European Journal of Neuroscience

Cover image for Vol. 39 Issue 3


February 2014

Volume 39, Issue 3

Pages 331–519


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      Neurotrophin and endocannabinoid interactions in the neurobiology of pain (pages 331–333)

      Tibor Harkany, Hanns Ulrich Zeilhofer and Antonino Cattaneo

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12483

    2. The molecular interplay between endocannabinoid and neurotrophin signals in the nervous system and beyond (pages 334–343)

      Erik Keimpema, Tomas Hökfelt, Tibor Harkany and Patrick Doherty

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12431

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      The molecular biology of pain involves the coincident activation of endocannabinoid and neurotrophin signaling. This review establishes receptor specificities, and molecular nodes of cross-modulation between neurotrophin and endocannabinoid signaling networks in relation to pain signaling and somatosensation. Both developmental mechanisms relevant to synapse formation and homeostatic regulation of neuronal network activity in adult are discussed.

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      The consequences of pain in early life: injury-induced plasticity in developing pain pathways (pages 344–352)

      Fred Schwaller and Maria Fitzgerald

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12414

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      Pain in infancy influences pain reactivity in later life, but how and why this occurs is poorly understood. Here we review the evidence for developmental plasticity of nociceptive pathways in animal models and discuss the peripheral and central mechanisms that underlie this plasticity.

    4. Neurotrophins, endocannabinoids and thermo-transient receptor potential: a threesome in pain signalling (pages 353–362)

      Isabel Devesa and Antonio Ferrer-Montiel

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12455

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      Pain transduction is a very complex process that involves a plethora of signalling pathways. Neurotrophins, endocannabinoids and thermoTRPs assemble a threesome that produce nociception or anti-nociception in a context-dependent manner. Thus, a systems pain approach needs to be implemented to uncover the dynamics and interplay of this intricate signalling cascade, taking into consideration the molecular complexity and cellular heterogeneity of nociceptor populations.

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      Pro-neurotrophins, sortilin, and nociception (pages 363–374)

      Gary R. Lewin and Anders Nykjaer

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12466

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      Nerve growth factor (NGF) signaling is important in the development and functional maintenance of nociceptors, but it also plays a central role in initiating and sustaining heat and mechanical hyperalgesia following inflammation. Pro-forms of the neurotrophins may also modulate of nociceptors and their connectivity under pathophysiological conditions. Here we review the mechanisms by which neurotrophins and possibly their pro-forms initiate and sustain mechanical and heat hyperalgesia.

    6. Neurobiology of pain, interoception and emotional response: lessons from nerve growth factor-dependent neurons (pages 375–391)

      Yasuhiro Indo

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12448

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      Patients with congenital insensitivity to pain with anhidrosis lack NGF-dependent neurons in the peripheral nervous system, including NGF-dependent primary afferent neurons and sympathetic postganglionic neurons. These neurons mediate reciprocal communication between the brain and the ‘body-proper’. Together with various NGF-dependent neurons in the brain, they constitute part of a neuronal network for interoception and homeostasis and play important roles in emotion and adaptive behavior.

    7. From genes to pain: nerve growth factor and hereditary sensory and autonomic neuropathy type V (pages 392–400)

      Simona Capsoni

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12461

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      Hereditary sensory and autonomic neuropathy type V (HSAN V) is an autosomal recessive disorder characterized by the loss of deep pain perception linked to missense mutation (R100W) in the NGF gene. This review highlights the recent key findings in the understanding of HSAN V, including insights into the molecular mechanisms of the disease, derived from genetic studies of patients with this disorder.

    8. Endocannabinoids and neuropathic pain: focus on neuron–glia and endocannabinoid–neurotrophin interactions (pages 401–408)

      Livio Luongo, Sabatino Maione and Vincenzo Di Marzo

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12440

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      Although originally described as a signaling system encompassing the cannabinoid CB1 and CB2 receptors, their endogenous agonists (the endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically-related endocannabinoid-like mediators and their molecular targets as well. The function and dysfunction of this complex signaling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades.

    9. Anandamide in primary sensory neurons: too much of a good thing? (pages 409–418)

      João Sousa-Valente, Angelika Varga, Kajaluxy Ananthan, Ankur Khajuria and Istvan Nagy

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12467

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      A major sub-population of nocicetive primary sensory neurons is able to accumulate, synthesise and hydrolyse the endovanilloid/endocannabinoid anandamide. These cells also express two main targets, the excitatory TRPV1 and the inhibitory CB1 receptor, for anandamide. Here, we discuss the effect of anandamide on nociceptive processing in these neurons, which could provide an explanation why increasing the tissue levels of anandamide for providing analgesia has not fulfilled its promise.

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      Heterogeneous presynaptic distribution of monoacylglycerol lipase, a multipotent regulator of nociceptive circuits in the mouse spinal cord (pages 419–434)

      Eszter Horváth, Stephen G. Woodhams, Rita Nyilas, Christopher M. Henstridge, Masanobu Kano, Kenji Sakimura, Masahiko Watanabe and István Katona

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12470

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      Inhibition of monoacylglycerol lipase (MGL), a key regulator of endocannabinoid and prostaglandin signaling produces potent analgesia. We show that MGL is highly concentrated in the spinal dorsal horn and provide confocal and electron microscopic evidence that it is presynaptically located in a heterogeneous population of axon terminals, particularly in peptidergic nociceptive primary afferents. This implies that MGL plays distinct regulatory roles in nociception at multiple synaptic locations.

    11. Microinjection of 2-arachidonoyl glycerol into the rat ventral hippocampus differentially modulates contextually induced fear, depending on a persistent pain state (pages 435–443)

      Kieran Rea, Gemma K. Ford, Weredeselam M. Olango, Brendan Harhen, Michelle Roche and David P. Finn

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12452

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      Schematic depicting the role of the vHip in both contextual fear conditioning and pain processing and the putative neural circuitry and mechanisms mediating the effects of intra-vHip 2-AG injection observed in the present study. The vHip shares connectivity with the lateral amygdala (LA), basolateral amygdala (BLA) and central nucleus of the amygdala (CeA), as well as cortical regions, from which neurons project to the periaqueductal gray (PAG) to regulate the behavioural expression of pain and fear. The re-exposure of an animal to an environment where it has previously been exposed to footshock recruits neurons in the vHip, amygdala and cortical regions to engage neurons in the PAG, resulting in the expression of conditioned fear. Upon activation of peripheral nociceptors by a noxious stimulus, nociceptive information is relayed through the dorsal horn of the spinal cord, and reaches higher centres in the brain. The ventrolateral aspect of the periaqueductal gray (vlPAG) is critically involved in the expression of contextual fear and formalin-evoked nociception. AEA (anandamide) and 2-AG (2-arachidonoyl glycerol) levels were significantly decreased in left vlPAG of fear-conditioned, formalin-treated rats i.e. the vlPAG side contralateral to the hindpaw into which formalin was injected. The suppression of conditioned freezing as a consequence of CB1 receptor activation in the vHip by 2-AG was not apparent in formalin-treated rats. These differential effects of intra-vHip 2-AG on conditioned fear responding in the absence versus presence of formalin-evoked nociceptive tone do not appear to be due to formalin-evoked alterations in levels of endocannabinoids locally in the vHip but may be related to the formalin-evoked reduction in endocannabinoid levels observed in the contralateral vlPAG. CB1R: cannabinoid receptor type 1, AEA: anandamide, 2-AG: 2-arachidonoyl glycerol, vHip: ventral hippocampus, CeA: central nucleus of the amygdala, LA: lateral amygdala, BLA: basolateral amygdala, vlPAG: ventrolateral periaqueductal gray, RVM: rostral ventromedial medulla, FC: fear-conditioned, Form: formalin.

    12. Supraspinal metabotropic glutamate receptors: a target for pain relief and beyond (pages 444–454)

      Enza Palazzo, Ida Marabese, Vito de Novellis, Francesco Rossi and Sabatino Maione

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12398

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      Glutamate is the main excitatory neurotransmitter in central nervous system controlling the majority of synapses. Apart from neurodegenerative diseases, growing evidence suggest glutamate involvement in psychiatric and neurological disorders including pain.

    13. CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model (pages 455–466)

      Guangchen Ji and Volker Neugebauer

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12432

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      Coactivation of mGluR5 and CB1 receptors in the medial prefrontal cortex (mPFC) with VU0360172 and ACEA increased the decreased activity of a subpopulation of mPFC pyramidal cells excited by nociceptive input in a rodent model of arthritis pain. Coactivation of mGluR5 and CB1 receptors in the mPFC also inhibited the increased activity of neurons in the central nucleus of the amygdala in the pain model, suggesting that restoring mPFC activity can control abnormally enhanced amygdala output.

    14. No more pain upon Gq-protein-coupled receptor activation: role of endocannabinoids (pages 467–484)

      Sherry Shu-Jung Hu, Yu-Cheng Ho and Lih-Chu Chiou

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12475

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      Marijuana has been used to relieve pain for centuries. The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2) two decades ago.

      Corrected by:

      Retraction: No more pain upon Gq-protein-coupled receptor activation: role of endocannabinoids

      Vol. 43, Issue 7, 991, Version of Record online: 3 APR 2016

    15. Involvement of the endocannabinoid system in osteoarthritis pain (pages 485–500)

      Carmen La Porta, Simona A. Bura, Roger Negrete and Rafael Maldonado

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12468

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      Osteoarthritis is a degenerative joint disease that results from damage to the articular cartilage induced by a complex interplay of genetic, metabolic, biochemical and biomechanical factors. The major clinical outcomes of osteoarthritis are disability and pain. Osteoarthritis pain represents a complex state that includes inflammatory and neuropathic components and involves a number of abnormal cellular mechanisms at both peripheral (local joint inflammation and altered cartilage and bone turnover) and central (spinal and supra-spinal) levels of the nervous system. Currently, the therapeutic approaches for osteoarthritis are limited as no drugs are available to control the disease progression and the analgesic treatment has restricted efficacy. Increasing evidence from pre-clinical studies supports the interest of the endocannabinoid system as an emerging therapeutic target for osteoarthritis pain. Indeed, pharmacological studies have shown the antinociceptive effects of cannabinoids in different rodent models of osteoarthritis and compelling evidence suggests an active participation of the endocannabinoid system in the pathophysiology of this disease. The ubiquitous distribution of cannabinoid receptors, together with the physiological role of the endocannabinoid system in the regulation of pain, inflammation and even joint function further support the therapeutic interest of cannabinoids for osteoarthritis.

    16. The upstream Variable Number Tandem Repeat polymorphism of the monoamine oxidase type A gene influences trigeminal pain-related evoked responses (pages 501–507)

      Cherubino Di Lorenzo, Andrea Daverio, Patrizio Pasqualetti, Gianluca Coppola, Ioannis Giannoudas, Ylenia Barone, Gaetano S. Grieco, Cinzia Niolu, Esterina Pascale, Filippo M. Santorelli, Ferdinando Nicoletti, Francesco Pierelli, Alberto Siracusano, Stefano Seri and Giorgio Di Lorenzo

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12458

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      Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type A (MAOA) is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing.

    17. The neurobiology of skeletal pain (pages 508–519)

      Patrick W. Mantyh

      Version of Record online: 4 FEB 2014 | DOI: 10.1111/ejn.12462

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      Skeletal pain is common and frequently difficult to fully control. Recent data suggests that the skeleton is innervated by a restricted set of nociceptors and that many skeletal pains have both a nociceptive and a neuropathic component. Significant progress has been made in defining the mechanisms that drive skeletal pain and the factors that control skeletal remodeling. These insights have the potential to fundamentally transform our understanding and ability to prevent and/or treat skeletal pain due to injury, disease, and aging.