Insight into Pain Modulation: Nociceptors Sensitization and Therapeutic Targets

Author(s): Amna Khan, Salman Khan*, Yeong Shik Kim.

Journal Name: Current Drug Targets

Volume 20 , Issue 7 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Pain is a complex multidimensional concept that facilitates the initiation of the signaling cascade in response to any noxious stimuli. Action potential generation in the peripheral nociceptor terminal and its transmission through various types of nociceptors corresponding to mechanical, chemical or thermal stimuli lead to the activation of receptors and further neuronal processing produces the sensation of pain. Numerous types of receptors are activated in pain sensation which vary in their signaling pathway. These signaling pathways can be regarded as a site for modulation of pain by targeting the pain transduction molecules to produce analgesia. On the basis of their anatomic location, transient receptor potential ion channels (TRPV1, TRPV2 and TRPM8), Piezo 2, acid-sensing ion channels (ASICs), purinergic (P2X and P2Y), bradykinin (B1 and B2), α-amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), metabotropic glutamate (mGlu), neurokinin 1 (NK1) and calcitonin gene-related peptide (CGRP) receptors are activated during pain sensitization. Various inhibitors of TRPV1, TRPV2, TRPM8, Piezo 2, ASICs, P2X, P2Y, B1, B2, AMPA, NMDA, mGlu, NK1 and CGRP receptors have shown high therapeutic value in experimental models of pain. Similarly, local inhibitory regulation by the activation of opioid, adrenergic, serotonergic and cannabinoid receptors has shown analgesic properties by modulating the central and peripheral perception of painful stimuli. This review mainly focused on various classes of nociceptors involved in pain transduction, transmission and modulation, site of action of the nociceptors in modulating pain transmission pathways and the drugs (both clinical and preclinical data, relevant to targets) alleviating the painful stimuli by exploiting nociceptor-specific channels and receptors.

Keywords: Pain modulating receptor, pain transmission pathway, pain pharmacological target, brain and spinal cord, nociceptors sensitization, N-methyl-D-aspartate (NMDA).

[1]
Ellison DL. Physiology of Pain. Critical Care Nursing Clinics 2017; 29(4): 397-406.
[2]
Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell 2009; 139(2): 267-84.
[3]
Freedman M, Gehret J, Young G, Kamen L. Challenging neuropathic pain syndromes: Evaluation and evidence-based treatment: Elsevier Health Sciences; 2017.
[4]
Price DD, Verne GN, Schwartz JM. Plasticity in brain processing and modulation of pain. Prog Brain Res 2006; 157: 333-405.
[5]
Caterina PM, Beatrice PM, Lorenzo DN, et al. Nociceptor plasticity: a closer look. J Cell Physiol 2017; 233(4): 2824-38.
[6]
Ossipov M. Pain pathways: descending modulation 2009.
[7]
Carpenter K, Dickenson A. Molecular aspects of pain research. Pharmacogenomics J 2002; 2(2): 87.
[8]
Steeds CE. The anatomy and physiology of pain. Surgery-Oxford Int Edition 2009; 27(12): 507-11.
[9]
Schaible H-G. Peripheral and central mechanisms of pain generation Analgesia. Springer 2006; pp. 3-28.
[10]
Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009; 32: 1-32.
[11]
Świeboda P, Filip R, Prystupa A, Drozd M. Assessment of pain: types, mechanism and treatment. Pain 2013; 1: 2-7.
[12]
Sun L, Richard DY. Role of G protein-coupled receptors in inflammation. Acta Pharmacol Sin 2012; 33(3): 342.
[13]
Boddeke EW. Involvement of chemokines in pain. Eur J Pharmacol 2001; 429(1-3): 115-9.
[14]
Geppetti P, Veldhuis NA, Lieu T, Bunnett NW. G protein-coupled receptors: dynamic machines for signaling pain and itch. Neuron 2015; 88(4): 635-49.
[15]
Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 2002; 3(8): 655.
[16]
Okuse K. Pain signalling pathways: from cytokines to ion channels. Int J Biochem Cell Biol 2007; 39(3): 490-6.
[17]
Gold MS, Gebhart GF. Nociceptor sensitization in pain pathogenesis. Nat Med 2010; 16(11): 1248.
[18]
Das V. An introduction to pain pathways and pain “targets” Progress in molecular biology and translational science 131. Elsevier 2015; pp. 1-30.
[19]
Moore C, Gupta R, Jordt S-E, Chen Y, Liedtke WB. Regulation of pain and itch by TRP channels. Neurosci Bull 2018; 1-23.
[20]
Davis JB, Gray J, Gunthorpe MJ, et al. Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nat 2000; 405(6783): 183.
[21]
Levine JD, Alessandri-Haber N. TRP channels: targets for the relief of pain. Biochim Biophys Acta 2007; 1772(8): 989-1003.
[22]
Han Y, Li Y, Xiao X, et al. Formaldehyde up-regulates TRPV1 through MAPK and PI3K signaling pathways in a rat model of bone cancer pain. Neurosci Bull 2012; 28(2): 165-72.
[23]
Ching L-C, Kou YR, Shyue S-K, et al. Molecular mechanisms of activation of endothelial nitric oxide synthase mediated by transient receptor potential vanilloid type 1. Cardiovasc Res 2011; 91(3): 492-501.
[24]
Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: on the road to pain relief. Curr Mol Pharmacol 2008; 1(3): 255-69.
[25]
Carnevale V, Rohacs T. TRPV1: a target for rational drug design. Pharmaceuticals 2016; 9(3): 52.
[26]
Johnson E, Lambert D. Receptor Mechanisms. Core Topics In Pain.49.
[27]
Brower V. New paths to pain relief. Nat Biotechnol 2000; 18(4): 387.
[28]
Manitpisitkul P, Brandt M, Flores CM, et al. TRPV1 antagonist JNJ-39439335 (mavatrep) demonstrates proof of pharmacology in healthy men: a first-in-human, double-blind, placebo-controlled, randomized, sequential group study. Pain Rep 2016; 1(4): e576.
[29]
Niyom S, Mama K, Gustafson D, Rezende M. Single‐and multiple dose pharmacokinetics and multiple dose pharmacodynamics of oral ABT‐116 (a TRPV 1 antagonist) in dogs. J Veterinary Pharmacol Therap 2015; 38(4): 336-43.
[30]
Hu H-Z, Gu Q, Wang C, et al. 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. J Biol Chem 2004; 279(34): 35741-8.
[31]
Hernández-García E, Rosenbaum T. Lipid modulation of thermal transient receptor potential channels. Curr Top Membr 2014; 74: 135-80.
[32]
Wang H, Woolf CJ. Pain TRPs. Neuron 2005; 46(1): 9-12.
[33]
Cohen MR, Huynh KW, Cawley D, Moiseenkova-Bell VY. Understanding the cellular function of TRPV2 channel through generation of specific monoclonal antibodies. PLoS One 2013; 8(12): e85392.
[34]
Peier AM, Moqrich A, Hergarden AC, et al. A TRP channel that senses cold stimuli and menthol. Cell 2002; 108(5): 705-15.
[35]
Voets T, Owsianik G, Nilius B. Trpm8 Transient Receptor Potential (TRP) Channels. Springer 2007; pp. 329-44.
[36]
Yin K, Zimmermann K, Vetter I, Lewis RJ. Therapeutic opportunities for targeting cold pain pathways. Biochem Pharmacol 2015; 93(2): 125-40.
[37]
Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 2009; 8(1): 55.
[38]
Andrews MD, Af Forselles K, Beaumont K, et al. Discovery of a selective TRPM8 antagonist with clinical efficacy in cold-related pain. ACS Med Chem Lett 2015; 6(4): 419-24.
[39]
Kaneko Y, Szallasi A. Transient receptor potential (TRP) channels: a clinical perspective. Br J Pharmacol 2014; 171(10): 2474-507.
[40]
Fernández-Peña C, Viana F. Targeting TRPM8 for pain relief. Channels 2013; 9: 17.
[41]
Sharif-Naeini R. Contribution of mechanosensitive ion channels to somatosensation. Prog Mol Biol Transl Sci 2015; 131: 53-71.
[42]
Florez-Paz D, Bali KK, Kuner R, Gomis A. A critical role for Piezo2 channels in the mechanotransduction of mouse proprioceptive neurons. Sci Rep 2016; 6: 25923.
[43]
Ranade SS, Syeda R, Patapoutian A. Mechanically activated ion channels. Neuron 2015; 87(6): 1162-79.
[44]
Wu J, Lewis AH, Grandl J. Touch, tension, and transduction–the function and regulation of Piezo ion channels. Trends Biochem Sci 2017; 42(1): 57-71.
[45]
Borbiro I, Rohacs T. Regulation of piezo channels by cellular signaling pathways. Curr Top Membr 2017; 245-61.
[46]
Parpaite T, Coste B. Piezo channels. Curr Biol 2017; 27(7): R250-.
[47]
Gold M, Caterina M. Molecular biology of the nociceptor/transduction The Senses: A Comprehensive Reference. Elsevier Inc. 2010.
[48]
Kweon H-J, Suh B-C. Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation. BMB Rep 2013; 46(6): 295.
[49]
Zeng W-Z, Liu D-S, Xu T-L. Acid-sensing ion channels: trafficking and pathophysiology. Channels 2014; 8(6): 481-7.
[50]
Dube G, Lehto SG, Breese NM, et al. Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain 2005; 117(1-2): 88-96.
[51]
Gu Q, Lee L-Y. Acid-sensing ion channels and pain. Pharmaceuticals 2010; 3(5): 1411-25.
[52]
Squire LR, Dronkers N, Baldo J. Encyclopedia of neuroscience. Elsevier 2009.
[53]
Burnstock G, Knight GE. Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 2004; 240(1): 31-304.
[54]
Gourine AV, Llaudet E, Dale N, Spyer KM. ATP is a mediator of chemosensory transduction in the central nervous system. Nat 2005; 436(7047): 108.
[55]
Khakh BS. Molecular physiology of P2X receptors and ATP signalling at synapses. Nat Rev Neurosci 2001; 2(3): 165.
[56]
Surprenant A, North RA. Signaling at purinergic P2X receptors. Annu Rev Physiol 2009; 71: 333-59.
[57]
Burnstock G. Purinergic receptors and pain. Current Pharmaceutical Des 2009; 15(15): 1717-35.
[58]
Donnelly-Roberts D, McGaraughty S, Shieh C-C, Honore P, Jarvis MF. Painful purinergic receptors. J Pharmacol Exp Ther 2008; 324(2): 409-15.
[59]
Burnstock G. Purines and purinoceptors: molecular biology overview 2010.
[60]
McGuirk S, Dolphin A. G-protein mediation in nociceptive signal transduction: an investigation into the excitatory action of bradykinin in a subpopulation of cultured rat sensory neurons. Neurosci 1992; 49(1): 117-28.
[61]
Pethő G, Reeh PW. Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev 2012; 92(4): 1699-775.
[62]
Pethő G, Reeh PW. Effects of bradykinin on nociceptors. NeuroImmune Biol 2009; 8: 135-68.
[63]
Cabrini DA, Campos MM, Tratsk KS, et al. Molecular and pharmacological evidence for modulation of kinin B1 receptor expression by endogenous glucocorticoids hormones in rats. Br J Pharmacol 2001; 132(2): 567-77.
[64]
Carpenter K, Dickenson A. Peripheral and central sensitization. Core topics in pain. 2005:29.
[65]
Cafferty W. Peripheral mechanisms. Core Topics Pain 2005; pp. 7-16.
[66]
Ikeda SR, Dunlap K. Calcium channels diversify their signaling portfolio. Nat Neurosci 2007; 10(3): 269.
[67]
Park C-G, Suh B-C. Modulation mechanisms of voltage-gated calcium channels. Curr Opin Physiol 2018; 2: 77-83.
[68]
Stevens E, Patel MBS. Barker1, GT Young2, CH Soubrane2, GJ Stephens3. Conn’s. Transl Neurosci 2016; 11.
[69]
Altier C, Zamponi GW. Targeting Ca2+ channels to treat pain: T-type versus N-type. Trends Pharmacol Sci 2004; 25(9): 465-70.
[70]
Channels NV-GC. Voltage-Gated Calcium Channels. Cold Spring Harb Perspect Biol 2011; 3(8): a003947.
[71]
Sprengel R. Ionotropic glutamate receptors Neuroscience in the 21st Century. Springer 2013; pp. 59-80.
[72]
Chiechio S. Modulation of chronic pain by metabotropic glutamate receptors. Adv Pharmacol 2016; 63-89.
[73]
Wang J, Goffer Y. AMPA receptors and pain—A future therapeutic intervention? Techniques in Regional Anesthesia & Pain Management 2010; 14(2): 59-64.
[74]
Dravid S, Yuan H, Traynelis S. AMPA Receptors: Molecular Biology and Pharmacology Encyclopedia of Neuroscience. Elsevier Ltd 2010.
[75]
Wang Y, Wu J, Wu Z, et al. Regulation of AMPA receptors in spinal nociception. Mol Pain 2010; 6(1): 5.
[76]
Hartmann B, Ahmadi S, Heppenstall PA, et al. The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron 2004; 44(4): 637-50.
[77]
Willard SS, Koochekpour S. Glutamate, glutamate receptors, and downstream signaling pathways. Int J Biol Sci 2013; 9(9): 948.
[78]
Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003; 97(4): 1108-16.
[79]
Iacobucci GJ, Popescu GK. NMDA receptors: linking physiological output to biophysical operation. Nat Rev Neurosci 2017; 18(4): 236.
[80]
Liu H, Mantyh PW, Basbaum AI. NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nat 1997; 386(6626): 721.
[81]
Zito K, Scheuss V. NMDA receptor function and physiological modulation. In: Encyclopedia of Neuroscience. 2009; p. pp.1157-1164.
[82]
Chen J, Li L, Chen S-R, et al. The α2δ-1-NMDA receptor complex is critically involved in neuropathic pain development and gabapentin therapeutic actions. Cell Reports 2018; 22(9): 2307-21.
[83]
Lee C-H, Lü W, Michel JC, et al. NMDA receptor structures reveal subunit arrangement and pore architecture. Nat 2014; 511(7508): 191.
[84]
Bennett GJ. Update on the neurophysiology of pain transmission and modulation: focus on the NMDA-receptor. J Pain Symptom Manage 2000; 19(1): 2-6.
[85]
Palazzo E, Marabese I, Novellis V, Rossi F, Maione S. Supraspinal metabotropic glutamate receptors: a target for pain relief and beyond. Eur J Neurosci 2014; 39(3): 444-54.
[86]
Grueter B, Winder D. Metabotropic glutamate receptors (mGluRs). Functions 2009.
[87]
C Montana M. W Gereau R. Metabotropic glutamate receptors as targets for analgesia: antagonism, activation, and allosteric modulation. Curr Pharmaceutical Biotechnol 2011; 12(10): 1681-8.
[88]
Carlton SM, Neugebauer V. Peripheral metabotropic glutamate receptors as drug targets for pain relief. Expert Opin Ther Targets 2002; 6(3): 349-61.
[89]
Goudet C, Magnaghi V, Landry M, et al. Metabotropic receptors for glutamate and GABA in pain. Brain Res Brain Res Rev 2009; 60(1): 43-56.
[90]
Karim F, Bhave G, Gereau IVR. Metabotropic glutamate receptors on peripheral sensory neuron terminals as targets for the development of novel analgesics. Nature Publishing Group 2001.
[91]
De Blasi A, Conn PJ, Pin J-P, Nicoletti F. Molecular determinants of metabotropic glutamate receptor signaling. Trends Pharmacol Sci 2001; 22(3): 114-20.
[92]
Trafton JA, Basbaum AI. The contribution of spinal cord neurokinin-1 receptor signaling to pain. J Pain 2000; 1(3): 57-65.
[93]
Jimenez-Andrade J, Mantyh P. Neuropeptides Internalization Encyclopedia of Neuroscience. Elsevier Ltd 2010.
[94]
Schank JR, Heilig M. Substance P and the Neurokinin-1 Receptor: The New CRF International review of neurobiology 136. Elsevier 2017; pp. 151-75.
[95]
Gautam M, Prasoon P, Kumar R, et al. Role of neurokinin type 1 receptor in nociception at the periphery and the spinal level in the rat. Spinal Cord 2016; 54(3): 172.
[96]
Goldsmith L, Kwatra M. Tachykinin/Substance P/Neurokinin-1 Receptors. 2013.
[97]
Pintér E, Pozsgai G, Hajna Z, Helyes Z, Szolcsányi J. Neuropeptide receptors as potential drug targets in the treatment of inflammatory conditions. Br J Clin Pharmacol 2014; 77(1): 5-20.
[98]
Kenchappa R, Carter B. Neurotrophin Receptor Signaling 2013.
[99]
Sanger GJ. Neurokinin NK1 and NK3 receptors as targets for drugs to treat gastrointestinal motility disorders and pain. Br J Clin Pharmacol 2004; 141(8): 1303-12.
[100]
Iyengar S, Ossipov MH, Johnson KW. The role of calcitonin gene–related peptide in peripheral and central pain mechanisms including migraine. Pain 2017; 158(4): 543.
[101]
Schou WS, Ashina S, Amin FM, Goadsby PJ, Ashina M. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain 2017; 18(1): 34.
[102]
Ma W, Chabot J-G, Quirion R. Calcitonin Gene-Related Peptide (CGRP) and Receptors. 2009.
[103]
Benemei S, Nicoletti P, Capone JG, Geppetti P. CGRP receptors in the control of pain and inflammation. Curr Opin Pharmacol 2009; 9(1): 9-14.
[104]
Russell F, King R, Smillie S-J, Kodji X, Brain S. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 2014; 94(4): 1099-142.
[105]
Chan HS, McCarthy D, Li J, Palczewski K, Yuan S. Designing safer analgesics via μ-opioid receptor pathways. Trends Pharmacol Sci 2017; 38(11): 1016-37.
[106]
McDonald J, Lambert D. Opioid receptors. Continuing Education in Anaesthesia Critical Care Pain 2005; 5(1): 22-5.
[107]
Rice F, Albrecht P. The senses: a comprehensive reference. Basbaum, AI 2008; 1-32.
[108]
Waldhoer M, Bartlett SE, Whistler JL. Opioid Receptors. Annu Rev Biochem 2004; 73: 953-90.
[109]
François A, Low SA, Sypek EI, et al. A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by GABA and enkephalins. Neuron 2017; 93(4): 822-39. e6.
[110]
Kieffer B. Opioid peptides and receptors. Elsevier Ltd 2009.
[111]
Nagi K, Piñeyro G. Regulation of opioid receptor signalling: implications for the development of analgesic tolerance. Mol Brain 2011; 4(1): 25.
[112]
Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology: J Am Society Anesthesiol 2011; 115(6): 1363-81.
[113]
Hieble J. Adrenergic receptors 2009.
[114]
Bylund DB. Adrenergic receptors 2004.
[115]
Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog 2015; 62(1): 31-8.
[116]
Carroll I, Mackey S, Gaeta R. editors. The role of adrenergic receptors and pain: The good, the bad, and the unknown. Seminars in Anesthesia, Perioperative Medicine and Pain; 2007: Elsevier.
[117]
Fairbanks CA, Stone LS, Wilcox GL. Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis. Pharmacol Ther 2009; 123(2): 224-38.
[118]
Nguyen V, Tiemann D, Park E, Salehi A. Alpha-2 agonists. Anesthesiol Clin 2017; 35(2): 233-45.
[119]
Bardin L. The complex role of serotonin and 5-HT receptors in chronic pain. Behav Pharmacol 2011; 22(5 and 6): 390-404.
[120]
Loyd DR, Henry MA, Hargreaves KM. editors. Serotonergic neuromodulation of peripheral nociceptors. Seminars in cell & developmental biology; 2013: Elsevier.
[121]
Ramage A. Serotonin (5-hydroxtryptamine; 5-HT): neurotransmission and neuromodulation. Academic Press; 2009.
[122]
Viguier F, Michot B, Hamon M, Bourgoin S. Multiple roles of serotonin in pain control mechanisms—implications of 5-HT7 and other 5-HT receptor types. Eur J Pharmacol 2013; 716(1-3): 8-16.
[123]
Sommer C. Serotonin in pain and analgesia. Mol Neurobiol 2004; 30(2): 117-25.
[124]
Gresch PJ. Serotonin Receptor Signaling 2013.
[125]
Turner JH, Gelasco AK, Ayiku HB, Coaxum SD, Arthur JM, Garnovskaya MN. 5-HT receptor signal transduction pathways The serotonin receptors. Springer 2006; pp. 143-206.
[126]
Millan MJ. editor Serotonin (5-HT) and pain: a reappraisal of its role in the light of receptor multiplicity. Seminars in Neuroscience; 1995: Elsevier.
[127]
De Ponti F. Pharmacology of serotonin: what a clinician should know. Gut 2004; 53(10): 1520-35.
[128]
Lutz B, Marsicano G. Endocannabinoid role in synaptic plasticity and learning 2009.
[129]
Chiou L-C, Hu SS-J, Ho Y-C. Targeting the cannabinoid system for pain relief? Acta Anaesthesiol Taiwan 2013; 51(4): 161-70.
[130]
Piomelli D. Endocannabinoids. 2013.
[131]
Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes 2006; 30(S1): S13.
[132]
Brooks JW, Farquhar‐Smith WP. Cannabinoids and pain. Bja Cepd Rev 2003; 3(6): 175-8.
[133]
Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol 2006; 4(3): 239-57.
[134]
Lu D, Potter D. Cannabinoids and the cannabinoid receptors: An overview Handbook of Cannabis and Related Pathologies. Elsevier 2017; pp. 553-63.
[135]
Akopian AN, Ruparel NB, Jeske NA, Patwardhan A, Hargreaves KM. Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol Sci 2009; 30(2): 79-84.
[136]
Piomelli D, Giuffrida A, Calignano A. de Fonseca FRg. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol Sci 2000; 21(6): 218-24.
[137]
Zhuo M. Ionotropic glutamate receptors contribute to pain transmission and chronic pain. Neuropharmacology 2017; 112: 228-34.
[138]
Christian K, Song H, Ming G-L. Biochemistry of Neurogenesis 2013.
[139]
Sałat K, Jakubowska A, Kulig K. Zucapsaicin for the treatment of neuropathic pain. Expert Opin Investig Drugs 2014; 23(10): 1433-40.
[140]
Lee J, Kim B-H, Yu K-S, et al. A first-in-human, double-blind, placebo-controlled, randomized, dose escalation study of DWP05195, a novel TRPV1 antagonist, in healthy volunteers. Drug Des Devel Ther 2017; 11: 1301.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 7
Year: 2019
Page: [775 - 788]
Pages: 14
DOI: 10.2174/1389450120666190131114244
Price: $58

Article Metrics

PDF: 50
HTML: 5