Lee, F.A. Lenz, A. Schwartz, C. Vierck, L. Rowland,

P.M. Dougherty, Functional plasticity in primate somatosensory tha-

lamus following chronic lesion of the ventral lateral spinal cord,

Neuroscience 101 (2000) 393–401.

[100] M. Wiberg, A. Blomqvist, The spinomesencephalic tract in the cat:

its cells of origin and termination pattern as demonstrated by the

intraaxonal transport method, Brain Res. 291 (1984) 1–18.

[101] W.D. Willis Jr., Pain pathways in the primate, Prog. Clin. Biol. Res.

176 (1985) 117–133.

[102] W.D. Willis, K.N. Westlund, Neuroanatomy of the Pain System that

modulate pain, J. Clin. Neurophysiol. 14 (1997) 2–31.

[103] W.D. Willis, K.A. Sluka, H. Rees, Cooperative mechanisms of neu-

rotransmitter action in central nervous sensitization, Prog. Brain Res.

110 (1996) 151–166.

[104] W.D. Willis Jr., X. Zhang, C.N. Honda, G.J. Giesler Jr., Pain 92

(2001) 267–276.

[105] H. Yamamura, K. Iwata, Y. Tsuboi, Morphological and electrophy-

siological properties of ACCx nociceptive neurons in rats, Brain

Res. 735 (1996) 83–92.

[106] R.P. Yezierski, Spinomesencephalic tract: projections from the lum-

bosacral spinal cord of the rat, cat, and monkey, J. Comp. Neurol.

267 (1988) 131–146.

[107] R.P. Yezierski, Effects of midbrain and medullary stimulation on

spinomesencephalic tract in the cat, J. Neurophysiol. 63 (1990)

240–255.

[108] R.P. Yezierski, J.G. Broton, Functional properties of spinomesence-


phalic tract (SMT) cells in the upper cervical spinal cord of the cat,

Pain 45 (1991) 187–196.

[109] R.P. Yezierski, C.M. Mendez, Spinal distribution and collateral pro-

jections of rats spinomesencephalic tract cells, Neuroscience 44

(1991) 113–130.

[110] R.P. Yezierski, R.H. Schwartz, Response and receptive-field proper-

ties of spinomesencephalic tract cells in the cat, J. Neurophysiol. 55

(1986) 76–96.

[111] E.T. Zhang, A.D. Craig, Morphology and distribution of spinotha-

lamic lamina I neurons in the monkey, J. Neurosci. 17 (1997)

3274–3284.

[112] D.X. Zhang, S.M. Carlton, L.S. Sorkin, W.D. Willis, Collaterals

of primate spinothalamic tract neurons to the periaqueductal gray,

J. Comp. Neurol. 296 (1990) 277–290.

[113] X. Zhang, H.N. Wenk, A.P. Gokin, C.N. Honda, G.J. Giesler Jr.,

Physiological studies of spinohypothalamic tract neurons in the

lumbar enlargement of monkeys, J. Neurophysiol. 82 (1999)

1054–1058.

[114] X. Zhang, C.N. Honda, G.J. Giesler Jr., Position of spinothalamic

tract axons in upper cervical spinal cord of monkeys, J. Neurophy-

siol. 84 (2000) 1180–1185.

[115] X. Zhang, A.P. Gokin, G.J. Giesler Jr., Responses of spinohypotha-

lamic tract neurons in the thoracic spinal cord of rats to somatic

stimuli and to graded distention of the bile duct, Somatosens. Motor

Res. 19 (2002) 5–17.

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Afferent pain pathways: a neuroanatomical review