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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


Medical College, rue de la Milètrie, 86000 Poitiers, Fr);
The understanding of pain perception is essential for optimal • UIC Library of Health Sciences (University of Illinois at Chicago,
diagnosis and treatment of the back pain component in Failed Back 1912 Polk St., Chicago, US);
Surgery Syndrome (FBSS) [1]. Its treatment remains a challenge for • Dorsch Neuroscience Library (Institute of Neurology and Neu-
pain medicine. One of the main reasons arises from the extreme ropsychiatry, 712 S Wood St., Chicago, US), performed by some
complexity in the interactions between 1) a residual mechani- of the authors (RD, PR).
cal or inflammatory pain after surgery (which both correspond
to a nociceptive component and involve the physiological pain This list of book chapters was updated by searching the
processing system) and, 2) a progressive transition into chronic following electronic databases from 1930 to August 2013: MED-
pain involving Central Nervous System (CNS) plasticity and molec- LINE (Ovid), MEDLINE InProcess (Ovid), EMBASE (Ovid), Cochrane
ular reorganization. In order to improve functional outcomes in Library (Cochrane Central Register of Controlled Trials (CENTRAL),
these difficult-to-treat patients, advances in our understanding of Health Technology Assessment (HTA) databases. The search strat-
the underlying pathophysiological mechanisms have major impli- egy was developed in order to maximise sensitivity of article
cations for the management of both nociceptive pain generators identification and was not restricted by language, or any other
and chronic back pain component. On one hand, missing a potential limits. Citation lists in the chapters and papers consulted and
etiological conflict that could require further surgery, by focusing recent systematic reviews were checked for additional references.
on chronic pain aspects would irremediably lead to the failure of Two reviewers (RD and PR) independently scanned all titles and
“palliative” treatments. On the other hand, because it has been abstracts and identified potentially relevant articles for retrieval.
established that intense noxious stimulation produces autonomic Full-text copies of papers were obtained, analysed and summa-
sensitization of CNS neurons within time, it is possible to direct rized.
treatments not only at the site of peripheral tissue damage, but
also at the site of central changes [2]. The therapeutic plan has to
2.2. Keywords
be discussed with the patient, only after a meticulous “pathophy-
siological investigation” of all potential back pain generators.
The following keywords were used for these searches: path-
Pathophysiological changes in the pain system and associated
ophysiology; pain; nociception; neuropathic pain; inflammatory
changes in pain perception cannot be understood unless the func-
pain; central sensitization; chronic pain; anatomy; neuroanatomy;
tioning of the pain system under normal conditions is known. The
low back pain; failed back surgery syndrome; pain generators;
aim of this paper is to provide a fundamental overview of the pain
triggers; facet joints; sacroiliac joint; muscle pain; myogenic syn-
pathway supporting the nociceptive component of the back pain
drome; spine; biomechanics; molecular mechanisms; discogenic
(Part A). The potential back pain generators, accessible to etiologi-
pain; spine instability; spinal fusion; sagittal imbalance; dorsal
cal treatments in FBSS patients will be reviewed in the next article
horn; bulbospinal projections; ascending tracts; pain receptors;
(Part B) [3].
nociceptors; CNS afferents; CNS efferents; neurobiology; neuro-
matrix; gate control; pathological pain; physiological pain; pain
2. Methods threshold; pain tolerance; back pain; mechanisms of action;
neurostimulation; spinal cord stimulation; peripheral nerve stim-
2.1. Literature searches ulation; motor cortex stimulation; cordotomy; myelotomy; DREZ;
pain pathways.
References and book chapters were initially identified (Fig. 1)
from a systematic review of the electronic literature and of all path-
2.3. Literature analysis
ophysiology, anatomy and physiology textbooks available in the
following medical libraries:
Some well-written textbooks on pain management, pathophy-
siology and anatomy were particularly useful. The synopsis of
• Paris Medical Library (Université Descartes, Paris 5, rue de l’Ecole Waldman’s textbook on pain management [4] and the following
de Médecine, 75006 Paris, France); books [5–10] largely inspired this review and, whenever possible,
• Paris Anatomy Library (Anatomy Laboratory, Université des the reader is referred to the original publications for a more detailed
Saints-Pères, Paris 6e , Fr); 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
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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- 3.1. Pain transduction: primary afferents
lus is arising from (ligaments, bone, joints, muscles, nervous tissue,
cutaneous surface, etc.), the physiologic mechanisms involved in Pain is initiated by events that occur on the skin, or in deep
the mechanical component of the residual back pain following a tissues such as muscles, bones, or viscera and mediated trough
spine surgery are termed as nociception [5,6]. Nociception can be specialized primary afferent neurons [6]. These sensory neurons
divided in four stages: transduction, transmission, perception, and involve their terminals called “nociceptors” to constantly survey
modulation [6]. the environment, detect any alarm signal and to respond rapidly
Transduction is the process of converting stimuli to neuronal to mechanical, thermal, or chemical stimuli that are of sufficient
action potentials at the sensory receptor. Transmission refers to intensity to cause tissue damage or of quality that indicates existing
the propagation of action potentials along neurons from peripheral damage tissue. Upon activation, they transduce this information via
receptor to the spinal cord and then centrally to the brain. Percep- action potentials and neurotransmitter release through the spinal
tion occurs contemporarily to the signal integration at the brain cord dorsal horn for further transmission to the supra-spinal struc-
cortical level. This process involves then several cortical regions, tures and finally the brain (Fig. 2).
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. 3.1.1. Fibres classes
Three portions of the nervous system are responsible for the There is a process of sensory neurons (named as “glomerulus”)
sensation and perception of pain: 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.
• the afferent pathways, which begin in the peripheral nerve sys- Sensory input is relayed by the central axon to the brainstem or
tem (PNS), travel to the spinal level in the dorsal horn and then spinal cord. As outlined in Fig. 2, sensory axons are classified accord-
ascend to higher centers in the central nervous system (CNS); ing to their state of myelination, conduction velocity and diameter.
• the integration centers located in the brain stem, midbrain, dien- Ordinarily, conduction velocity alters directly with axon diameter
cephalon, and cerebral cortex; and the presence of myelination [11].

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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- 3.1.3. Electrophysiological characterization of nociceptors
duct rapidly; A∂ axons have a smaller diameter and are myelinated As touched above, nociceptors are often subclassified with
[12] and conduct slower; and C-fibres are small, unmyelinated and respect to three physiological criteria [16]:
conduct much more slowly [13].
• the conduction velocity of their parent axon (i.e. unmyelinated
C-fibre afferents versus myelinated I-fibre afferents);
3.1.2. Properties of primary afferent function • the stimulus modalities that evoke a response (i.e. mechanical,
As seen with the Pacini corpuscle found on the terminals of large heat, or chemical);
afferents, nerve endings can be morphologically specialized [11]. • the temporal characteristics of their response to a stimulus
The mechanical distortion of the structure is translated by the spe- modality (rapid versus slow response).
cialized structure into a transient opening of sodium channels in
the axon, thus bringing about a succinct burst of action potential
Activation of one branch of the nociceptor terminal by the injury
(see later).
leads to orthodromic action potential propagation into the parent
On the other hand, the axon terminal may be classified as a “free
axon as well as antidromic propagation into other branches [16].
nerve ending” whereby it displays no evident physical structure
The antidromic action potentials lead to the release of vasoactive
showing extensive branching as they proceed distally. These end-
neuropeptides (such as substance P and CGRP) that are found in
ings are ordinarily associated with small, unmyelinated C-fibres
terminal receptors [17,18]. Recent evidence suggests that mechani-
[14,15]. The simplicity of the nerve is misleading given its name.
cally insensitive afferents may play a major role in the development
A range of stimuli including thermal, chemical and mechanical can
of vasodilatation (or flare), often surrounding the painful area, espe-
be transduced. Low-threshold mechanical stimuli (i.e. mechanore-
cially after chemical stimuli such as capsaicin or histamine [19].
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 3.1.4. Afferents with high thresholds and pain behaviour
temperatures that are moderately noxious and their firing rates It is indicated by correlated behavioural and electrophysiologic
can increase to very high temperatures (52 ◦ C–55 ◦ C). The largest evidence that information that generates a pain sensation enters
population of afferent axons are slowly conducting afferents. These the central nervous system by the activation of small-diameter,
afferents are called “C-polymodal nociceptors” and are commonly myelinated (group III-A or A∂) or unmyelinated (group IV or C)
activated by high-threshold thermal, chemical and mechanical afferents [11]. These polymodal nociceptors have a significant char-
stimuli [11]. acteristic in that they are also readily activated in a concentration-
Three important characteristics are revealed from the recording dependant form by specific agents released into the chemical
of single peripheral afferent fibres. Firstly, with a lack of stimula- milieu [11]. Such agents, released from local injured cells or inflam-
tion, “spontaneous” afferent traffic occurs. Accordingly, the system matory cells, include a variety of amines (5-hydroxytryptamine,
operates on a very high signal-to-noise ratio. histamine), lipid mediators (prostaglandins), kinins (bradykinin),
Secondly, with rising intensities of applicable stimulus, regard- acidic pH, cytokines (interleukin-1ß) and enzymes (trypsin) [16].
less of fibre type examined, the more intense the stimulus, the This working may serve the mechanism of activating afferents post-
larger the depolarization of the terminal and the more frequently acute injury.
the axon will discharge. Under certain conditions, low-intensity tactile or thermal
Thirdly, dependant on the stimulus modality, different axons stimuli may, in fact, generate a pain state. Hyperalgesia is the name
may respond more efficiently. 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 3.1.6.2. Spike propagation/Action potential conduction. Two channel
allodynia. types are needed for spike propagation under “normal” condi-
Two practical examples may be cited: tions [16]: TTX-sensitive voltage-gated Na+ channels and a delayed
heightened tactile and thermal sensitivity from local tissue rectifier type of K+ channel. Under pathophysiological condi-
injury such as sunburn; tions, axonal conduction may become dependent on TTX-resistant
and more practically, peripheral nerve injury causing indispo- voltage-gated Na+ channels, recent researches have indicated [31].
sition to light touch. These aspects will be discussed in a separate Na+ channels drive membrane depolarization and K+ channels drive
paper [20]. membrane hyperpolarization of sufficient magnitude and duration
to enable the Na+ channel to recover from inactivation and thereby
3.1.5. Molecular mechanisms of nociceptive signal transduction enable subsequent spike propagation [32].
3.1.5.1. Molecular detection of noxious chemical stimuli. It has been
shown by electrophysiological and pharmacological studies of cul- 3.1.6.3. Transmitter release. The release of neurotransmitter at the
tured nociceptive neurons that certain agents (e.g. protons and central synapses is the final stride for afferents in the rapid trans-
vanilloid compunds) directly depolarize nociceptive neurons by mission of nociceptive information [33,34]. A large source of this
triggering the opening of cation channels permeable to sodium Ca2+ in many neurons is provided by voltage-gated Ca2+ channels.
and/or calcium [16]. Capsaicin possess a homovanillic acid moi- The mechanisms controlling transmitter release are also subject to
ety [21], which binds selectively to receptor sites located on the modulation, as with spike propagation and initiation. Under some
terminals of C-fibre nociceptors, triggers the influx of sodium conditions, TTX-resistant Na+ channels may play a role in the mod-
and calcium, and thereby initiate nociceptive transmission, and ulation (i.e. facilitation) of transmitter release [35]. There is also
ultimately pain [22]. In contrast, agents such as bradykinin [23], evidence for the collaboration of Ca2+ -dependent K+ channels in the
prostanglandin E2 [24] and nerve growth factor [25] act on G control of transmission release. Inhibition of transmitter release in
protein-coupled receptors and receptor tyrosine kinases, respec- CNS neurons is as a result of the activation of these channels [36].
tively, to trigger intracellular signaling cascades that in turn
sensitize depolarizing channels [26]. Still other agents (e.g. gluta- 3.2. Pain transmission: spinal cord and ascending spinal tracts
mate, acetylcholine, and adenosine triphosphate) activate both ion
channels and G protein-coupled receptors to produce a wide range 3.2.1. Spinal dorsal horn interface
of direct and indirect excitatory effects [8]. The dorsal horn contains four different neuronal components
[11]:
3.1.5.2. Transduction of painful mechanical stimuli. Intense
mechanical stimuli such as pinching a nerve or overloading a • the central terminals of primary afferents;
lumbar articular capsule are examples of familiar cause of pain. • neurons with long ascending axons that project to the brain (pro-
Despite this fact, relatively little is known about the molecular jection neurons);
mechanisms underlying nociceptive mechano-transduction [16]. • intrinsic spinal neurons (interneurons, many of which have axons
In a subset of cultured sensory neurons, the direct application of that terminate locally);
mechanical force evokes non-selective cationic transmembrane • axons that descend from various parts of the brain.
currents [27]. A number of candidate mechanosensory ion chan-
nels have been identified, including members of the ASIC [28], TRP 3.2.1.1. Central terminals of primary afferents [37]. Large and small
[29] and TREK [30] families. afferents are anatomically intermixed in assortments of fascicles in
the peripheral nerve [13]. The tendency is for the large myelinated
3.1.6. Beyond depolarization: spike initiation, action potential afferents to move medially as the nerve root reaches the spinal
propagation, and neurotransmitter release cord; and the small, unmyelinated afferents laterally. Therefore,
Neurotransmission by primary afferent nociceptors requires not large and small afferent axons enter the dorsal horn by the pos-
only that noxious stimuli are converted into an electrical signal (i.e. teromedial and ventrolateral aspects of the dorsal root entry zone
membrane depolarization), but also that this information is trans- (DREZ) [38–43] (Fig. 4).
mitted to the spinal cord [16]. At the level of the peripheral fibre,
this process requires several additional steps generally referred 3.2.1.2. Molecular architecture of the dorsal horn.
to as spike initiation, spike propagation and transmitter release 3.2.1.2.1. Cyto-architecture [44]. At each spinal level, in the
(Fig. 3). Each of these steps requires a number of distinct ion chan- transverse plane, the spinal cord is divided on the basis of descrip-
nels precisely positioned at discrete sites throughout the plasma tive anatomy into several laminae (Rexed laminae) (Fig. 2) [45].
membrane. The interrelationship between cyto-architecture and On entering the spinal cord, the central processes of the primary
ion channel composition or properties of nociceptors results in an afferents send their projections into the dorsal horn.
extraordinary capacity to encode the spatial, temporal, and inten- Generally, terminals from the small myelinated fibres (A∂) ter-
sity properties of noxious stimuli [16]. It is interesting to notice that minate in the marginal zone or lamina I of Rexed, the ventral portion
the molecules that mediate post-transduction neurotransmission of lamina II, and throughout lamina V. In lamina IV and the deep
serve as targets both for accentuation of pain after tissue injury and dorsal horn (laminae V to VI), larger myelinated fibres (Aß) termi-
pharmacological treatment of such pain. nate [45–50]. Fine-caliber, unmyelinated C-fibres often terminate
all through laminae I and II and in lamina X around the central canal
3.1.6.1. Spike initiation. It is widely considered that generator [48,51–53].
potentials are passively conducted along peripheral processes Primary afferents collateralize sending axons rostrally and cau-
towards sites of spike initiation [16]. Nonetheless, the existence of dally into the tract of Lissauer (small unmyelinated fibres) and
active conduction at nociceptor terminals is suggested by several into the dorsal columns (large myelinated axons), along with send-
factors. ing their axons into the dorsal horn at the segment of entry. At
The two vital classes of ion channels that underlie propagation various intervals, these afferents collateralize to send projections
and spike initiation are: voltage-gated Na+ channels and voltage- into progressively more distal segments. This governing property
gated Ca2+ channels [13]. 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- complex pre- and postsynaptic neurotransmission pathways (e.g.
rons in segments distal to the segment of entry. several classes of NT, including aminoacids (Asp, Glu), inhibitory
In summary, lamina II represents a key anatomic region of aminoacids (Gly, ␥-aminobutyric acid (GABA), Tau), some peptides
the cord involved in pain transmission known as the substan- (CGRP, kinin, somatostatin, endo-opioids), some amines (serotonin,
tia gelatinosa [54,55]. This anatomical region is characterized by catecholamines), NO and prostaglandins.
multiple synaptic connections among primary sensory afferent 3.2.1.2.3. Interneurons [44]. A vast number of neurons in each
neurons, interneurons and ascending/descending fibres. There is lamina of the dorsal horn are interneurons, with axons that reside
great opportunity at this point for pain signal transmission to be in the spinal cord. They are referred to as “local circuit neurons”.
modulated by other sensory input or from CNS activity. Pain signals There is a distinction to be made between excitatory and inhibitory
can either be enhanced or blocked at these synapses. interneurons. GABA and glycine are the major inhibitory transmit-
Other key synaptic areas involved in nociception are laminae ters in the dorsal horn. GABA exists in both cell bodies and axon
V and VI. Numerous A∂ and C-fibres deliver somatic input from terminals in the upper part of the dorsal horn (principally lami-
mechanical, thermal, and chemical receptors in the periphery of nae I–III); however, glycine is in relatively few cell bodies and axon
lamina V. The dorsal horns are sites where dynamic activities terminals in laminae I–II, but in numerous of those in deeper lam-
inhibition, excitation and modulation occur, not simply passive inae (III–VI), and also the ventral horn [44,56]. GABA is found in
transmission stations [11]. almost half of neurons in lamina III, and around one third of the neu-
3.2.1.2.2. Neurotransmission. At the dorsal horn level, the rons in laminae I and II. Glycine enrichment is restricted to neurons
action potential, arising from the afferent neuron, will induce that are GABA-immunoreactive. It has been suggested that many
a release of different classes of neurotransmitters (NT). The neurons in these laminae use GABA and glycine as co-transmitters.
main NT involved in the nociceptive transmission includes gluta- Glutamate is the foremost transmitter used by excitatory neurons
mate (Glu) Aspartate (Asp), Substance P (SP) and other peptides. in the spinal cord along with being used by projection neurons and
One must insist on the role of glutaminergic receptors, such primary afferents. It is probable that the majority of dorsal horn
as ␣−amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) neurons that do not use GABA or glycine as their transmitter are
and N-methyl-D-aspartate (NMDA) receptors (see later), initiating glutamatergic [44].
intracellular chain reactions, which could ultimately modify cell 3.2.1.2.4. Introduction to the gate control theory. The synap-
genomic expression in response to noxious stimuli. This process tic connections between the cells of primary and second-order
can be considered as the substrate of a « cellular memory », recor- neurons located in the substantia gelatinosa and other Rexed lam-
ding and analysing any of the nociceptive inputs and regulated by 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 primary afferents transmitting tactile sensation and limb proprio-
with the segmental location of the cell. Thus, L1 root stimulation ception (Fig. 2). Fibres of the medial lemniscal system rise from the
activates WDR neurons that are also excited by kidney capsule spinal cord ipsilaterally to the medulla, here they synapse on neu-
or ureter compressions. The phenomenon of referred (visceral or rons in the caudal brainstem dorsal column nuclei that send axons
deep muscle or bone) pain to particular body surfaces (low back across the medulla to form the medial lemniscus [62].
and groin pain) is underlined by viscerosomatic and musculoso-
matic convergences onto dorsal horn neurons; 3.2.2.3. Intersegmental systems. Rostral transmission of nocicep-
• low-frequency (> ≈0.33 Hz) repetitive stimulation of C-fibres (but tive information may be contributed to by systems that project for
not A fibres) produces a steady increase in the frequency dis- short distances ipsilaterally. The lateral tract of Lissauer, the dorso-
charge until the neuron is in a position of almost continuous lateral propriospinal system and the dorsal intracornual tract are
discharge (“wind-up”). examples of segmental pathways relevant to the rostral transmis-
sion of nociceptive information.
3.2.2. Ascending spinal tracts [37,60,61]
The following pathways were mainly described in different 3.2.3. Supra-spinal projections [63,64]
animal species but their existence and functional anatomical orga- 3.2.3.1. Neuroanatomy [10]. The supra-spinal tracts travelling in
nisation need to be confirmed in humans. the ventrolateral quadrant project into the mesencephalon, the
medulla, and the diencephalon (Fig. 6). Neurons from these areas
3.2.2.1. Ventral funicular projection systems. Many systems have then project further directly to cortical structures or rostrally to the
been identified within the ventrolateral quadrant of the spinal cord cortex and diencephalon [11].
on the basis of their supra-spinal projections. Included in these are On entering in the spinal cord, the pain signals take two path-
the spino-mesencephalic, spinoreticular, spino-parabrachial and ways to the brain, through:
spino-thalamic tracts. These constitute the anterolateral system
[62]. • the neo-spino-thalamic tract (for sharp/fast discriminative pro-
These systems derive from the dorsal horn neurons that are cess), which corresponds to the spino-thalamic projections and;
postsynaptic to primary afferents. In the spinal cord, these cells • the paleo-spino-thalamic tract (much older system), which
may project either ipsilaterally or contralaterally. Past studies have corresponds to the association of the spino-reticulo-thalamic,
shown that unilateral section of the ventrolateral quadrant yields a the spino-mesencephalic and the spino-parabrachial projections
contralateral loss in pain and temperature sense in the dermatomes [65].
below the spinal level of the section. This finding indicates that
the ascending tracts may travel rostrally several segments before The paleo-spino-thalamic tract is a slower-conducting, multisy-
crossing [11] (Fig. 4). naptic tract. Fibres of this system also travel up the contralateral
anterolateral pathway to terminate in several thalamic regions,
3.2.2.2. Dorsal funiculi projection systems. The dorsal column, including the intralateral nuclei, which project to the limbic system
which becomes the medial lemniscal system at the brainstem level, [66].
transmits sensory information [37] along an ascending pathway 3.2.3.1.1. Spino-reticulo-thalamic projections. This tract termi-
(Fig. 6). The system is comprised of collaterals of larger-diameter 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-
Fig. 6. An artistic view of the spino-thalamic tract and cortical projections. mus [62]. In the thalamus, synapses are made with a third-order
Vue artistique du tractus spino-thalamique et de ses projections corticales. thalamo-cortical neuron and the pathway continues to the contro-
Graphic conception: K. Nivole, R. David and P. Rigoard. 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 sensations in the brain. Pain perception includes an awareness and
stabbing in nature [66]. This predominantly crossed system dis- interpretation of the meaning of the sensation [77]. Information
plays the following three principal targets of termination (Fig. 6). from tissue injury is carried from the spinal cord via the thalamus
The somatosensory thalamic nucleus is represented by the ven- to the brain centers, where the basic sensation of hurtfulness, or
trobasal thalamus: pain, occurs. In the neo-spino-thalamic system, the interconnec-
tions between the lateral thalamus and the somatosensory cortex
• in a somatotopic pattern, the region projects to the somatosen- are necessary to add precision, discrimination, and meaning to the
sory cortex [73–76]; pain sensation [66]. The paleo-spino-thalamic tract projects dif-
• the VM then projects into the insula; fusely from the intra-laminar nuclei of the thalamus to large areas
• the medial thalamus receives primary input from lamina I (high- of the limbic cortex. These connections may be related to the mood-
threshold nociceptive-specific cells). Cells in this region, then shifting and attention decrease effect of pain.
project to the anterior cingulate cortex. Cortical representation of fast-sharp and slow-chronic pain sen-
sation has been established by modern research [78–81]. C afferent
3.2.3.2. Neurobiological aspects [11]. stimulation is linked to activation of the secondary cortical areas,
3.2.3.2.1. Ascending projection system transmitters. Many the anterior cingulated cortex, and the posterior operculo-insular
peptides (including dynorphin, somatostatin, cholecystokinin, cortex; unlike nociceptive A∂ afferent stimulation which is related
bombesin, substance P, VIPs) are found in dorsal horn neurons to activation of the controlateral primary somatosensory cortex
projecting to brainstem sites. Also, glutamate has been seen in in the parietal lobe. This cortical area corresponds to the unique
spino-thalamic projections, suggesting the role of excitatory amino and specific location on which electrical stimulation can produce a
acid. Glutamate binding to its NMDA receptors on the postsynaptic painful sensation and whose destruction leads to chronic pain [82].
neuron is thought to induce a kind of synaptic memory in the pain With the use of positron emission tomography (PET) and func-
pathway. Substance P-containing fibres arising from brainstem tional magnetic resonance imaging (fMRI), the exact areas of the
sites have been shown to project to the parafascicular and central brain that are involved in the perception of pain in humans are
medial nuclei of the thalamus. now becoming apparent [10]. Imaging studies have implicated the
3.2.3.2.2. Plastic modulation of ascending projections. In addi- SI and SII somatosensory receiving areas of the cortex, as well as
tion to the physical characteristics of an effective stimulus, the the anterior cingulate gyrus and the insula, as important structures
encoding of a pain message also depends on the properties of for the higher processing of the pain that is evoked by acute nox-
associated systems that can modulate the excitability of synaptic ious stimuli [83–86]. All these areas systematically activated by
linkages. Therefore, glycine at the level of the spinal dorsal horn nociceptive stimuli are involved in a network classically described
and interneurons releasing GABA often regulate the frequency of as the pain neuromatrix.
discharge of second-order neurons excited by large afferent input.
3.4. Pain modulation: descending pathways
3.3. Pain perception: the cortical interface
On pain messages being sent to the brain, reciprocal projections
As the pain signals reach the cortex via thalamo-cortical pro- back to the spinal cord through descending controls are triggered by
jections, perception is the result of neural processing of pain 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- enhance serotonin activity in the brain. It also has to be noted that
ulators of pain response through monoamine systems [8]. These by stimulating the neurons projecting to the raphe magnus from
descending pathways originate in a brainstem nucleus called the the rostral pons, it is possible to produce an analgesic effect using
raphe magnus and project to the dorsal horn regions at laminae the norepinephrine pathway.
I, II, and IV [3,7]. Neurotransmitters release by these neurons can A central means for gating the flow of pain impulses from the
inhibit synaptic transmission of pain signals. Presynaptic inhibition periphery to the brain are the descending pathways. In receiving
of substance P release from nociceptor neurons is one way to inhibit input by way of thalamus and limbic structures, the PAG region is
synaptic transmission. It has also been suggested that opioids are notified of the flow of pain signals (Fig. 8).
the main mediators of presynaptic inhibition. The majority of work completed since the introduction of
The raphe magnus receives input from two other brain areas the gate control theory has concentrated on the complexity of
which have a significant role in the pain response [87–89]: inhibitory modulation beyond the segmental level (i.e. heteroseg-
mental modulation). Our grasp of heterosegmental, supra-spinal
• the periaqueductal gray (PAG) area in the midbrain; mechanisms elicited by noxious and non-noxious stimuli is ever
• the rostral pons in the brainstem. increasing. The understanding is that powerful heterosegmental
control of nociception arises from the cortex as all nociceptive
The PAG area receives input from widespread areas of CNS, relays within the CNS are under top-down (corticofugal) mod-
including the cerebral cortex, hypothalamus, brain stem reticu- ulation that most of the times occurs in the absence of painful
lar formation, and spinal cord, via the paleo-spino-thalamic tract stimuli [59]. These pathways will be developed later in this
[88,89]. This region is ultimately connected to the limbic sys- paper.
tem, which is associated with emotional experience [90]. The PAG Diffuse noxious inhibitory controls (DNIC) are inhibitory enti-
area has a high concentration of endogeneous opioids (endorphins, ties in which the caudal medulla plays a part. In this case, a noxious
enkephalins and dynorphines) that induce major analgesic effects. peripheral stimulation remote from the pain site relieves pain (e.g.
Afferent stimulation of the PAG in the midbrain and ventro- acupuncture) [59]. Responding simultaneously to the noxious stim-
medial medulla cause a release of endogenous opioids and via ulus, ascending and descending bulbospinal pathways partake in
serotonin (5-hydroxytryptamine, 5HT) also sends nerve impulses DNIC [93–95]. The total result of these supra-spinal structures is to
to the raphe magnus. The PAG region of the midbrain is often accurately encode the intensity of the noxious stimulus and trans-
referred to as the endogenous analgesia centre by stimulating effer- mit descending feedback, mainly to the deep dorsal horns.
ent pathways which modulate or inhibit afferent pain signals at The role of this modulation is reflected by the findings of work
the dorsal horn [59]. The descending pathways are thought to be by Pierre Rainville et al. [96]. Hypnotic suggestions leading to
inhibitory; the inhibitory effect is possibly the result of noradren- enhanced pain (in response to a given experimental stimulus)
ergic systems [91,92]. Serotonergic systems are known to provide a resulted in greater activity in the anterior cingulate. Indeed,
vital role in the wind-up shown in WDR neurons aroused by small disconnection syndromes, produced by prefrontal lobectomies,
afferent input. This explains the pain-relieving action of drugs that cingulotomies, and temporal lobe–amygdala lesions, lead to

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dissociation between the perception of a physical sensation and experience influence tolerance to pain. Ultimately, pain expres-
its affective component. 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-
4. Conclusion
cially with chronic back pain patients, while the famous expression:
« J’en ai plein le dos ! »/“I am sick to the back teeth!”, worldwide
4.1. Functional overview of pain nociceptive processing system
used, brings them together. This leads us to move from anatomical
concepts to practical applications and discuss about the potential
The circuitry that serves in the transduction and encoding of
spinal generators in the next paper (Part B).
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 Disclosure of interest
synaptic contact with numerous dorsal horn neurons [11]. Dor-
sal horns are areas where enterprising activities occur (inhibition, Dr. Rigoard is a consultant for Medtronic Inc. and received hon-
modulation and excitation), not simply passive transmission sta- oraria for medical training from St-Jude Medical, research grants
tions. The information is passed through long spinal tracts and from Medtronic Inc & St-Jude Medical.
an assortment of intersegmental systems to supra-spinal centres The other authors declare that they have no conflicts of interest
found in the brainstem and in the thalamus. Stimuli give rise to concerning this article.
escape behaviour and verbal report of pain via these rostrally pro-
jecting systems to the brain. This circuitry constitutes the afferent Acknowledgements
limb of the pain pathway.
The authors would like to thank Mr Lee Wesley for reviewing
this manuscript, Nancy Ladmirault for her technical help, the N3Lab
4.2. Two functionally distinct pathways for two dimensions of for its assistance and Poitiers University Hospital (Department of
pain perception Research Management, Mr Carles De Bideran, Ms Sarah Guyon) for
their support.
It is possible to characterize two different families of response
at the spinal level: physical pain and emotional pain. These are
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