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Rapport : Douleurs lombaires postopératoires

Anatomy, physiology and neurobiology of the nociception:

A focus on low back pain (part A)
Bases anatomiques, physiologiques et neurobiologiques de la nociception,
appliquées à la pathologie douloureuse lombaire (partie A)
P. Mertens a,b , S. Blond c , R. David d,e , P. Rigoard d,e,f,∗
a
Department of Neurosurgery, Lyon University hospital, 69677 Lyon cedex, France
b
Laboratory of Anatomy, Faculty of Medicine, 69677 Lyon cedex, France
c
Department of Neurosurgery, Lille University Hospital, 59037 Lille cedex , France
d
Service de neurochirurgie, unité rachis et neurostimulation, Poitiers University Hospital, 2, rue de la Milétrie, 86021 Poitiers cedex, France
e 3
N Lab: Neuromodulation & Neural Networks, Poitiers University Hospital, Poitiers, France
f
Inserm CIC 802, 86021 Poitiers, France

a r t i c l e i n f o a b s t r a c t

Article history: Introduction. – The treatment of Failed Back Surgery Syndrome (FBSS) remains a challenge for pain
Received 1st July 2014 medicine due to the complexity in the interactions between [1] a residual mechanical pain after surgery
Received in revised form 5 September 2014 and, [2] a progressive transition into chronic pain involving central nervous system plasticity and molec-
Accepted 21 September 2014
ular reorganization. The aim of this paper is to provide a fundamental overview of the pain pathway
Available online xxx
supporting the nociceptive component of the back pain.
Methods. – Literature searches included an exhaustive review of 643 references and 74 book chapters
Keywords:
updated by searching the major electronic databases from 1930 to August 2013.
Pain perception
Nociception
Results. – Pain input is gathered by the peripheral fibre from the innervated tissue’s environment and
Pathophysiology relayed by two contiguous central axons to the brain, via the spinal cord. At this level, it is possible to
Pain characterize physical pain and emotional pain. These are supported by two different pathways, encoding
Back pain two dimensions of pain perception: In Neo-spino-thalamic pathway, the wide dynamic range neuron
Failed back surgery syndrome system is able to provide the information needed for mapping the “sensory-discriminative” dimension
of pain. The second projection system (Paleo-spino-thalamic pathway) also involves the ventromedial
thalamus but projects to the amygdala, the insula and the anterior cingulate cortex. These areas are
associated with emotionality and affect.
Conclusion. – The mechanical component of FBSS cannot be understood unless the functioning of the pain
system is known. But ultimately, the highly variable nature of back pain expression among individuals
would require a careful pathophysiological dissection of the potential generators of back pain to guide
pain management strategies.
© 2014 Elsevier Masson SAS. All rights reserved.

r é s u m é

Mots clés : Introduction. – La prise en charge des lombo-radiculalgies postopératoires (LRPO) reste un défi pour la
Perception de la douleur médecine de la douleur, notamment en raison de la complexité des interactions existant entre [1] la com-
Nociception posante douloureuse nociceptive résiduelle d’origine multi-factorielle et, [2] la transition possible vers
Physiopathologie une douleur chronique, impliquant une réorganisation progressive, plastique et moléculaire du système
Douleur aiguë
nerveux central. Le but de cet article est de décrire les mécanismes fondamentaux des voies de la douleur
Lombalgies
caractérisant la composante nociceptive des lombalgies postopératoires.
Lombo-radiculalgies chroniques
post-opératoires Méthodes. – Les recherches bibliographiques ont inclus une revue exhaustive de 643 références et
74 chapitres de livres mis à jour en consultant les principales bases de données électroniques de 1930 à
août 2013.

∗ Corresponding author. Service de neurochirurgie, unité rachis et neurostimulation, Poitiers University Hospital, 2, rue de la Milétrie, 86021 Poitiers cedex, France.
E-mail address: philipperigoard@yahoo.fr (P. Rigoard).

http://dx.doi.org/10.1016/j.neuchi.2014.09.001
0028-3770/© 2014 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Mertens P, et al. Anatomy, physiology and neurobiology of the nociception: A focus on low back pain
(part A). Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.09.001
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Résultats. – Le message douloureux nociceptif provient d’une stimulation des nocicepteurs périphériques
de l’environnement tissulaire. Il est véhiculé par la fibre périphérique, relayée par deux axones cen-
traux contigus jusqu’au cerveau, par l’intermédiaire de la moelle épinière. À ce niveau, il est possible de
caractériser une douleur physique et une douleur dite « émotionnelle ». Ces deux dimensions dans la per-
ception de la douleur sont prises en charge par deux voies différentes : la voie néo-spino-thalamique
reposant sur un système de neurones de gamme dynamique étendue (neurones WDR) est capable
de fournir au thalamus, puis au cortex les informations nécessaires pour cartographier la dimension
« sensori-discriminative » de la douleur. La voie paléo-spino-thalamique implique également le thala-
mus ventro-médian mais projette sur l’amygdale, l’insula et le cortex cingulaire antérieur. Ces aires sont
associées à l’émotivité et à l’affect.
Conclusion. – La composante mécanique des LRPO ne peut être appréhendée sans une bonne connaissance
des voies de la nociception. Néanmoins, la nature éminemment variable de l’expression clinique des
lombalgies nécessitera une dissection physiopathologique minutieuse des générateurs potentiels de ces
lombalgies, afin d’orienter les stratégies de prise en charge de ces douleurs vers les options les plus
adaptées au mécanisme lésionnel.
© 2014 Elsevier Masson SAS. Tous droits réservés.

1. Introduction • Poitiers Anatomy Library (Department of Morphology, Poitiers

The understanding of pain perception is essential for optimal
diagnosis and treatment of the back pain component in Failed Back
Surgery Syndrome (FBSS) [1]. Its treatment remains a challenge for
pain medicine. One of the main reasons arises from the extreme
complexity in the interactions between 1) a residual mechani-
cal or inflammatory pain after surgery (which both correspond
to a nociceptive component and involve the physiological pain
processing system) and, 2) a progressive transition into chronic
pain involving Central Nervous System (CNS) plasticity and molec-
ular reorganization. In order to improve functional outcomes in
these difficult-to-treat patients, advances in our understanding of
the underlying pathophysiological mechanisms have major impli-
cations for the management of both nociceptive pain generators
and chronic back pain component. On one hand, missing a potential
etiological conflict that could require further surgery, by focusing
on chronic pain aspects would irremediably lead to the failure of
“palliative” treatments. On the other hand, because it has been
established that intense noxious stimulation produces autonomic
sensitization of CNS neurons within time, it is possible to direct
treatments not only at the site of peripheral tissue damage, but
also at the site of central changes [2]. The therapeutic plan has to
be discussed with the patient, only after a meticulous “pathophy-
siological investigation” of all potential back pain generators.
Pathophysiological changes in the pain system and associated
changes in pain perception cannot be understood unless the func-
tioning of the pain system under normal conditions is known. The
aim of this paper is to provide a fundamental overview of the pain
pathway supporting the nociceptive component of the back pain
(Part A). The potential back pain generators, accessible to etiologi-
cal treatments in FBSS patients will be reviewed in the next article
(Part B) [3].
2. Methods
2.1. Literature searches
References and book chapters were initially identified (Fig. 1)
from a systematic review of the electronic literature and of all path-
ophysiology, anatomy and physiology textbooks available in the
following medical libraries:
• Paris Medical Library (Université Descartes, Paris 5, rue de l’Ecole
de Médecine, 75006 Paris, France);
• Paris Anatomy Library (Anatomy Laboratory, Université des
Saints-Pères, Paris 6e , Fr);
Medical College, rue de la Milètrie, 86000 Poitiers, Fr);
• UIC Library of Health Sciences (University of Illinois at Chicago,
1912 Polk St., Chicago, US);
• Dorsch Neuroscience Library (Institute of Neurology and Neu-
ropsychiatry, 712 S Wood St., Chicago, US), performed by some
of the authors (RD, PR).
This list of book chapters was updated by searching the
following electronic databases from 1930 to August 2013: MED-
LINE (Ovid), MEDLINE InProcess (Ovid), EMBASE (Ovid), Cochrane
Library (Cochrane Central Register of Controlled Trials (CENTRAL),
Health Technology Assessment (HTA) databases. The search strat-
egy was developed in order to maximise sensitivity of article
identification and was not restricted by language, or any other
limits. Citation lists in the chapters and papers consulted and
recent systematic reviews were checked for additional references.
Two reviewers (RD and PR) independently scanned all titles and
abstracts and identified potentially relevant articles for retrieval.
Full-text copies of papers were obtained, analysed and summa-
rized.
2.2. Keywords
The following keywords were used for these searches: path-
ophysiology; pain; nociception; neuropathic pain; inflammatory
pain; central sensitization; chronic pain; anatomy; neuroanatomy;
low back pain; failed back surgery syndrome; pain generators;
triggers; facet joints; sacroiliac joint; muscle pain; myogenic syn-
drome; spine; biomechanics; molecular mechanisms; discogenic
pain; spine instability; spinal fusion; sagittal imbalance; dorsal
horn; bulbospinal projections; ascending tracts; pain receptors;
nociceptors; CNS afferents; CNS efferents; neurobiology; neuro-
matrix; gate control; pathological pain; physiological pain; pain
threshold; pain tolerance; back pain; mechanisms of action;
neurostimulation; spinal cord stimulation; peripheral nerve stim-
ulation; motor cortex stimulation; cordotomy; myelotomy; DREZ;
pain pathways.
2.3. Literature analysis
Some well-written textbooks on pain management, pathophy-
siology and anatomy were particularly useful. The synopsis of
Waldman’s textbook on pain management [4] and the following
books [5–10] largely inspired this review and, whenever possible,
the reader is referred to the original publications for a more detailed
discussion.

Please cite this article in press as: Mertens P, et al. Anatomy, physiology and neurobiology of the nociception: A focus on low back pain
(part A). Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.09.001
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Fig. 1. Literature searches methodology.

Méthodologie de recherche documentaire.

3. The nociception processing system (the example of back • the efferent pathways that descend from the CNS back to the
pain) spinal cord.

Whatever anatomical structure of the back, the noxious stimu-
lus is arising from (ligaments, bone, joints, muscles, nervous tissue,
cutaneous surface, etc.), the physiologic mechanisms involved in
the mechanical component of the residual back pain following a
spine surgery are termed as nociception [5,6]. Nociception can be
divided in four stages: transduction, transmission, perception, and
modulation [6].
Transduction is the process of converting stimuli to neuronal
action potentials at the sensory receptor. Transmission refers to
the propagation of action potentials along neurons from peripheral
receptor to the spinal cord and then centrally to the brain. Percep-
tion occurs contemporarily to the signal integration at the brain
cortical level. This process involves then several cortical regions,
named as pain matrix, which influence all the components of the
pain sensation. The complex mechanism whereby synaptic trans-
mission of painful signals is modified is called modulation.
Three portions of the nervous system are responsible for the
sensation and perception of pain:
• the afferent pathways, which begin in the peripheral nerve sys-
tem (PNS), travel to the spinal level in the dorsal horn and then
ascend to higher centers in the central nervous system (CNS);
• the integration centers located in the brain stem, midbrain, dien-
cephalon, and cerebral cortex;
3.1. Pain transduction: primary afferents
Pain is initiated by events that occur on the skin, or in deep
tissues such as muscles, bones, or viscera and mediated trough
specialized primary afferent neurons [6]. These sensory neurons
involve their terminals called “nociceptors” to constantly survey
the environment, detect any alarm signal and to respond rapidly
to mechanical, thermal, or chemical stimuli that are of sufficient
intensity to cause tissue damage or of quality that indicates existing
damage tissue. Upon activation, they transduce this information via
action potentials and neurotransmitter release through the spinal
cord dorsal horn for further transmission to the supra-spinal struc-
tures and finally the brain (Fig. 2).
3.1.1. Fibres classes
There is a process of sensory neurons (named as “glomerulus”)
that bifurcates into peripheral fibre in dorsal root ganglia and a
central axon at the spinal cord interface. Sensory input is gathered
by the peripheral fibre from the innervated tissue’s environment.
Sensory input is relayed by the central axon to the brainstem or
spinal cord. As outlined in Fig. 2, sensory axons are classified accord-
ing to their state of myelination, conduction velocity and diameter.
Ordinarily, conduction velocity alters directly with axon diameter
and the presence of myelination [11].

Please cite this article in press as: Mertens P, et al. Anatomy, physiology and neurobiology of the nociception: A focus on low back pain
(part A). Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.09.001
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Fig. 2. Diagram showing the anatomo-physiological organization of the different classes of fibres and their connections at the dorsal horn level.
Schéma montrant l’organisation anatomo-physiologique des différentes catégories de fibres et de leurs connexions au niveau de la corne dorsale.
Graphic conception: K. Nivole, R. David and P. Rigoard, adapted from Waldman et al., 2011.
Therefore, Aß axons are large and myelinated and they con-
duct rapidly; A∂ axons have a smaller diameter and are myelinated
[12] and conduct slower; and C-fibres are small, unmyelinated and
conduct much more slowly [13].
3.1.2. Properties of primary afferent function
As seen with the Pacini corpuscle found on the terminals of large
afferents, nerve endings can be morphologically specialized [11].
The mechanical distortion of the structure is translated by the spe-
cialized structure into a transient opening of sodium channels in
the axon, thus bringing about a succinct burst of action potential
(see later).
On the other hand, the axon terminal may be classified as a “free
nerve ending” whereby it displays no evident physical structure
showing extensive branching as they proceed distally. These end-
ings are ordinarily associated with small, unmyelinated C-fibres
[14,15]. The simplicity of the nerve is misleading given its name.
A range of stimuli including thermal, chemical and mechanical can
be transduced. Low-threshold mechanical stimuli (i.e. mechanore-
ceptors) activate the Aß (group II) fibres. Fibres that conduct at A∂
velocity may pertain to populations that are high or low thresh-
old and mechanical or thermal. A∂ fibres can show activation at
temperatures that are moderately noxious and their firing rates
can increase to very high temperatures (52 ◦ C–55 ◦ C). The largest
population of afferent axons are slowly conducting afferents. These
afferents are called “C-polymodal nociceptors” and are commonly
activated by high-threshold thermal, chemical and mechanical
stimuli [11].
Three important characteristics are revealed from the recording
of single peripheral afferent fibres. Firstly, with a lack of stimula-
tion, “spontaneous” afferent traffic occurs. Accordingly, the system
operates on a very high signal-to-noise ratio.
Secondly, with rising intensities of applicable stimulus, regard-
less of fibre type examined, the more intense the stimulus, the
larger the depolarization of the terminal and the more frequently
the axon will discharge.
Thirdly, dependant on the stimulus modality, different axons
may respond more efficiently.
Please cite this article in press as: Mertens P, et al. Anatomy, physiology and neurobiology of the nociception: A focus on low back pain
(part A). Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.09.001
3.1.3. Electrophysiological characterization of nociceptors
As touched above, nociceptors are often subclassified with
respect to three physiological criteria [16]:
• the conduction velocity of their parent axon (i.e. unmyelinated
C-fibre afferents versus myelinated I-fibre afferents);
• the stimulus modalities that evoke a response (i.e. mechanical,
heat, or chemical);
• the temporal characteristics of their response to a stimulus
modality (rapid versus slow response).
Activation of one branch of the nociceptor terminal by the injury
leads to orthodromic action potential propagation into the parent
axon as well as antidromic propagation into other branches [16].
The antidromic action potentials lead to the release of vasoactive
neuropeptides (such as substance P and CGRP) that are found in
terminal receptors [17,18]. Recent evidence suggests that mechani-
cally insensitive afferents may play a major role in the development
of vasodilatation (or flare), often surrounding the painful area, espe-
cially after chemical stimuli such as capsaicin or histamine [19].
3.1.4. Afferents with high thresholds and pain behaviour
It is indicated by correlated behavioural and electrophysiologic
evidence that information that generates a pain sensation enters
the central nervous system by the activation of small-diameter,
myelinated (group III-A or A∂) or unmyelinated (group IV or C)
afferents [11]. These polymodal nociceptors have a significant char-
acteristic in that they are also readily activated in a concentration-
dependant form by specific agents released into the chemical
milieu [11]. Such agents, released from local injured cells or inflam-
matory cells, include a variety of amines (5-hydroxytryptamine,
histamine), lipid mediators (prostaglandins), kinins (bradykinin),
acidic pH, cytokines (interleukin-1ß) and enzymes (trypsin) [16].
This working may serve the mechanism of activating afferents post-
acute injury.
Under certain conditions, low-intensity tactile or thermal
stimuli may, in fact, generate a pain state. Hyperalgesia is the name
given to the atypical association between non-injurious stimuli and
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pain. If it involves light mechanical stimuli it is referred to as tactile
allodynia.
Two practical examples may be cited:
heightened tactile and thermal sensitivity from local tissue
injury such as sunburn;
and more practically, peripheral nerve injury causing indispo-
sition to light touch. These aspects will be discussed in a separate
paper [20].
3.1.5. Molecular mechanisms of nociceptive signal transduction
3.1.5.1. Molecular detection of noxious chemical stimuli. It has been
shown by electrophysiological and pharmacological studies of cul-
tured nociceptive neurons that certain agents (e.g. protons and
vanilloid compunds) directly depolarize nociceptive neurons by
triggering the opening of cation channels permeable to sodium
and/or calcium [16]. Capsaicin possess a homovanillic acid moi-
ety [21], which binds selectively to receptor sites located on the
terminals of C-fibre nociceptors, triggers the influx of sodium
and calcium, and thereby initiate nociceptive transmission, and
ultimately pain [22]. In contrast, agents such as bradykinin [23],
prostanglandin E2 [24] and nerve growth factor [25] act on G
protein-coupled receptors and receptor tyrosine kinases, respec-
tively, to trigger intracellular signaling cascades that in turn
sensitize depolarizing channels [26]. Still other agents (e.g. gluta-
mate, acetylcholine, and adenosine triphosphate) activate both ion
channels and G protein-coupled receptors to produce a wide range
of direct and indirect excitatory effects [8].
3.1.5.2. Transduction of painful mechanical stimuli. Intense
mechanical stimuli such as pinching a nerve or overloading a
lumbar articular capsule are examples of familiar cause of pain.
Despite this fact, relatively little is known about the molecular
mechanisms underlying nociceptive mechano-transduction [16].
In a subset of cultured sensory neurons, the direct application of
mechanical force evokes non-selective cationic transmembrane
currents [27]. A number of candidate mechanosensory ion chan-
nels have been identified, including members of the ASIC [28], TRP
[29] and TREK [30] families.
3.1.6. Beyond depolarization: spike initiation, action potential
propagation, and neurotransmitter release
Neurotransmission by primary afferent nociceptors requires not
only that noxious stimuli are converted into an electrical signal (i.e.
membrane depolarization), but also that this information is trans-
mitted to the spinal cord [16]. At the level of the peripheral fibre,
this process requires several additional steps generally referred
to as spike initiation, spike propagation and transmitter release
(Fig. 3). Each of these steps requires a number of distinct ion chan-
nels precisely positioned at discrete sites throughout the plasma
membrane. The interrelationship between cyto-architecture and
ion channel composition or properties of nociceptors results in an
extraordinary capacity to encode the spatial, temporal, and inten-
sity properties of noxious stimuli [16]. It is interesting to notice that
the molecules that mediate post-transduction neurotransmission
serve as targets both for accentuation of pain after tissue injury and
pharmacological treatment of such pain.
3.1.6.1. Spike initiation. It is widely considered that generator
potentials are passively conducted along peripheral processes
towards sites of spike initiation [16]. Nonetheless, the existence of
active conduction at nociceptor terminals is suggested by several
factors.
The two vital classes of ion channels that underlie propagation
and spike initiation are: voltage-gated Na+ channels and voltage-
gated Ca2+ channels [13].
Please cite this article in press as: Mertens P, et al. Anatomy, physiology and neurobiology of the nociception: A focus on low back pain
(part A). Neurochirurgie (2014), http://dx.doi.org/10.1016/j.neuchi.2014.09.001
5
3.1.6.2. Spike propagation/Action potential conduction. Two channel
types are needed for spike propagation under “normal” condi-
tions [16]: TTX-sensitive voltage-gated Na+ channels and a delayed
rectifier type of K+ channel. Under pathophysiological condi-
tions, axonal conduction may become dependent on TTX-resistant
voltage-gated Na+ channels, recent researches have indicated [31].
Na+ channels drive membrane depolarization and K+ channels drive
membrane hyperpolarization of sufficient magnitude and duration
to enable the Na+ channel to recover from inactivation and thereby
enable subsequent spike propagation [32].
3.1.6.3. Transmitter release. The release of neurotransmitter at the
central synapses is the final stride for afferents in the rapid trans-
mission of nociceptive information [33,34]. A large source of this
Ca2+ in many neurons is provided by voltage-gated Ca2+ channels.
The mechanisms controlling transmitter release are also subject to
modulation, as with spike propagation and initiation. Under some
conditions, TTX-resistant Na+ channels may play a role in the mod-
ulation (i.e. facilitation) of transmitter release [35]. There is also
evidence for the collaboration of Ca2+ -dependent K+ channels in the
control of transmission release. Inhibition of transmitter release in
CNS neurons is as a result of the activation of these channels [36].
3.2. Pain transmission: spinal cord and ascending spinal tracts
3.2.1. Spinal dorsal horn interface
The dorsal horn contains four different neuronal components
[11]:
• the central terminals of primary afferents;
• neurons with long ascending axons that project to the brain (pro-
jection neurons);
• intrinsic spinal neurons (interneurons, many of which have axons
that terminate locally);
• axons that descend from various parts of the brain.
3.2.1.1. Central terminals of primary afferents [37]. Large and small
afferents are anatomically intermixed in assortments of fascicles in
the peripheral nerve [13]. The tendency is for the large myelinated
afferents to move medially as the nerve root reaches the spinal
cord; and the small, unmyelinated afferents laterally. Therefore,
large and small afferent axons enter the dorsal horn by the pos-
teromedial and ventrolateral aspects of the dorsal root entry zone
(DREZ) [38–43] (Fig. 4).
3.2.1.2. Molecular architecture of the dorsal horn.
3.2.1.2.1. Cyto-architecture [44]. At each spinal level, in the
transverse plane, the spinal cord is divided on the basis of descrip-
tive anatomy into several laminae (Rexed laminae) (Fig. 2) [45].
On entering the spinal cord, the central processes of the primary
afferents send their projections into the dorsal horn.
Generally, terminals from the small myelinated fibres (A∂) ter-
minate in the marginal zone or lamina I of Rexed, the ventral portion
of lamina II, and throughout lamina V. In lamina IV and the deep
dorsal horn (laminae V to VI), larger myelinated fibres (Aß) termi-
nate [45–50]. Fine-caliber, unmyelinated C-fibres often terminate
all through laminae I and II and in lamina X around the central canal
[48,51–53].
Primary afferents collateralize sending axons rostrally and cau-
dally into the tract of Lissauer (small unmyelinated fibres) and
into the dorsal columns (large myelinated axons), along with send-
ing their axons into the dorsal horn at the segment of entry. At
various intervals, these afferents collateralize to send projections
into progressively more distal segments. This governing property
accentuates that input from a sole root may primarily activate cells
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Fig. 3. Schematic representation of pain pathway molecular mechanisms, from noxious stimuli to brain perception.
Représentation schématique des mécanismes moléculaires des voies de la douleur. Du stimulus nociceptif à l’intégration corticale du message douloureux.
Graphic conception: K. Nivole, R. David and P. Rigoard, adapted from Caterina et al., 2005.

in the segment of entry but can also coerce the excitability of neu-
rons in segments distal to the segment of entry.
In summary, lamina II represents a key anatomic region of
the cord involved in pain transmission known as the substan-
tia gelatinosa [54,55]. This anatomical region is characterized by
multiple synaptic connections among primary sensory afferent
neurons, interneurons and ascending/descending fibres. There is
great opportunity at this point for pain signal transmission to be
modulated by other sensory input or from CNS activity. Pain signals
can either be enhanced or blocked at these synapses.
Other key synaptic areas involved in nociception are laminae
V and VI. Numerous A∂ and C-fibres deliver somatic input from
mechanical, thermal, and chemical receptors in the periphery of
lamina V. The dorsal horns are sites where dynamic activities
inhibition, excitation and modulation occur, not simply passive
transmission stations [11].
3.2.1.2.2. Neurotransmission. At the dorsal horn level, the
action potential, arising from the afferent neuron, will induce
a release of different classes of neurotransmitters (NT). The
main NT involved in the nociceptive transmission includes gluta-
mate (Glu) Aspartate (Asp), Substance P (SP) and other peptides.
One must insist on the role of glutaminergic receptors, such
as ␣−amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)
and N-methyl-D-aspartate (NMDA) receptors (see later), initiating
intracellular chain reactions, which could ultimately modify cell
genomic expression in response to noxious stimuli. This process
can be considered as the substrate of a « cellular memory », recor-
ding and analysing any of the nociceptive inputs and regulated by
complex pre- and postsynaptic neurotransmission pathways (e.g.
several classes of NT, including aminoacids (Asp, Glu), inhibitory
aminoacids (Gly, ␥-aminobutyric acid (GABA), Tau), some peptides
(CGRP, kinin, somatostatin, endo-opioids), some amines (serotonin,
catecholamines), NO and prostaglandins.
3.2.1.2.3. Interneurons [44]. A vast number of neurons in each
lamina of the dorsal horn are interneurons, with axons that reside
in the spinal cord. They are referred to as “local circuit neurons”.
There is a distinction to be made between excitatory and inhibitory
interneurons. GABA and glycine are the major inhibitory transmit-
ters in the dorsal horn. GABA exists in both cell bodies and axon
terminals in the upper part of the dorsal horn (principally lami-
nae I–III); however, glycine is in relatively few cell bodies and axon
terminals in laminae I–II, but in numerous of those in deeper lam-
inae (III–VI), and also the ventral horn [44,56]. GABA is found in
almost half of neurons in lamina III, and around one third of the neu-
rons in laminae I and II. Glycine enrichment is restricted to neurons
that are GABA-immunoreactive. It has been suggested that many
neurons in these laminae use GABA and glycine as co-transmitters.
Glutamate is the foremost transmitter used by excitatory neurons
in the spinal cord along with being used by projection neurons and
primary afferents. It is probable that the majority of dorsal horn
neurons that do not use GABA or glycine as their transmitter are
glutamatergic [44].
3.2.1.2.4. Introduction to the gate control theory. The synap-
tic connections between the cells of primary and second-order
neurons located in the substantia gelatinosa and other Rexed lam-
inae function as a “pain gate”, providing one of the major tenets

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Fig. 4. Destructive procedures and pharmacological agents on pain nociceptive pathway.

Cibles potentielles des chirurgies lésionnelles et des agents pharmacologiques utilisés dans les douleurs réfractaires.
Graphic conception: K. Nivole, R. David and P. Rigoard.

advanced by the gate control theory [57]. This “gate” in the spinal comingling of excitation for a visceral organ and a specific
cord regulates the transmission of the pain impulses that ascend to area of the body surface (dermatomes) and leads to referral of
supra-spinal structures for further processing and interpretation. input from a visceral organ to that area of the body surface.
Melzack and Wall, provided in 1965, the first cohesive explanation Neurons are excited in a given population of WDR by cuta-
for the emerging complexities of pain phenomena [58]. Stimulation neous and/or deep (muscle and joint) inputs applied within the
of non-nociceptive larger A fibres such as touch, vibration or ther-
mal stimuli cause the cells in the substantia gelatinosa to “close the
pain gate”, decreasing pain perception. The CNS through efferent
pathways may also close partially close or open the gate (Fig. 5).
This concept was described as a possibility of segmental inhibition
of the pain [59].

3.2.1.3. Physiological properties of dorsal horn neurons.

3.2.1.3.1. Nociceptive specificity. Two functional classes of neu-
rons can be distinguished:

• nociceptive-specific neurons (their threshold increases in dis-

charge and is amplified over the progressing aversive range of
stimulus intensities);
• wide dynamic range (WDR) neurons.

3.2.1.3.2. Wide dynamic range neurons. It has been reported by

Yaksh that a number of cells in the nucleus proprius (Laminae III et
IV) have three interesting functional characteristics [11]:

• driven by low- and high- threshold afferent inputs, these neurons

display excitation. As the stimulus intensity is elevated from a
very low intensity to a very high intensity, it gives the WDR neu-
rons the property of responding with increased frequency (e.g.
they have a wide dynamic response range);
• organ convergence: a neuron in the nucleus proprius can be Fig. 5. The gate control’s theory.
activated by activation of visceral afferent and somatic stimuli La théorie du gate control.
depending on the spinal level. This assemblage results in a Graphic conception: K. Nivole, R. David and P. Rigoard, adapted from Wall, 1989.

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corresponding embryonary myotome and dermatome coinciding
with the segmental location of the cell. Thus, L1 root stimulation
activates WDR neurons that are also excited by kidney capsule
or ureter compressions. The phenomenon of referred (visceral or
deep muscle or bone) pain to particular body surfaces (low back
and groin pain) is underlined by viscerosomatic and musculoso-
matic convergences onto dorsal horn neurons;
• low-frequency (> ≈0.33 Hz) repetitive stimulation of C-fibres (but
not A fibres) produces a steady increase in the frequency dis-
charge until the neuron is in a position of almost continuous
discharge (“wind-up”).
3.2.2. Ascending spinal tracts [37,60,61]
The following pathways were mainly described in different
animal species but their existence and functional anatomical orga-
nisation need to be confirmed in humans.
3.2.2.1. Ventral funicular projection systems. Many systems have
been identified within the ventrolateral quadrant of the spinal cord
on the basis of their supra-spinal projections. Included in these are
the spino-mesencephalic, spinoreticular, spino-parabrachial and
spino-thalamic tracts. These constitute the anterolateral system
[62].
These systems derive from the dorsal horn neurons that are
postsynaptic to primary afferents. In the spinal cord, these cells
may project either ipsilaterally or contralaterally. Past studies have
shown that unilateral section of the ventrolateral quadrant yields a
contralateral loss in pain and temperature sense in the dermatomes
below the spinal level of the section. This finding indicates that
the ascending tracts may travel rostrally several segments before
crossing [11] (Fig. 4).
3.2.2.2. Dorsal funiculi projection systems. The dorsal column,
which becomes the medial lemniscal system at the brainstem level,
transmits sensory information [37] along an ascending pathway
(Fig. 6). The system is comprised of collaterals of larger-diameter
Fig. 6. An artistic view of the spino-thalamic tract and cortical projections.
Vue artistique du tractus spino-thalamique et de ses projections corticales.
Graphic conception: K. Nivole, R. David and P. Rigoard.
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primary afferents transmitting tactile sensation and limb proprio-
ception (Fig. 2). Fibres of the medial lemniscal system rise from the
spinal cord ipsilaterally to the medulla, here they synapse on neu-
rons in the caudal brainstem dorsal column nuclei that send axons
across the medulla to form the medial lemniscus [62].
3.2.2.3. Intersegmental systems. Rostral transmission of nocicep-
tive information may be contributed to by systems that project for
short distances ipsilaterally. The lateral tract of Lissauer, the dorso-
lateral propriospinal system and the dorsal intracornual tract are
examples of segmental pathways relevant to the rostral transmis-
sion of nociceptive information.
3.2.3. Supra-spinal projections [63,64]
3.2.3.1. Neuroanatomy [10]. The supra-spinal tracts travelling in
the ventrolateral quadrant project into the mesencephalon, the
medulla, and the diencephalon (Fig. 6). Neurons from these areas
then project further directly to cortical structures or rostrally to the
cortex and diencephalon [11].
On entering in the spinal cord, the pain signals take two path-
ways to the brain, through:
• the neo-spino-thalamic tract (for sharp/fast discriminative pro-
cess), which corresponds to the spino-thalamic projections and;
• the paleo-spino-thalamic tract (much older system), which
corresponds to the association of the spino-reticulo-thalamic,
the spino-mesencephalic and the spino-parabrachial projections
[65].
The paleo-spino-thalamic tract is a slower-conducting, multisy-
naptic tract. Fibres of this system also travel up the contralateral
anterolateral pathway to terminate in several thalamic regions,
including the intralateral nuclei, which project to the limbic system
[66].
3.2.3.1.1. Spino-reticulo-thalamic projections. This tract termi-
nates throughout the brainstem reticular formation [67] and
represents axons that are mainly ipsilateral to the cell or origin.
It is suggested that spinomedullar input plays an imperative role
in initiating cardiovascular reflexes involved in pain response. The
medullary reticular formation can also act as a relay station for the
rostral transmission of nociceptive information. These medullary
neurons project into the intra-laminar thalamic nucleus. Forming
part of the classic ascending reticular activating system and relat-
ing to mechanisms leading to increased global cortical activation
[11], the nucleus forms a shell around the medial dorsal aspects of
the thalamus. The intra-laminar nucleus projects diffusely to wide
areas of the cerebral cortex, consisting of the frontal, parietal, and
limbic regions (Fig. 7).
3.2.3.1.2. Spino-mesencephalic projections. Ipsilateral projec-
tions terminate in mesencephalic and periaqueductal gray
formation [68,69]. Periaqueductal gray and reticular neurons
project caudally to the dorsal horn and rostrally into the lateral
thalamus [11].
3.2.3.1.3. Spino-parabrachial projections. Originating largely
from neurons in contralateral laminae are some of the ascending
nociceptive fibres. In the parabrachial area, projections of these
neurons terminate in a group of neurons that transmit axons to
the central nucleus of the amygdala and the posterior part of the
ventral medial nucleus (VM) in the thalamus [70–72]. The VM
projects principally to the insula [10].
3.2.3.1.4. Spino-thalamic projections. The faster-conducting
fibres of the neo-spino-thalamic tract are associated mainly with
the transmission of sharp-fast pain information to the thala-
mus [62]. In the thalamus, synapses are made with a third-order
thalamo-cortical neuron and the pathway continues to the contro-
lateral parietal somatosensory area to provide the precise location
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Fig. 7. Diagram showing the supra-spinal ascending projections, including spino-reticulo-thalamic projections, spino-mesencephalic projections, spino-parabrachial pro-
jections and neo-spino-thalamic projections.
Schéma montrant les projections ascendantes supra-spinales, y compris les projections spino-réticulo-thalamiques, spino-mésencéphaliques, spino-parabrachiales et néo-spino-
thalamiques.
Graphic conception: K. Nivole, R. David and P. Rigoard.
of the pain. Typically, the pain is experienced as bright, sharp, or
stabbing in nature [66]. This predominantly crossed system dis-
plays the following three principal targets of termination (Fig. 6).
The somatosensory thalamic nucleus is represented by the ven-
trobasal thalamus:
• in a somatotopic pattern, the region projects to the somatosen-
sory cortex [73–76];
• the VM then projects into the insula;
• the medial thalamus receives primary input from lamina I (high-
threshold nociceptive-specific cells). Cells in this region, then
project to the anterior cingulate cortex.
3.2.3.2. Neurobiological aspects [11].
3.2.3.2.1. Ascending projection system transmitters. Many
peptides (including dynorphin, somatostatin, cholecystokinin,
bombesin, substance P, VIPs) are found in dorsal horn neurons
projecting to brainstem sites. Also, glutamate has been seen in
spino-thalamic projections, suggesting the role of excitatory amino
acid. Glutamate binding to its NMDA receptors on the postsynaptic
neuron is thought to induce a kind of synaptic memory in the pain
pathway. Substance P-containing fibres arising from brainstem
sites have been shown to project to the parafascicular and central
medial nuclei of the thalamus.
3.2.3.2.2. Plastic modulation of ascending projections. In addi-
tion to the physical characteristics of an effective stimulus, the
encoding of a pain message also depends on the properties of
associated systems that can modulate the excitability of synaptic
linkages. Therefore, glycine at the level of the spinal dorsal horn
and interneurons releasing GABA often regulate the frequency of
discharge of second-order neurons excited by large afferent input.
3.3. Pain perception: the cortical interface
As the pain signals reach the cortex via thalamo-cortical pro-
jections, perception is the result of neural processing of pain
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9
sensations in the brain. Pain perception includes an awareness and
interpretation of the meaning of the sensation [77]. Information
from tissue injury is carried from the spinal cord via the thalamus
to the brain centers, where the basic sensation of hurtfulness, or
pain, occurs. In the neo-spino-thalamic system, the interconnec-
tions between the lateral thalamus and the somatosensory cortex
are necessary to add precision, discrimination, and meaning to the
pain sensation [66]. The paleo-spino-thalamic tract projects dif-
fusely from the intra-laminar nuclei of the thalamus to large areas
of the limbic cortex. These connections may be related to the mood-
shifting and attention decrease effect of pain.
Cortical representation of fast-sharp and slow-chronic pain sen-
sation has been established by modern research [78–81]. C afferent
stimulation is linked to activation of the secondary cortical areas,
the anterior cingulated cortex, and the posterior operculo-insular
cortex; unlike nociceptive A∂ afferent stimulation which is related
to activation of the controlateral primary somatosensory cortex
in the parietal lobe. This cortical area corresponds to the unique
and specific location on which electrical stimulation can produce a
painful sensation and whose destruction leads to chronic pain [82].
With the use of positron emission tomography (PET) and func-
tional magnetic resonance imaging (fMRI), the exact areas of the
brain that are involved in the perception of pain in humans are
now becoming apparent [10]. Imaging studies have implicated the
SI and SII somatosensory receiving areas of the cortex, as well as
the anterior cingulate gyrus and the insula, as important structures
for the higher processing of the pain that is evoked by acute nox-
ious stimuli [83–86]. All these areas systematically activated by
nociceptive stimuli are involved in a network classically described
as the pain neuromatrix.
3.4. Pain modulation: descending pathways
On pain messages being sent to the brain, reciprocal projections
back to the spinal cord through descending controls are triggered by
inputs into the midbrain [77]. Descending pathways from the brain
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Fig. 8. Diagram showing descending pathways involved in pain modulation.

Schéma montrant les voies descendantes impliquées dans la modulation de la douleur.
Graphic conception: K. Nivole, R. David and P. Rigoard, adapted from Waldman et al., 2011.

to the dorsal horn region of the spinal cord are important mod-
ulators of pain response through monoamine systems [8]. These
descending pathways originate in a brainstem nucleus called the
raphe magnus and project to the dorsal horn regions at laminae
I, II, and IV [3,7]. Neurotransmitters release by these neurons can
inhibit synaptic transmission of pain signals. Presynaptic inhibition
of substance P release from nociceptor neurons is one way to inhibit
synaptic transmission. It has also been suggested that opioids are
the main mediators of presynaptic inhibition.
The raphe magnus receives input from two other brain areas
which have a significant role in the pain response [87–89]:
• the periaqueductal gray (PAG) area in the midbrain;
• the rostral pons in the brainstem.
The PAG area receives input from widespread areas of CNS,
including the cerebral cortex, hypothalamus, brain stem reticu-
lar formation, and spinal cord, via the paleo-spino-thalamic tract
[88,89]. This region is ultimately connected to the limbic sys-
tem, which is associated with emotional experience [90]. The PAG
area has a high concentration of endogeneous opioids (endorphins,
enkephalins and dynorphines) that induce major analgesic effects.
Afferent stimulation of the PAG in the midbrain and ventro-
medial medulla cause a release of endogenous opioids and via
serotonin (5-hydroxytryptamine, 5HT) also sends nerve impulses
to the raphe magnus. The PAG region of the midbrain is often
referred to as the endogenous analgesia centre by stimulating effer-
ent pathways which modulate or inhibit afferent pain signals at
the dorsal horn [59]. The descending pathways are thought to be
inhibitory; the inhibitory effect is possibly the result of noradren-
ergic systems [91,92]. Serotonergic systems are known to provide a
vital role in the wind-up shown in WDR neurons aroused by small
afferent input. This explains the pain-relieving action of drugs that
enhance serotonin activity in the brain. It also has to be noted that
by stimulating the neurons projecting to the raphe magnus from
the rostral pons, it is possible to produce an analgesic effect using
the norepinephrine pathway.
A central means for gating the flow of pain impulses from the
periphery to the brain are the descending pathways. In receiving
input by way of thalamus and limbic structures, the PAG region is
notified of the flow of pain signals (Fig. 8).
The majority of work completed since the introduction of
the gate control theory has concentrated on the complexity of
inhibitory modulation beyond the segmental level (i.e. heteroseg-
mental modulation). Our grasp of heterosegmental, supra-spinal
mechanisms elicited by noxious and non-noxious stimuli is ever
increasing. The understanding is that powerful heterosegmental
control of nociception arises from the cortex as all nociceptive
relays within the CNS are under top-down (corticofugal) mod-
ulation that most of the times occurs in the absence of painful
stimuli [59]. These pathways will be developed later in this
paper.
Diffuse noxious inhibitory controls (DNIC) are inhibitory enti-
ties in which the caudal medulla plays a part. In this case, a noxious
peripheral stimulation remote from the pain site relieves pain (e.g.
acupuncture) [59]. Responding simultaneously to the noxious stim-
ulus, ascending and descending bulbospinal pathways partake in
DNIC [93–95]. The total result of these supra-spinal structures is to
accurately encode the intensity of the noxious stimulus and trans-
mit descending feedback, mainly to the deep dorsal horns.
The role of this modulation is reflected by the findings of work
by Pierre Rainville et al. [96]. Hypnotic suggestions leading to
enhanced pain (in response to a given experimental stimulus)
resulted in greater activity in the anterior cingulate. Indeed,
disconnection syndromes, produced by prefrontal lobectomies,
cingulotomies, and temporal lobe–amygdala lesions, lead to

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dissociation between the perception of a physical sensation and
its affective component.
4. Conclusion
4.1. Functional overview of pain nociceptive processing system
The circuitry that serves in the transduction and encoding of
nociceptive pain has been extensively reviewed in this article. Pri-
marily, activity is evoked by stimuli in specific groups of small
myelinated or unmyelinated primary afferents. These create their
synaptic contact with numerous dorsal horn neurons [11]. Dor-
sal horns are areas where enterprising activities occur (inhibition,
modulation and excitation), not simply passive transmission sta-
tions. The information is passed through long spinal tracts and
an assortment of intersegmental systems to supra-spinal centres
found in the brainstem and in the thalamus. Stimuli give rise to
escape behaviour and verbal report of pain via these rostrally pro-
jecting systems to the brain. This circuitry constitutes the afferent
limb of the pain pathway.
4.2. Two functionally distinct pathways for two dimensions of
pain perception
It is possible to characterize two different families of response
at the spinal level: physical pain and emotional pain. These are
supported by two different pathways, encoding two dimensions
of pain perception. In neo-spino-thalamic pathway (Fig. 6), WDR
neurons encode information onto their dentrites and soma over
a wide array of non-noxious to severely aversive intensities con-
sistent with the convergence of low and high-threshold afferent
neurons. The WDR system can retain spatial localisation informa-
tion and information regarding the stimulus over a range of various
intensities. This type of system is able to provide the informa-
tion needed for mapping the “sensory-discriminative” dimension
of pain. These cells project massively into several brainstem and
diencephalic sites to the somatosensory cortex. At every level, the
map of the body surface is precisely preserved, as is the broad range
of intensity-frequency encoding.
As determined by the high-threshold afferent input they
receive, populations of superficial marginal cells show a strong
nociceptive-specific encoding characteristic in the second supra-
spinal projection system (paleo-spino-thalamic pathway (Fig. 6).
These marginal cells project heavily to the parabrachial nuclei, to
the amygdala, to the VM, the insula, the medial thalamic nuclei,
and then to the anterior cingulate cortex. These areas are associated
with emotionality and affect [11], thus providing an important sub-
strate for systems underlying the affective-motivational elements
of the pain experience.
As demonstrated by fMRI and PET, strong somatic and visceral
stimuli initiate activation within the anterior cingulate cortex [97],
whereas non-noxious stimuli generally have minimal effect. This
substrate with its pinpoint somatosensory map portrays a sys-
tem competent of mapping a sensory-discriminative dimension of
pain. In comparison, an “affective-motivation” component of the
pain pathway is suggested with the system involving the limbic
forebrain. Pain perception is influenced by attention, distraction,
anxiety, fear, fatigue and previous experiences and expectations
[77]. Pain perception can be also described in terms of pain thresh-
old and pain tolerance [5]. Pain threshold is the level of painful
stimulation required to be perceived and is remarkably similar from
an individual to another. Pain tolerance is the degree of pain that
is willing to bear before seeking relief. Pain tolerance varies widely
among individuals and within the same individual under different
conditions. Age, culture, family, upbringing, gender, and previous
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11
experience influence tolerance to pain. Ultimately, pain expres-
sion is the way in which the pain experience is communicated
to others [98]. Thus, the highly variable nature of pain expression
among individuals makes accurate pain assessment difficult, espe-
cially with chronic back pain patients, while the famous expression:
« J’en ai plein le dos ! »/“I am sick to the back teeth!”, worldwide
used, brings them together. This leads us to move from anatomical
concepts to practical applications and discuss about the potential
spinal generators in the next paper (Part B).
Disclosure of interest
Dr. Rigoard is a consultant for Medtronic Inc. and received hon-
oraria for medical training from St-Jude Medical, research grants
from Medtronic Inc & St-Jude Medical.
The other authors declare that they have no conflicts of interest
concerning this article.
Acknowledgements
The authors would like to thank Mr Lee Wesley for reviewing
this manuscript, Nancy Ladmirault for her technical help, the N3Lab
for its assistance and Poitiers University Hospital (Department of
Research Management, Mr Carles De Bideran, Ms Sarah Guyon) for
their support.
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