You are on page 1of 13

G Model

NEUCHI-665; No. of Pages 13 ARTICLE IN PRESS
Neurochirurgie xxx (2014) xxx–xxx

Disponible en ligne sur

ScienceDirect
www.sciencedirect.com

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

biomechanics. performed by some complexity in the interactions between 1) a residual mechani. tioning of the pain system under normal conditions is known.3. http://dx. Université des the reader is referred to the original publications for a more detailed Saints-Pères. spinal cord stimulation. spinal fusion. The low back pain. 1) from a systematic review of the electronic literature and of all path- 2. analysed and summa- sensitization of CNS neurons within time. The following keywords were used for these searches: path- Pathophysiological changes in the pain system and associated ophysiology. Neurochirurgie (2014). aim of this paper is to provide a fundamental overview of the pain triggers. muscle pain. 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. EMBASE (Ovid).neuchi. Chicago. 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. rue de la Milètrie. neurobiology. inflammatory changes in pain perception cannot be understood unless the func- pain. missing a potential limits. Keywords be discussed with the patient. on chronic pain aspects would irremediably lead to the failure of Two reviewers (RD and PR) independently scanned all titles and “palliative” treatments.G Model NEUCHI-665. Chicago. MEDLINE InProcess (Ovid). accessible to etiologi- pain. myelotomy. The therapeutic plan has to 2. nociceptors. Its treatment remains a challenge for • Dorsch Neuroscience Library (Institute of Neurology and Neu- pain medicine. mechanisms of action. Fr). peripheral nerve stim- 2. par l’intermédiaire de la moelle épinière. pain. CNS afferents. Introduction • Poitiers Anatomy Library (Department of Morphology. neurostimulation. myogenic syn- pathway supporting the nociceptive component of the back pain drome.doi. CNS efferents. The understanding of pain perception is essential for optimal • UIC Library of Health Sciences (University of Illinois at Chicago. Citation lists in the chapters and papers consulted and etiological conflict that could require further surgery. The synopsis of • Paris Medical Library (Université Descartes. Methods threshold. No. neuro- matrix. neuropathic pain. sagittal imbalance.09. Mertens et al. – Le message douloureux nociceptif provient d’une stimulation des nocicepteurs périphériques de l’environnement tissulaire. Surgery Syndrome (FBSS) [1]. 86000 Poitiers.. PR). One of the main reasons arises from the extreme ropsychiatry. ascending tracts. discussion. whenever possible. Paris 5. spine. relayée par deux axones cen- traux contigus jusqu’au cerveau. • Paris Anatomy Library (Anatomy Laboratory. 1. gate control. US). Il est véhiculé par la fibre périphérique.. Literature analysis ophysiology.2014. anatomy and physiology textbooks available in the following medical libraries: Some well-written textbooks on pain management. chronic pain. neuroanatomy. On the other hand. Conclusion.1. pain generators.2.001 . 2) a progressive transition into chronic following electronic databases from 1930 to August 2013: MED- pain involving Central Nervous System (CNS) plasticity and molec. In order to improve functional outcomes in Library (Cochrane Central Register of Controlled Trials (CENTRAL). of Pages 13 ARTICLE IN PRESS 2 P. puis au cortex les informations nécessaires pour cartographier la dimension « sensori-discriminative » de la douleur. – La composante mécanique des LRPO ne peut être appréhendée sans une bonne connaissance des voies de la nociception. DREZ. la nature éminemment variable de l’expression clinique des lombalgies nécessitera une dissection physiopathologique minutieuse des générateurs potentiels de ces lombalgies. Tous droits réservés. France).org/10. pain pathways. but also at the site of central changes [2]. et al. afin d’orienter les stratégies de prise en charge de ces douleurs vers les options les plus adaptées au mécanisme lésionnel. facet joints. rue de l’Ecole Waldman’s textbook on pain management [4] and the following de Médecine. 75006 Paris. Literature searches ulation. these difficult-to-treat patients. pain receptors. nociception. or any other and chronic back pain component. Poitiers Medical College. The potential back pain generators. because it has been abstracts and identified potentially relevant articles for retrieval. it is possible to direct rized. / Neurochirurgie xxx (2014) xxx–xxx Résultats. References and book chapters were initially identified (Fig. Please cite this article in press as: Mertens P. Fr). Ces aires sont associées à l’émotivité et à l’affect. central sensitization. Néanmoins. Anatomy. pathophy- siology and anatomy were particularly useful. 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. back pain. cordotomy. US). © 2014 Elsevier Masson SAS. bulbospinal projections. spine instability. physiology and neurobiology of the nociception: A focus on low back pain (part A). À ce niveau. pain tolerance. only after a meticulous “pathophy- siological investigation” of all potential back pain generators. pain 2. pathological pain. physiological pain. of the authors (RD. dorsal cal treatments in FBSS patients will be reviewed in the next article horn. Cochrane ular reorganization. il est possible de caractériser une douleur physique et une douleur dite « émotionnelle ». failed back surgery syndrome. LINE (Ovid). treatments not only at the site of peripheral tissue damage. advances in our understanding of Health Technology Assessment (HTA) databases. 712 S Wood St. Paris 6e . by focusing recent systematic reviews were checked for additional references. established that intense noxious stimulation produces autonomic Full-text copies of papers were obtained. sacroiliac joint. diagnosis and treatment of the back pain component in Failed Back 1912 Polk St. La voie paléo-spino-thalamique implique également le thala- mus ventro-médian mais projette sur l’amygdale. The search strat- the underlying pathophysiological mechanisms have major impli. l’insula et le cortex cingulaire antérieur. books [5–10] largely inspired this review and. discogenic (Part A).1016/j. molecular mechanisms. anatomy. (Part B) [3]. motor cortex stimulation. On one hand.

/ Neurochirurgie xxx (2014) xxx–xxx 3 Fig. Ordinarily. Please cite this article in press as: Mertens P. nervous tissue. • the afferent pathways. Mertens et al. bone. 3. Percep. detect any alarm signal and to respond rapidly Transduction is the process of converting stimuli to neuronal to mechanical. Neurochirurgie (2014). • the integration centers located in the brain stem.G Model NEUCHI-665. 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.1. Whatever anatomical structure of the back. Nociception can be specialized primary afferent neurons [6]. and involve their terminals called “nociceptors” to constantly survey modulation [6].neuchi. conduction velocity alters directly with axon diameter cephalon. 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. 2. et al. ing to their state of myelination. No. 3. joints. The nociception processing system (the example of back • the efferent pathways that descend from the CNS back to the pain) spinal cord. physiology and neurobiology of the nociception: A focus on low back pain (part A).6]. 3.2014. named as pain matrix.09. Sensory input is gathered by the peripheral fibre from the innervated tissue’s environment. As outlined in Fig. The complex mechanism whereby synaptic trans- mission of painful signals is modified is called modulation. cutaneous surface.1. bones. Sensory input is relayed by the central axon to the brainstem or tem (PNS). conduction velocity and diameter. or chemical stimuli that are of sufficient action potentials at the sensory receptor.1016/j. the noxious stimu.doi. Upon activation. dien. which begin in the peripheral nerve sys. Pain transduction: primary afferents lus is arising from (ligaments. 2). travel to the spinal level in the dorsal horn and then spinal cord. and cerebral cortex. etc. 1. or in deep the mechanical component of the residual back pain following a tissues such as muscles. Literature searches methodology. transmission.1. or viscera and mediated trough spine surgery are termed as nociception [5. perception. muscles. midbrain. This process involves then several cortical regions. and the presence of myelination [11]. they transduce this information via receptor to the spinal cord and then centrally to the brain. the physiologic mechanisms involved in Pain is initiated by events that occur on the skin.001 . the environment. which influence all the components of the pain sensation. http://dx. Anatomy. tures and finally the brain (Fig. 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.). of Pages 13 ARTICLE IN PRESS P. These sensory neurons divided in four stages: transduction.org/10. sensory axons are classified accord- ascend to higher centers in the central nervous system (CNS). Méthodologie de recherche documentaire. thermal.

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. thus bringing about a succinct burst of action potential Activation of one branch of the nociceptor terminal by the injury (see later). mechanore- cially after chemical stimuli such as capsaicin or histamine [19]. acidic pH. Neurochirurgie (2014).18]. dependant on the stimulus modality.e. David and P. histamine). 2011.4. the axon terminal may be classified as a “free axon as well as antidromic propagation into other branches [16]. A∂ axons have a smaller diameter and are myelinated As touched above.1016/j.2014. These end- neuropeptides (such as substance P and CGRP) that are found in ings are ordinarily associated with small. Firstly. physiology and neurobiology of the nociception: A focus on low back pain (part A). http://dx. the axon will discharge. “spontaneous” afferent traffic occurs. 2. regard. Mertens et al.1.neuchi. kinins (bradykinin). chemical and mechanical can of vasodilatation (or flare). lipid mediators (prostaglandins). of Pages 13 ARTICLE IN PRESS 4 P. No. include a variety of amines (5-hydroxytryptamine. Aß axons are large and myelinated and they con. unmyelinated and respect to three physiological criteria [16]: conduct much more slowly [13]. with rising intensities of applicable stimulus. released from local injured cells or inflam- tion.e.15]. low-intensity tactile or thermal Thirdly. A∂ fibres can show activation at 3.. the system matory cells. Anatomy. generate a pain state. given to the atypical association between non-injurious stimuli and Please cite this article in press as: Mertens P. with a lack of stimula.doi. nerve endings can be morphologically specialized [11].001 .1. or chemical). Nivole. adapted from Waldman et al. different axons stimuli may. Such agents. cialized structure into a transient opening of sodium channels in the axon. The simplicity of the nerve is misleading given its name. As seen with the Pacini corpuscle found on the terminals of large heat. in fact. afferents. 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. modality (rapid versus slow response). Graphic conception: K.2. Fibres that conduct at A∂ velocity may pertain to populations that are high or low thresh- old and mechanical or thermal. The largest evidence that information that generates a pain sensation enters population of afferent axons are slowly conducting afferents. leads to orthodromic action potential propagation into the parent On the other hand. Electrophysiological characterization of nociceptors duct rapidly. R. These the central nervous system by the activation of small-diameter. Secondly. milieu [11]. chemical and mechanical afferents [11]. the This working may serve the mechanism of activating afferents post- larger the depolarization of the terminal and the more frequently acute injury. Rigoard. 3. and C-fibres are small. These polymodal nociceptors have a significant char- stimuli [11]. Properties of primary afferent function • the stimulus modalities that evoke a response (i. Diagram showing the anatomo-physiological organization of the different classes of fibres and their connections at the dorsal horn level.3. mechanical. Therefore. 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. cally insensitive afferents may play a major role in the development A range of stimuli including thermal. Under certain conditions.G Model NEUCHI-665. the more intense the stimulus. Schéma montrant l’organisation anatomo-physiologique des différentes catégories de fibres et de leurs connexions au niveau de la corne dorsale. nociceptors are often subclassified with [12] and conduct slower. 3. Low-threshold mechanical stimuli (i. operates on a very high signal-to-noise ratio. et al. Recent evidence suggests that mechani- [14. Hyperalgesia is the name may respond more efficiently. unmyelinated C-fibres terminal receptors [17. ceptors) activate the Aß (group II) fibres. often surrounding the painful area. • the temporal characteristics of their response to a stimulus The mechanical distortion of the structure is translated by the spe. Accordingly. less of fibre type examined. 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). espe- be transduced. / Neurochirurgie xxx (2014) xxx–xxx Fig.org/10. • the conduction velocity of their parent axon (i.1.e. cytokines (interleukin-1ß) and enzymes (trypsin) [16]. unmyelinated C-fibre afferents versus myelinated I-fibre afferents).09.

It is widely considered that generator [48. 3. The interrelationship between cyto-architecture and On entering the spinal cord. agents such as bradykinin [23].2. Spike initiation.5. • intrinsic spinal neurons (interneurons.2. Nonetheless. Large and small [29] and TREK [30] families. tively. action potential afferents to move medially as the nerve root reaches the spinal propagation. These aspects will be discussed in a separate Na+ channels drive membrane depolarization and K+ channels drive paper [20].doi.3. Fine-caliber. In lamina IV and the deep serve as targets both for accentuation of pain after tissue injury and dorsal horn (laminae V to VI). Transduction of painful mechanical stimuli.2014. Molecular detection of noxious chemical stimuli.1. facilitation) of transmitter release [35]. Molecular architecture of the dorsal horn. nate [45–50]. In contrast. / Neurochirurgie xxx (2014) xxx–xxx 5 pain.6.6. these afferents collateralize to send projections and spike initiation are: voltage-gated Na+ channels and voltage. of Pages 13 ARTICLE IN PRESS P. Therefore. acetylcholine. which binds selectively to receptor sites located on the modulation. It is interesting to notice that minate in the marginal zone or lamina I of Rexed. TRP 3. as with spike propagation and initiation. terminals from the small myelinated fibres (A∂) ter- sity properties of noxious stimuli [16]. Intense mechanical stimuli such as pinching a nerve or overloading a • the central terminals of primary afferents.g. Under pathophysiological condi- injury such as sunburn. peripheral nerve injury causing indispo. along with send- factors. and thereby initiate nociceptive transmission. the ventral portion the molecules that mediate post-transduction neurotransmission of lamina II.1. membrane. and adenosine triphosphate) activate both ion channels and G protein-coupled receptors to produce a wide range 3. unmyelinated afferents laterally. to as spike initiation. Central terminals of primary afferents [37]. Transmitter release. The mechanisms controlling transmitter release are also subject to ety [21]. Each of these steps requires a number of distinct ion chan. and ulation (i. The dorsal horn contains four different neuronal components [11]: 3. 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. At each spinal level. It has been shown by electrophysiological and pharmacological studies of cul. and the small.e. No. • neurons with long ascending axons that project to the brain (pro- Despite this fact. the direct application of that terminate locally).g. teromedial and ventrolateral aspects of the dorsal root entry zone membrane depolarization). afferents are anatomically intermixed in assortments of fascicles in the peripheral nerve [13]. axonal conduction may become dependent on TTX-resistant and more practically.09. Still other agents (e. 3. 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. Pain transmission: spinal cord and ascending spinal tracts mate. Spinal dorsal horn interface of direct and indirect excitatory effects [8]. Inhibition of transmitter release in protein-coupled receptors and receptor tyrosine kinases. Capsaicin possess a homovanillic acid moi.neuchi.1. gluta. accentuates that input from a sole root may primarily activate cells Please cite this article in press as: Mertens P. many of which have axons In a subset of cultured sensory neurons. transverse plane. including members of the ASIC [28]. At the level of the peripheral fibre. 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. unmyelinated C-fibres often terminate all through laminae I and II and in lamina X around the central canal 3. (DREZ) [38–43] (Fig. 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 [33.1. 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. 3).2. mitted to the spinal cord [16].51–53].1016/j. The release of neurotransmitter at the tured nociceptive neurons that certain agents (e. At The two vital classes of ion channels that underlie propagation various intervals. temporal. tions. larger myelinated fibres (Aß) termi- pharmacological treatment of such pain.1. in the (Fig. and/or calcium [16].1.2. triggers the influx of sodium conditions. Spike propagation/Action potential conduction.1.2.1. Anatomy. This governing property gated Ca2+ channels [13].1. Generally. Under some terminals of C-fibre nociceptors.1. If it involves light mechanical stimuli it is referred to as tactile 3. voltage-gated Na+ channels. recent researches have indicated [31].2. There is also ultimately pain [22]. mechanical force evokes non-selective cationic transmembrane • axons that descend from various parts of the brain. The tendency is for the large myelinated 3. lumbar articular capsule are examples of familiar cause of pain. 2) [45]. and inten. spike propagation and transmitter release 3.e. and throughout lamina V. this process requires several additional steps generally referred 3. Two channel allodynia.6. the central processes of the primary ion channel composition or properties of nociceptors results in an afferents send their projections into the dorsal horn. 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).6.2. respec. A number of candidate mechanosensory ion chan- nels have been identified. Beyond depolarization: spike initiation.5.1.5. membrane hyperpolarization of sufficient magnitude and duration to enable the Na+ channel to recover from inactivation and thereby 3. http://dx. but also that this information is trans. potentials are passively conducted along peripheral processes Primary afferents collateralize sending axons rostrally and cau- towards sites of spike initiation [16]. and neurotransmitter release cord. et al. Neurochirurgie (2014).2. 4).1. Molecular mechanisms of nociceptive signal transduction enable subsequent spike propagation [32]. currents [27]. Cyto-architecture [44].org/10. CNS neurons is as a result of the activation of these channels [36]. 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. to trigger intracellular signaling cascades that in turn sensitize depolarizing channels [26]. TTX-resistant Na+ channels may play a role in the mod- and calcium. Mertens et al. ing their axons into the dorsal horn at the segment of entry.G Model NEUCHI-665.1.2. mechanisms underlying nociceptive mechano-transduction [16]. extraordinary capacity to encode the spatial. into progressively more distal segments. sition to light touch.1.001 . relatively little is known about the molecular jection neurons).34]. physiology and neurobiology of the nociception: A focus on low back pain (part A). 3.1.

modulated by other sensory input or from CNS activity. Du stimulus nociceptif à l’intégration corticale du message douloureux. Rigoard.2. initiating glutamatergic [44]. Pain signals There is a distinction to be made between excitatory and inhibitory can either be enhanced or blocked at these synapses. It has been suggested that many a release of different classes of neurotransmitters (NT). 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). Glycine enrichment is restricted to neurons action potential. Glu).G Model NEUCHI-665. Anatomy. excitation and modulation occur. Tau). Mertens et al.56]. http://dx. Schematic representation of pain pathway molecular mechanisms.001 .1. will induce that are GABA-immunoreactive. not simply passive inae (III–VI). arising from the afferent neuron. Interneurons [44].neuchi. interneurons and ascending/descending fibres. A vast number of neurons in each neurons. R.2. There is lamina of the dorsal horn are interneurons. David and P. ␥-aminobutyric acid (GABA).1. Substance P (SP) and other peptides.. however. No.2. Numerous A∂ and C-fibres deliver somatic input from terminals in the upper part of the dorsal horn (principally lami- mechanical. adapted from Caterina et al. and also the ventral horn [44. Introduction to the gate control theory. Glutamate is the foremost transmitter used by excitatory neurons mate (Glu) Aspartate (Asp).2. GABA and glycine are the major inhibitory transmit- Other key synaptic areas involved in nociception are laminae ters in the dorsal horn.2. This anatomical region is characterized by catecholamines). Neurotransmission. several classes of NT.2. such primary afferents. kinin. rons in segments distal to the segment of entry.3. intracellular chain reactions. Graphic conception: K. including aminoacids (Asp.org/10. 3. thermal. providing one of the major tenets Please cite this article in press as: Mertens P. Représentation schématique des mécanismes moléculaires des voies de la douleur.doi. but in numerous of those in deeper lam- inhibition. tia gelatinosa [54.and postsynaptic neurotransmission pathways (e. (CGRP.4. physiology and neurobiology of the nociception: A focus on low back pain (part A). et al. At the dorsal horn level. of Pages 13 ARTICLE IN PRESS 6 P. NO and prostaglandins. 2005. main NT involved in the nociceptive transmission includes gluta. glycine is in relatively few cell bodies and axon lamina V. with axons that reside great opportunity at this point for pain signal transmission to be in the spinal cord.g.2. in the segment of entry but can also coerce the excitability of neu.09.1. almost half of neurons in lamina III. This process tic connections between the cells of primary and second-order can be considered as the substrate of a « cellular memory ». some peptides the cord involved in pain transmission known as the substan.55]. Neurochirurgie (2014). multiple synaptic connections among primary sensory afferent 3. inhibitory In summary. They are referred to as “local circuit neurons”. in the spinal cord along with being used by projection neurons and One must insist on the role of glutaminergic receptors. complex pre. The neurons in these laminae use GABA and glycine as co-transmitters. from noxious stimuli to brain perception. GABA exists in both cell bodies and axon V and VI. and chemical receptors in the periphery of nae I–III). Nivole.2014. The dorsal horns are sites where dynamic activities terminals in laminae I–II. lamina II represents a key anatomic region of aminoacids (Gly. and around one third of the neu- 3. which could ultimately modify cell 3. / Neurochirurgie xxx (2014) xxx–xxx Fig. 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”.1016/j. GABA is found in transmission stations [11]. the rons in laminae I and II. The synap- genomic expression in response to noxious stimuli. recor. interneurons. endo-opioids). some amines (serotonin. somatostatin.

09. Destructive procedures and pharmacological agents on pain nociceptive pathway.3. 5).G Model NEUCHI-665. provided in 1965. David and P. David and P. Nivole. 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. R. As the stimulus intensity is elevated from a very low intensity to a very high intensity.001 .1. The gate control’s theory. Anatomy.2014. Graphic conception: K. Rigoard.1. activated by activation of visceral afferent and somatic stimuli La théorie du gate control.org/10. these neurons display excitation. adapted from Wall. Physiological properties of dorsal horn neurons. 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).2. Mertens et al. Nivole. • wide dynamic range (WDR) neurons. R.3. they have a wide dynamic response range). 3. vibration or ther- mal stimuli cause the cells in the substantia gelatinosa to “close the pain gate”.threshold afferent inputs. et al. Rigoard.1. depending on the spinal level. Neurochirurgie (2014). 5. Wide dynamic range neurons. http://dx. • organ convergence: a neuron in the nucleus proprius can be Fig. of Pages 13 ARTICLE IN PRESS P. decreasing pain perception. / Neurochirurgie xxx (2014) xxx–xxx 7 Fig. advanced by the gate control theory [57]. No. the first cohesive explanation Neurons are excited in a given population of WDR by cuta- for the emerging complexities of pain phenomena [58]. Cibles potentielles des chirurgies lésionnelles et des agents pharmacologiques utilisés dans les douleurs réfractaires. 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.2. 1989.doi. Melzack and Wall. 4. Stimulation neous and/or deep (muscle and joint) inputs applied within the of non-nociceptive larger A fibres such as touch. This assemblage results in a Graphic conception: K. Nociceptive specificity. physiology and neurobiology of the nociception: A focus on low back pain (part A). The CNS through efferent pathways may also close partially close or open the gate (Fig.1.neuchi. Please cite this article in press as: Mertens P.2.g. 3. input from a visceral organ to that area of the body surface.2.3. it gives the WDR neu- rons the property of responding with increased frequency (e. This concept was described as a possibility of segmental inhibition of the pain [59]. 3.1016/j.

spino-parabrachial and ways to the brain. Dorsal funiculi projection systems. The VM projects principally to the insula [10]. 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.3. thalamo-cortical neuron and the pathway continues to the contro- Graphic conception: K. physiology and neurobiology of the nociception: A focus on low back pain (part A). which project to the limbic system which becomes the medial lemniscal system at the brainstem level.09. naptic tract. examples of segmental pathways relevant to the rostral transmis- sion of nociceptive information. Spino-thalamic projections. 3.2. Spino-mesencephalic projections. parietal. 3.2. 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]. 4). In the spinal cord. 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.2.neuchi. of Pages 13 ARTICLE IN PRESS 8 P.1. Ventral funicular projection systems. Neuroanatomy [10]. In the thalamus. which may project either ipsilaterally or contralaterally. This finding indicates that the ascending tracts may travel rostrally several segments before The paleo-spino-thalamic tract is a slower-conducting.2014. Ascending spinal tracts [37. which corresponds to the spino-thalamic projections and. 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. consisting of the frontal.3.1. spinoreticular. http://dx. 7). Supra-spinal projections [63. below the spinal level of the section. Included in these are On entering in the spinal cord. The lateral tract of Lissauer. Neurochirurgie (2014).2.3.1.2. These constitute the anterolateral system [62]. these cells • the paleo-spino-thalamic tract (much older system).G Model NEUCHI-665. David and P. • the neo-spino-thalamic tract (for sharp/fast discriminative pro- These systems derive from the dorsal horn neurons that are cess). the nucleus forms a shell around the medial dorsal aspects of the thalamus. et al.2. This tract termi- (Fig. 6. and the diencephalon (Fig.1016/j. 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”). synapses are made with a third-order Vue artistique du tractus spino-thalamique et de ses projections corticales. These medullary neurons project into the intra-laminar thalamic nucleus. The intra-laminar nucleus projects diffusely to wide areas of the cerebral cortex. here they synapse on neu- or ureter compressions. transmits sensory information [37] along an ascending pathway 3. L1 root stimulation ception (Fig. 3. including the intralateral nuclei. It is suggested that spinomedullar input plays an imperative role in initiating cardiovascular reflexes involved in pain response. Thus.3. 3.2.2. The supra-spinal tracts travelling in nisation need to be confirmed in humans. on the basis of their supra-spinal projections. 3. Nivole. Anatomy.1. Neurons from these areas 3.doi.2.2. Rostral transmission of nocicep- • low-frequency (> ≈0. The medullary reticular formation can also act as a relay station for the rostral transmission of nociceptive information.61] The following pathways were mainly described in different 3. Mertens et al.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. through: spino-thalamic tracts.3. 3.2.4. No. Rigoard. 6). / Neurochirurgie xxx (2014) xxx–xxx corresponding embryonary myotome and dermatome coinciding primary afferents transmitting tactile sensation and limb proprio- with the segmental location of the cell.1.3. Originating largely from neurons in contralateral laminae are some of the ascending nociceptive fibres. Fibres of this system also travel up the contralateral anterolateral pathway to terminate in several thalamic regions. 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]. [66]. In the parabrachial area. the medulla. 3.2.001 . Spino-reticulo-thalamic projections. Ipsilateral projec- tions terminate in mesencephalic and periaqueductal gray formation [68. 6).3.1. Intersegmental systems.2.3.2.64] animal species but their existence and functional anatomical orga. The dorsal column. multisy- crossing [11] (Fig. Spino-parabrachial projections. lateral parietal somatosensory area to provide the precise location Please cite this article in press as: Mertens P. the ventrolateral quadrant project into the mesencephalon.1.2. and groin pain) is underlined by viscerosomatic and musculoso- matic convergences onto dorsal horn neurons.60. mus [62]. the pain signals take two path- the spino-mesencephalic. 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]. Periaqueductal gray and reticular neurons project caudally to the dorsal horn and rostrally into the lateral thalamus [11].org/10. postsynaptic to primary afferents. 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 limbic regions (Fig. Past studies have corresponds to the association of the spino-reticulo-thalamic.69]. R. Forming part of the classic ascending reticular activating system and relat- ing to mechanisms leading to increased global cortical activation [11].2. An artistic view of the spino-thalamic tract and cortical projections. short distances ipsilaterally. 2).

Descending pathways from the brain Please cite this article in press as: Mertens P. reciprocal projections As the pain signals reach the cortex via thalamo-cortical pro. or trobasal thalamus: pain. Many the anterior cingulated cortex. interpretation of the meaning of the sensation [77].G Model NEUCHI-665. project to the anterior cingulate cortex.2.2. C afferent 3. In the neo-spino-thalamic system.2.3. substance P. to the brain centers. Therefore. sharp.3. 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]. spino-parabrachiales et néo-spino- thalamiques. spino-parabrachial pro- jections and neo-spino-thalamic projections. http://dx. Ascending projection system transmitters.2. including spino-reticulo-thalamic projections. 6). 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. Diagram showing the supra-spinal ascending projections. Pain perception includes an awareness and stabbing in nature [66]. This predominantly crossed system dis. Pain perception: the cortical interface On pain messages being sent to the brain. The paleo-spino-thalamic tract projects dif- • the VM then projects into the insula. These connections may be related to the mood- threshold nociceptive-specific cells). Cortical representation of fast-sharp and slow-chronic pain sen- sation has been established by modern research [78–81]. from tissue injury is carried from the spinal cord via the thalamus The somatosensory thalamic nucleus is represented by the ven. Neurobiological aspects [11]. physiology and neurobiology of the nociception: A focus on low back pain (part A). Plastic modulation of ascending projections. y compris les projections spino-réticulo-thalamiques. somatostatin. 3. 3. stimulation is linked to activation of the secondary cortical areas.001 . No.09. unlike nociceptive A∂ afferent stimulation which is related bombesin. Anatomy. then shifting and attention decrease effect of pain.4. and meaning to the sory cortex [73–76]. Substance P-containing fibres arising from brainstem tional magnetic resonance imaging (fMRI). of the pain.2.3. are necessary to add precision. back to the spinal cord through descending controls are triggered by jections. 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. cortex. In addi. the the anterior cingulate gyrus and the insula. This cortical area corresponds to the unique spino-thalamic projections. of Pages 13 ARTICLE IN PRESS P. perception is the result of neural processing of pain inputs into the midbrain [77]. VIPs) are found in dorsal horn neurons to activation of the controlateral primary somatosensory cortex projecting to brainstem sites.2014. David and P. suggesting the role of excitatory amino and specific location on which electrical stimulation can produce a acid.1016/j. Rigoard. pain sensation [66]. SI and SII somatosensory receiving areas of the cortex. Typically. neuron is thought to induce a kind of synaptic memory in the pain With the use of positron emission tomography (PET) and func- pathway. occurs. Nivole. the interconnec- tions between the lateral thalamus and the somatosensory cortex • in a somatotopic pattern. All these areas systematically activated by linkages. and the posterior operculo-insular peptides (including dynorphin. of the limbic cortex. Neurochirurgie (2014).neuchi.3. or sensations in the brain. spino-mésencéphaliques. Cells in this region. spino-mesencephalic projections.2. R. discharge of second-order neurons excited by large afferent input. 7. where the basic sensation of hurtfulness. Also. Schéma montrant les projections ascendantes supra-spinales. et al. / Neurochirurgie xxx (2014) xxx–xxx 9 Fig. fusely from the intra-laminar nuclei of the thalamus to large areas • the medial thalamus receives primary input from lamina I (high. Glutamate binding to its NMDA receptors on the postsynaptic painful sensation and whose destruction leads to chronic pain [82]. as well as tion to the physical characteristics of an effective stimulus.org/10. the region projects to the somatosen. Graphic conception: K. Information plays the following three principal targets of termination (Fig. Imaging studies have implicated the 3.1. cholecystokinin. discrimination. Pain modulation: descending pathways 3.doi.2. glutamate has been seen in in the parietal lobe. now becoming apparent [10]. Mertens et al. the pain is experienced as bright.

enhance serotonin activity in the brain. vital role in the wind-up shown in WDR neurons aroused by small disconnection syndromes. increasing. This explains the pain-relieving action of drugs that cingulotomies. and IV [3. Diagram showing descending pathways involved in pain modulation. 8. In receiving of substance P release from nociceptor neurons is one way to inhibit input by way of thalamus and limbic structures.neuchi. Indeed. It has also been suggested that opioids are notified of the flow of pain signals (Fig. mainly to the deep dorsal horns. hypothalamus. 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. Neurochirurgie (2014). Hypnotic suggestions leading to inhibitory.2014. These pathways will be developed later in this [88. peripheral stimulation remote from the pain site relieves pain (e.G Model NEUCHI-665. the PAG region is synaptic transmission. / Neurochirurgie xxx (2014) xxx–xxx Fig. Mertens et al. In this case. et al. These by stimulating the neurons projecting to the raphe magnus from descending pathways originate in a brainstem nucleus called the the rostral pons.09. ties in which the caudal medulla plays a part. mechanisms elicited by noxious and non-noxious stimuli is ever • the rostral pons in the brainstem. The descending pathways are thought to be by Pierre Rainville et al.7]. This region is ultimately connected to the limbic sys. No. 8). to the dorsal horn region of the spinal cord are important mod. produced by prefrontal lobectomies. adapted from Waldman et al. lead to Please cite this article in press as: Mertens P.org/10. 5HT) also sends nerve impulses DNIC [93–95].doi. and temporal lobe–amygdala lesions. physiology and neurobiology of the nociception: A focus on low back pain (part A). it is possible to produce an analgesic effect using raphe magnus and project to the dorsal horn regions at laminae the norepinephrine pathway. Graphic conception: K. enhanced pain (in response to a given experimental stimulus) ergic systems [91. I. the main mediators of presynaptic inhibition.001 . David and P. relays within the CNS are under top-down (corticofugal) mod- including the cerebral cortex. Presynaptic inhibition periphery to the brain are the descending pathways. 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]. Rigoard. brain stem reticu. paper. mit descending feedback. It also has to be noted that ulators of pain response through monoamine systems [8]. ascending and descending bulbospinal pathways partake in serotonin (5-hydroxytryptamine. Our grasp of heterosegmental.e. The PAG Diffuse noxious inhibitory controls (DNIC) are inhibitory enti- area has a high concentration of endogeneous opioids (endorphins. Nivole. Anatomy. supra-spinal • the periaqueductal gray (PAG) area in the midbrain.92]. afferent input. Responding simultaneously to the noxious stim- medial medulla cause a release of endogenous opioids and via ulus. Neurotransmitters release by these neurons can A central means for gating the flow of pain impulses from the inhibit synaptic transmission of pain signals. of Pages 13 ARTICLE IN PRESS 10 P. [96]..1016/j. via the paleo-spino-thalamic tract stimuli [59]. Schéma montrant les voies descendantes impliquées dans la modulation de la douleur. the inhibitory effect is possibly the result of noradren.g. and spinal cord. ulation that most of the times occurs in the absence of painful lar formation. II. 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. 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. acupuncture) [59]. Serotonergic systems are known to provide a resulted in greater activity in the anterior cingulate. Afferent stimulation of the PAG in the midbrain and ventro.89]. which is associated with emotional experience [90]. 2011. tem. a noxious enkephalins and dynorphines) that induce major analgesic effects. The total result of these supra-spinal structures is to to the raphe magnus. heteroseg- mental modulation). R. http://dx.

Anatomy. Thus. not simply passive transmission sta. the highly variable nature of pain expression among individuals makes accurate pain assessment difficult. Nancy Ladmirault for her technical help. Vanilloid (Capsaicin) receptors and mechanisms. Mertens et al.2. Weidner C. pain expres- its affective component. Pathophysiology of pain perception. [15] Sugiura Y. The authors would like to thank Mr Lee Wesley for reviewing this manuscript. Spinal termination of functionally identified primary the amygdala. as is the broad range Saunders. an “affective-motivation” component of the induced responses in acutely isolated rat spinal dorsal horn neurons. and received hon- modulation and excitation). tem competent of mapping a sensory-discriminative dimension of [17] Murase K. escape behaviour and verbal report of pain via these rostrally pro- jecting systems to the brain. These cells project massively into several brainstem and [6] Huether S. nociceptive pain has been extensively reviewed in this article. Hunt S.org/10. gender. No. Mertens P.11(3):645–8. while the famous expression: « J’en ai plein le dos ! »/“I am sick to the back teeth!”. 2012. Mo: Elsevier. among individuals and within the same individual under different [21] Szallasi A. rophysiol 1989. Blumberg PM. 2005.234(4774):358–61. Huether SE. tion needed for mapping the “sensory-discriminative” dimension [5] Copstead LE. Ultimately. a wide array of non-noxious to severely aversive intensities con. Difference in distribution of central terminals As demonstrated by fMRI and PET. Randic M. Pa. J Neu- stimuli initiate activation within the anterior cingulate cortex [97]. Ryu PD. substrate with its pinpoint somatosensory map portrays a sys- Koltzenburg M. thus providing an important sub. [19] Schmelz M. and previous Pharmacol Rev 1999. (Hors-série)). Rigoard P.. Functional overview of pain nociceptive processing system used. encoding two dimensions of pain perception. conditions. 2010. (Hors-série)). [3] Rigoard P. Mo: Mosby Elsevier. Hosoya Y. 2009. Perl ER. Gold M.20(3):404–19 [Discus- sistent with the convergence of low and high-threshold afferent sion 435–513].neuchi. In comparison. [9] McCance KL. David R.103(1):56–63. 2004. strong somatic and visceral between visceral and somatic unmyelinated (C) primary afferent fibers. These marginal cells project heavily to the parabrachial nuclei. Pain man- agement. the medial thalamic nuclei. / Neurochirurgie xxx (2014) xxx–xxx 11 dissociation between the perception of a physical sensation and experience influence tolerance to pain. Oxford University Press. Mosby Inc. whereas non-noxious stimuli generally have minimal effect. Blond S. Lee CL. Conclusion cially with chronic back pain patients. populations of superficial marginal cells show a strong adults and children. This circuitry constitutes the afferent Acknowledgements limb of the pain pathway.G Model NEUCHI-665. afferent neurons with slowly conducting myelinated fibers. Pathophysiology. Philadelphia. [10] Paxinos G. Behav Brain Sci 1997. Pathophysiological characterisation of tion and information regarding the stimulus over a range of various back pain generators in Failed Back Surgery Syndrome (Part B).62(4):834–40. It is possible to characterize two different families of response at the spinal level: physical pain and emotional pain. Please cite this article in press as: Mertens P. Neurosci pain pathway is suggested with the system involving the limbic Lett 1989. 2010. The information is passed through long spinal tracts and from Medtronic Inc & St-Jude Medical. These create their Disclosure of interest synaptic contact with numerous dorsal horn neurons [11]. 2004. to the VM. Factors Leading to the Chronification of Pain. Banasik JL. Two functionally distinct pathways for two dimensions of for its assistance and Poitiers University Hospital (Department of pain perception Research Management.47(1):85–93. spinal projection system (paleo-spino-thalamic pathway (Fig. WDR [1] Lautenbacher S. 6). McCance K. Pain tolerance is the degree of pain that [20] Blond S. Michael K. PA: Elsevier/Saunders. Oxford: Oxford University Press. In neo-spino-thalamic pathway (Fig. 2011. 6).51(2):159–212. Chapter 2. Pain perception is influenced by attention. These are References supported by two different pathways. San Diego: Elsevier. Philadelphia. http://dx. fatigue and previous experiences and expectations iontophoretic application of N-methyl-D-aspartic acid and substance P. is willing to bear before seeking relief. activity is evoked by stimuli in specific groups of small myelinated or unmyelinated primary afferents. of intensity-frequency encoding. Dor- sal horns are areas where enterprising activities occur (inhibition. Stimuli give rise to concerning this article. Age. Chapter 1. Meyer R. Torebjörk HE. Luo D. These areas are associated 1979. 2005. Pathophysiology: the biologic basis for disease in receive. Lapierre F. et al. brings them together.2014. Mertens P. oraria for medical training from St-Jude Medical. Neurochirurgie (2014). Peripheral and central hyperexcitability: differential signs and symptoms in persistent pain. research grants tions.doi. The human nervous system. the [7] Hall JE. [8] Hunt SP. distraction. sion is the way in which the pain experience is communicated to others [98]. (Submitted for publication in Neurochirurgie. Central projections of identified. [18] Dougherty PM. At every level.001 . 2011.55(4–5):360–74. upbringing. This [16] Caterina M. Mai JK. Pain [77]. This type of system is able to provide the informa- [4] Waldman SD. Molecular biology of nociceptors. to [12] Light AR. Katz J. Louis. The WDR system can retain spatial localisation informa. Science 1986. St. Excitatory and inhibitory amino acids and peptide- pain. From “mechanical” to “neuropathic” back pain in FBSS patients. London: map of the body surface is precisely preserved. an individual to another. Textbook of medical physiology. Neurochirurgie with emotionality and affect [11]. strate for systems underlying the affective-motivational elements [14] Sugiura Y. PA: Elsevier/Saunders. The neurobiology of pain: (molecular and cellular As determined by the high-threshold afferent input they neurobiology).186(2):133–50. Pain tolerance varies widely (Submitted for publication in Neurochirurgie. nociceptive-specific encoding characteristic in the second supra. In: The neurobiology of pain: (molecular and cellular neurobiology). Ms Sarah Guyon) for their support. Philadelphia. fear. Mr Carles De Bideran. Terui N. 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. (Part C). 1991. Pain threshold is the level of painful Which nerve fibers mediate the axon reflex flare in human skin? Neuroreport stimulation required to be perceived and is remarkably similar from 2000. Pathophysiology. Dr. Koltzenburg M. the insula. Guyton AC. responses to chemical and mechanical stimuli following combined micro- anxiety. neurons. Rappels sur le nerf périphérique. afferent fibers innervating mammalian skin. David R. family. old and pain tolerance [5]. [13] Rigoard P. Handwerker HO. Fillingim RB. Pain management. unmyelinated (C) of the pain experience. of pain. of Pages 13 ARTICLE IN PRESS P. Pri- marily. espe- 4. [2] Coderre TJ. culture. diencephalic sites to the somatosensory cortex. intensities.1016/j. physiology and neurobiology of the nociception: A focus on low back pain (part A). Online for understanding pathophy- siology. Pain perception can be also described in terms of pain thresh. Enhancement of spinothalamic neuron forebrain.1. Rigoard is a consultant for Medtronic Inc. 2013. New York: neurons encode information onto their dentrites and soma over Kluwer Academic/Plenum. Willis WD. worldwide 4. Schmidt R. 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). Anatomy of the pain processing system. J Comp Neurol and then to the anterior cingulate cortex.09. [11] Yaksh T. Maryland Heights. Perl ER. the N3Lab 4.

[64] Tracey I. Ascending projections from the area around [86] Bushnell MC. mesencephalon: an anatomical study in the monkey. Staats PS. Lazdunski M. [44] Todd A. Honoré E. the posterior [42] Rath SA. Treanor J. a targets for nociceptive primary afferents: do single neurone morphological nonselective cation channel that confers sensitivity to extracellular osmolarity. tation of pain: functional characterization of nociceptive areas near the lateral [49] Hayes NL. Wang R. Mo. Chung JM. Mechanical transduction by rat dorsal [59] Huether SE. J Pain Off J Am Pain Soc 2002. J Biol Chem 1999. system. Friston KJ. J Neurophysiol 2000. Sang CN. Chavoshy S. GABA(A) receptor facilitation of neurokinin release Lippincott Williams & Wilkins. system G Paxinos. J Comp localization of response to pain in man using positron emission tomography.(150): 1999. Neurosci Lett 1989.14(7):4095–108. Nunnenmacher K. [55] Willis WD. Carstens E. and glycine-like immunoreactivities in the spinal cord of the rat. horn.org/10.51(2–5):170–4. physiology and neurobiology of the nociception: A focus on low back pain (part A). from rat sensory neurons in culture through activation of P2Y receptors. and [56] Todd AJ. Lenz FA. Sunderland. [70] Burstein R. T2-T5 spinothalamic neurons [85] Di Piero V. Spinal dorsal horn neurone [29] Strotmann R. Somatosensory projection to the Soc Neurosci 2001. Schultz G. Reichardt LF. A thalamic nucleus specific for [41] Campbell JN. The hyperalgesic effects of 1990. Shao LR. Pain intensity processing a physiologically novel population of spinal cord neurons.5(5):861–74. Treat. Berger KL. de Abreu Castro MS. J Neurosci Off J [69] Wiberg M. Hodge CJ.2014. Meyer E.130(4):1013–27. Baltimore: Williams & Wilkins. [54] Schoenen J. Kim C-S. [26] Shu XQ. Antoniadis G. ulation. Spinothalamic asnd spinomedullary neurons in sulcus. In: Pathophysiology: the biologic basis for disease in adults and children [28] García-Añoveros J. In: The human nervous 3.96(14):7693–6. TRAAK is a mam. Weinreich D. Wu X. Ascending axon degeneration following [36] Hu H. 1381–7. Qi LY. [27] McCarter GC. distributed mechanism. Neurosci Lett 1999. Philadelphia. J Comp Neurol 1979. Sensory mechanisms of the spinal cord. J Comp Neurol [83] Coghill RC. Giesler Jr GJ. Ionic channels of excitable membranes. Plant TD. et al. Oxford University Press. Vasko MR. Neuroanatomy of the pain system and of the path- [40] Rawlings 3rd CE. Plenum Press. Sensory mechanisms of the spinal cord. In: Pharmacol Exp Ther 2003. Nature 1994.6(5):541–3.389(6652):749–53. Mertens et al. 1999. Anesth Analg 1998.92(1–2):267–76. Yezierski RP.3(2): [43] Jeanmonod D. 2005. [75] Willis Jr WD.54(1):73–89. A possible spino (trigemino)-ponto- [39] Nashold Jr BS. J Comp Neurol [24] Ferreira SH. Girardot MN. Brain J Neurol activated K+ channels in glutamatergic hippocampal terminals and their role 1960. Feferman ME. Touch at the molecular level. Brain Res Rev 2007. 167–73. Meyer E. Westlund KN. Br J Neurosurg 1989. Maisog JM. indication and results of 79 consecutive procedures. Curr Biol CB 1996. Philadelphia: [34] Lao L. Nashold Jr BS. Activation of ATP P2X receptors elicits glutamate release 1982. Ribeiro-da-Silva A. James CS. Somatosensory function following dorsal root entry 79–94.188(4):543–73. Molecular architecture of the dorsal horn. Honda CN.98(1):177–82. Soliman N. J Neurosurg [76] Zhang X. Pain system.2(10):695–702. Anatomy. Martin RF. el-Naggar AO. / Neurochirurgie xxx (2014) xxx–xxx [22] Robbins WR. MacDermott AB.74(6):916–32.26:1–30. Giesler Jr GJ. Lesage F. Chapter 35. Dis- 1989. Meller S.129:245–57.415(3):341–67. of the proposed VMpo nucleus in pain. Gerhart KD.21(24):9585–97.96(3):414–95.82(4):1934–43. Projections from the marginal [79] Talbot JD. [52] Ammons WS. Stereotact Funct Neuro. vier/Saunders. Foreman RD. et al. [31] Gold MS. Nauta WJ. Corey DP. Ha B.96(14):7705–9. Carrier B. 2012. Zhang ET. and headache. cervical spinal cord of monkeys. 1978. rons that project to medial and/or lateral thalamic nuclei: evidence for [84] Coghill RC. Neurotrophins: roles in neuronal development and human.68(1–4 Pt 1):161–7.23(1):158–66. Hofbauer RK. Pantano P. Cytoarchitectonic and immunohistochem- Appl Neurophysiol 1988. [68] Mehler WR.46(2):173–90.1016/j. Spinothalamic tract neu. Role of thalamus in pain. Pain perception: the spinal cord central canal: a phaseolus vulgaris leucoagglutinin study in rats.85(9):3245–9. Giesler Jr GJ. J Neurophysiol 1994. Iadarola MJ. Besson JM. Ferracuti S. Bushnell MC. Westman J. Peschanski M. Rustioni A. et al. [46] Willis Jr WD. Coggeshall.G Model NEUCHI-665. The cerebral signature for pain perception and its mod- [32] Hille B. nations of the dorsolateral and ventral spinothalamic pathways. Prog Brain Res 2000. Neurotrophins and hyperalgesia. The DREZ procedure: an update ways that modulate pain. Talbot JD. Brain J Neurol lations for deafferentation pain related to spinal and peripheral nerve lesions: 2000. Please cite this article in press as: Mertens P. Pain. J Neurosci [51] Giesler Jr GJ. et al. [65] Willis WD. [48] Willis WD. Bromm B. J Comp Neurol [37] Willis Jr WD. Essentials of pathophysiology: concepts of altered health states. anterolateral cordotomy. Solomon CT. PA: Else- function. Manning DC. A cere- projecting to medial thalamus with viscerosomatic input. [73] Craig AD. [57] Katz J. Mass: Sinaur Asso. Core text of neuroanatomy.273(3):179–82. Somatosensory and visceral input to the hypothalamus and limbic [38] Nashold Jr BS. A critical review of the role surg 1997. Frackowiak RS.doi. Pain mechanisms: labeled lines versus convergence in central malian neuronal mechano-gated K+ channel. Pain 1994. Levine JD. McCance KL. characteristics suggest how nociceptive information is processed at the spinal Nat Cell Biol 2000. The cytoarchitectonic organization of the spinal cord in the cat. Soc Neurosci 2003. Willis WD. Willis WD. from sensory neuron synapses. on technique. http://dx. New York: Kluwer Aca- [33] Huang H. Lenzi GL. OTRPC4. [30] Maingret F. Haber LH. Koeppe RA. Mantyh PW. Sabatini U. Fosset M. The posterior insular-opercular region and the search 1980. 15. level.296(3):496–505. Minoshima S. Cortical represen- spinothalamic tract.14(1):2–31. Light microscope study of the coexistence of GABA-like antagonists have analgesic actions. Pain mechanisms: a new theory. Wall P. Melzack R. The Hopkins experience with lesions of the pain and temperature sensation.3(6):633–42. Seitz K. Bushnell MC. of Pages 13 ARTICLE IN PRESS 12 P. zone and deep dorsal horn to the ventrobasal nuclei of the primate thalamus.100(1–3):83–8. Mendell LM.55(3):377–91. J Comp Neurol [35] Gu JG. Blomqvist A. Allen RW. J Neu.86(3):579–83. Prog Brain Res 1996. Redistribu. Science 1965.306(3):1137–44. 2010. J Neurophysiol bral blood flow study on tonic pain activation in man.001 . Science Pain 2001. prostacyclin and prostaglandin E2. Neurol 1952.83:718–50. Dorsal root entry zone lesions for pain relief. J Neurosci Off J [63] Dostrovsky JO.16(1):31–7. Maxwell D. Porreca F. ATP augments peptide release demic/Plenum Publishers. Chapter root ganglion neurons in vitro.274(3): processing. [53] Wang CC. 2011. Leonard RB. Zhang X. Marvizón JCG. Neuroscience [82] Garcia-Larrea L. 1999. Annu Rev Neurosci 2003. The dendritic organization of the human spinal cord: the dorsal ment of intractable pain with topical large-dose capsaicin: preliminary report. p. 971–9. Maryland Heights. Evans AC. 1992. sleep and sensory function.56(2): 1985. Kenshalo Jr DR. Blomqvist A. Levine J. Frey KA. 2004. [78] Jones AK. Proc Natl Acad Sci U S A [58] Melzack R. with emphasis on structures impor. 1984.123(Pt 3):601–19. Pain 2000. Duncan GH. Duncan GH. [47] Trevino DL.251(4999):1355–8. [74] Blomqvist A. Chen JI. Ostdahl RH. Sindou M. in the human thalamus. Position of spinothalamic tract axons in upper 1991. emission tomographic analysis of cerebral structures activated specifically by Brain Res 1975. J Clin Neurophysiol 1997. Annu Rev Neurosci 2001. Craig AD. portion of the ventral medial nucleus. In: Pain management Waldman SD. Prostaglandins 1978. Nakamura M. in spike repolarization and regulation of transmitter release. Sullivan AC. Trieb M. J Neurophysiol within the human brain: a bilateral.46(6):1285–308. Richter HP. Cortical and subcortical [45] Rexed B. Campbell JN. 1994. [71] Bernard JF. New York: [23] Steranka LR. Hunt S. JK Mai. Somatosensory function. Bushnell MC. DREZ coagu. Neurosurgery amygdaloid pathway for pain. Thalamic termi. DeHaas CJ. Westlund KN. et al. Neuron 2007. Zhang ET. from primary afferent terminals in the rat spinal cord. Behrens R. Confirmation of the location of spinothalamic neurons [80] Casey KL. Multiple representations of pain in human cerebral cortex. Gjedde A. Nature 1997. repetitive noxious heat stimuli. Marrett S. Huether SE. Fields HL. Morrow TJ. Yezierski RP.372(6508):770–3. Koltzenburg M. In: The neurobiology of pain: (molecular and cellular neurobiology). Positron in the cat and monkey by the retrograde transport of horseradish peroxidase. Chapter 1. Zhang X. The cells of origin of the primate [81] Treede RD.87(2):113–9.55(2):297–313.7(9):2057–87. Chapter [77] Willis Jr WD. tributed processing of pain and vibration by the human brain. 1991. San Diego: Elsevier.24:677–736. Chapter 30. Reichling DB. Harteneck C. of a primary cortex for pain. Kahamba JF.09. tant for pain. Apkarian AV. Cells of origin of the spinoreticular tract in the monkey. 1991. Neuroscience 1982. Greenspan JD. J Neurophysiol 1981. A conceptuel framework for understanding pain in the [25] Huang EJ. Bradykinin as a pain mediator: receptors are localized to sensory neurons. et al. Connor JR. 1987. rosurg 1979. Borosky SA.107:257–67. Nicol GD. [60] Morris R.244(1309):39–44. dorsal horn (Nashold’s operation) for pain from avulsion of the brachial plexus. No. An experimental study in the monkey. temperature regulation. Primate spinothalamic pathways: III.8 in uninjured axons enables neuropathic pain. Proc Biol Sci 1991. Cheunsuang O. 481. 2004. is there a role for primary somatosensory cortex? Proc Natl Acad Sci F USA J Comp Neurol 1999.84(3):1180–5. Westlund KN.15(6):942–4. Gu N. ical characterization of a specific pain and temperature relay. Ferkany JW.42(5):299–313. Mechanosensation. pain. tion of Na(V)1. [61] Craig ADB. Brain Res Brain Res Rev 2004.264(1):92–117. Stewart A. Brown WD.neuchi. [72] Willis WD. Cruccu G. macaques: a single and double retrograde tracer study. Presynaptic Ca2+. [62] Carpenter MB. The somatosensory system. 2007. Honda CN.51(1):59–69. Neuroscience [67] Kevetter GA.: Mosby Elsevier. ciates. 2005. Willis WD. Neurochirurgie (2014). Honda CN.207(1):61–74.71(2):802–7. Evans AC. Neurophysiol Clin Clin Neurophysiol [50] Apkarian AV. Proc Natl Acad Sci U S A 1988. J [66] Mattson Porth C. Current status of the DREZ operation: 1984. zone lesions in patients with neurogenic pain or spasticity.288(3):493–511.

Pain 1979.187(3):513–31. Besson JM. Textbook of pain. Besson JM. et al. Brain Res 1983. Brain mechanisms of pain affect and pain modulation. Louis. Effects on dorsal horn convergent neurones in the rat. In: Pathophysiology LE Copstead. 1994. [89] Basbaum AI. [90] Fields HL. [96] Rainville P. 2013. Oliveras JL. Pain. Neurochirurgie (2014). J Comp Neurol 1979. Noradrenergic projections Mo: Elsevier.164:317–22.12(2):195–204. Bowker RM.org/10.G Model NEUCHI-665. http://dx. [97] Peyron R. Dickenson AH. Diffuse noxious inhibitory controls (DNIC). Besson JM. Anatomy.263(1):15–31. Biol Res and inhibitory effects on spinal cord interneurons. St. in stimulation producing analgesia in unrestrained freely moving cats. Guilbaud G. Descending projections of the locus coeruleus Parietal and cingulate processes in central pain.84(1):77–87.6(3):305–27. Coulter JD. physiology and neurobiology of the nociception: A focus on low back pain (part A). Richard A. [98] Marsh J.neuchi. Pain of pain modulation. Coulter JD. 1980. et al. Curr Opin tem mechanisms of pain modulation.2(3):235–64. Edinburgh: Neurobiol 2002. Please cite this article in press as: Mertens P. The activation of bulbo-spinal controls by ulation of the periaqueductal gray matter in the cat: behavioral observations peripheral nociceptive inputs: diffuse noxious inhibitory controls. 243–57. p. 1995. Dickenson AH. Le Bars D. to the spinal cord of the rat.28(1):113–25. Brain Res 1973. of Pages 13 ARTICLE IN PRESS P. supraspinal involvement and Res 1979. Churchhill Livingstone.doi. theoretical implications. Fields HL. A combined positron emission and subcoeruleus/medial parabrachial nuclei in monkey: axonal transport tomography (PET) and functional magnetic resonance imaging (fMRI) study of studies and dopamine-beta-hydroxylase immunocytochemistry. Lack of effect on non-convergent neurones. 1979. Mertens et al. I. Brain II. Diffuse noxious inhibitory controls funiculus of the spinal cord of the cat and rat: further studies on the anatomy (DNIC). Brain Res an unusual case. Melzack R. J Babasik. The origin of descending pathways in the dorsolateral [95] Le Bars D.50(2):441–6.001 .1016/j. Grégoire MC. Lavenne F. Chapter 47. 3rd ed. Besson JM. Basbaum AI.6(3):283–304. [91] Westlund KN. Analgesia from electrical stim. [93] Villanueva L. [88] Oliveras JL. editors. No. Central nervous sys. [92] Westlund KN. Convers P. Guilbaud G. García-Larrea L. / Neurochirurgie xxx (2014) xxx–xxx 13 [87] Liebeskind JC. A map of serotoninergic structures involved [94] Le Bars D.2014.09. Pain 2000. In: Wall PD. Ziegler MG.