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The Nav1.7 Channel Subtype As an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons Tânia C

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The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons Tânia C. Gonçalves, Evelyne Benoit, Michel Partiseti, Denis Servent To cite this version: Tânia C. Gonçalves, Evelyne Benoit, Michel Partiseti, Denis Servent. The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons. Frontiers in Pharmacology, Frontiers, 2018, 9, pp.1000. 10.3389/fphar.2018.01000. hal-02019554 HAL Id: hal-02019554 https://hal.archives-ouvertes.fr/hal-02019554 Submitted on 10 May 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. fphar-09-01000 October 23, 2018 Time: 12:20 # 1 REVIEW published: 04 September 2018 doi: 10.3389/fphar.2018.01000 The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons Tânia C. Gonçalves1,2, Evelyne Benoit2,3, Michel Partiseti1 and Denis Servent2* 1 Sanofi R&D, Integrated Drug Discovery – High Content Biology, Paris, France, 2 Service d’Ingénierie Moléculaire des Protéines, CEA de Saclay, Université Paris-Saclay, Gif-sur-Yvette, France, 3 Institut des Neurosciences Paris-Saclay, UMR CNRS/Université Paris-Sud 9197, Gif-sur-Yvette, France Although necessary for human survival, pain may sometimes become pathologic if long-lasting and associated with alterations in its signaling pathway. Opioid painkillers Edited by: are officially used to treat moderate to severe, and even mild, pain. However, the Yuri N. Utkin, consequent strong and not so rare complications that occur, including addiction and Institute of Bioorganic Chemistry (RAS), Russia overdose, combined with pain management costs, remain an important societal and Reviewed by: economic concern. In this context, animal venom toxins represent an original source Sandrine Cestèle, of antinociceptive peptides that mainly target ion channels (such as ASICs as well as UMR7275 Institut de Pharmacologie TRP, CaV,KV and NaV channels) involved in pain transmission. The present review Moléculaire et Cellulaire (IPMC), France aims to highlight the NaV1.7 channel subtype as an antinociceptive target for spider Maria Elena De Lima, toxins in adult dorsal root ganglia neurons. It will detail (i) the characteristics of these Universidade Federal de Minas Gerais, Brazil primary sensory neurons, the first ones in contact with pain stimulus and conveying the *Correspondence: nociceptive message, (ii) the electrophysiological properties of the different NaV channel Denis Servent subtypes expressed in these neurons, with a particular attention on the NaV1.7 subtype, [email protected] an antinociceptive target of choice that has been validated by human genetic evidence, Specialty section: and (iii) the features of spider venom toxins, shaped of inhibitory cysteine knot motif, This article was submitted to that present high affinity for the NaV1.7 subtype associated with evidenced analgesic Pharmacology of Ion Channels efficacy in animal models. and Channelopathies, a section of the journal Keywords: voltage-gated sodium channels, NaV1.7 channel subtype, spider toxins, pain, dorsal root ganglia Frontiers in Pharmacology neurons, electrophysiology Received: 22 June 2018 Accepted: 14 August 2018 Published: 04 September 2018 Abbreviations: ASIC, acid-sensitive ionic channel; BGB, blood-ganglia-barrier; BNB, blood-nerve-barrier; CaV channel, Citation: voltage-gated calcium channel; CNS, central nervous system; DRG, dorsal root ganglia; EC50, effective concentration Gonçalves TC, Benoit E, Partiseti M necessary for increasing the response by 50%; GDNF, glial cell line-derivated neurotrophic factor; GMT, gating modifier and Servent D (2018) The Na 1.7 toxin; GPCR, G-protein-coupled receptor; HnTx, hainantoxin; HwTx, huwentoxin; IC50, effective concentration necessary V for decreasing the response by 50%; iPSCs, induced pluripotent stem cells; JzTx, jingzhaotoxin; K channel, voltage-gated Channel Subtype as an V potassium channels; NaSpTx, spider NaV channel toxins; NAT, natural antisense transcript; NaV channel, voltage-gated Antinociceptive Target for Spider sodium channel; NGF, nerve growth factor; PaurTx, Phrixotoxin; PcTx-1, psalmotoxin-1; PNS, peripheral nervous system; Toxins in Adult Dorsal Root Ganglia ProTx, protoxin; PSN, primary sensory neuron; PTM, post-translational modification; Ret, “rearranged during transfection” Neurons. Front. Pharmacol. 9:1000. proto-oncogene; RUNX, Runt-related transcription factor; SSN, secondary sensory neuron; TRP channel, transient receptor doi: 10.3389/fphar.2018.01000 potential channel; TSN, tertiary sensory neuron; TTX, tetrodotoxin. Frontiers in Pharmacology| www.frontiersin.org 1 September 2018| Volume 9| Article 1000 fphar-09-01000 October 23, 2018 Time: 12:20 # 2 Gonçalves et al. NaV1.7 Target for Spider Toxins INTRODUCTION for the NaV1.7 channel subtype mainly expressed in DRG neurons. According to the International Association for the Study of Pain, at least 10% of the world’s population suffer from pain since 1 over 10 adults has experienced or had (acute, PRIMARY SENSORY NEURONS AS chronic, intermittent or combined) pain with a median of FRONT DOOR FOR PAIN suffering time around 7 years (Goldberg and McGee, 2011). The unpleasant sensation of pain is necessary to maintain The cellular elements involved in pain transmission from the the body integrity. However, it is often accompanied by peripheral to the CNS are detailed in Figure 1. The noxious long-term complications not only limited to comorbidities, as information is first detected by the nociceptors of peripheral and depression, but also including social and economic concerns visceral tissue, and then conveyed by the dendrites of primary as inability to work, social isolation and intrusive thoughts, sensory neurons (PSNs). The nociceptors are located at the leading to costs of more than 600 billion US dollars annually level of free nerve endings of Ad and C fibers of PSNs that (Holmes, 2016). Pain care is thus a global public health respond to noxious stimuli and are widely found throughout priority whose management must be regulated in its totality by skin and internal tissue. Three main types of pain receptors policies. exist: the thermal, the mechanical and the polymodal receptors, Nowadays, mild to moderate pain may be treated effectively activated by temperature, high pressure and mechanical, thermal with a combination of physical modalities (e.g., ice, rest or/and chemical stimuli, respectively (Figure 1, Box 1). The and splints) and non-opioid analgesics (e.g., non-steroidal PSNs are pseudo-bipolar neurons which send their axons, anti-inflammatory drugs, acetaminophen or other adjuvant components of dorsal roots, to the laminas I, II and V of medications). In contrast, the health system is pushed into its the dorsal horn of spinal cord and establish synapses with the limits to treat debilitating chronic pain because the therapy is dendrites of secondary sensory neurons (SSNs) (Figure 1, Box ineffective and/or associated with devastating effects. Indeed, 2). The SSNs, in turn, bring the noxious information to the management of chronic and severe pain, especially related to hypothalamus and connect to tertiary sensory neurons (TSNs) cancers or neuropathies, often requires opioids (Savage et al., whose cell bodies constitute, in part, the brain cortex (Figure 1, 2008). Unfortunately, the opioid abuse and overdose often Box 3). At each CNS level, the information is integrated and lead to death, which stimulates industries and academics to modulated by different ascending/descending control systems find an alternative with acceptable undesired effects (Negus, such as the medullary control, named “gate control,” and 2018). the diffuse inhibitory control including the noradrenergic and In this context, the likely promising target for therapeutic serotoninergic pathways induced by nociception from the higher treatment to fight pain and avoid central side-effects is centers to the dorsal horn, giving the affective, sensory and the neuron located in the periphery dorsal root ganglia cognitive dimensions to the human experience of pain (Porreca (DRG) which conveys pain from the skin and tendons to and Navratilova, 2017). the central nervous system (CNS). The DRG neurons are The neuron bodies of PSNs constitute the 31 pairs of DRG, well-known to express various families of transmembrane coming out all along the spinal marrow: 8 cervical (C1-C7, note proteins, including ion channels, G-protein-coupled receptors that the first cervical spinal nerve is born above C1 and the (GPCRs) and gap junctions/pannexins (Pan et al., 2008; eighth one below C7), 12 thoracic (T1–T12), 5 lumbar (L1– Spray and Hanani, 2017; Yekkirala et al., 2017). Among L5), 5 sacred (S1–S5), and 1 coccygeal (Co) which is vestigial. the ion channel family, the most extensively studied targets The cranial sensory (trigeminal or Gasser’s) ganglion (nerve for pain treatment are voltage-gated calcium (CaV) and V) conveys facial skin sensitivity, the spiral (or cochlear) and sodium (NaV) channels. In particular,
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  • Pain Research Product Guide | Edition 2

    Pain Research Product Guide | Edition 2

    Pain Research Product Guide | Edition 2 Chili plant Capsicum annuum A source of Capsaicin Contents by Research Area: • Nociception • Ion Channels • G-Protein-Coupled Receptors • Intracellular Signaling Tocris Product Guide Series Pain Research Contents Page Nociception 3 Ion Channels 4 G-Protein-Coupled Receptors 12 Intracellular Signaling 18 List of Acronyms 21 Related Literature 22 Pain Research Products 23 Further Reading 34 Introduction Pain is a major public health problem with studies suggesting one fifth of the general population in both the USA and Europe are affected by long term pain. The International Association for the Study of Pain (IASP) defines pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. Management of chronic pain in the clinic has seen only limited progress in recent decades. Treatment of pain has been reliant on, and is still dominated by two classical medications: opioids and non-steroidal anti-inflammatory drugs (NSAIDs). However, side effects such as dependence associated with opioids and gastric ulceration associated with NSAIDs demonstrates the need for new drug targets and novel compounds that will bring in a new era of pain therapeutics. Pain has been classified into three major types: nociceptive pain, inflammatory pain and neuropathic or pathological pain. Nociceptive pain involves the transduction of painful stimuli by peripheral sensory nerve fibers called nociceptors. Neuropathic pain results from damage or disease affecting the sensory system, and inflammatory pain represents the immunological response to injury through inflammatory mediators that contribute to pain. Our latest pain research guide focuses on nociception and the transduction of pain to the spinal cord, examining some of the main classical targets as well as emerging pain targets.