Advertisement

NaV1.7 Channel Blocker [Ala5, Phe6, Leu26, Arg28]GpTx-1 Attenuates CFA-induced Inflammatory Hypersensitivity in Rats via Endogenous Enkephalin Mechanism

  • Biao Xu
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Run Zhang
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Mengna Zhang
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Dan Chen
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Qinqin Zhang
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Nan Zhang
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Yonghang Shi
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Xuanran Hu
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Ning Li
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
  • Quan Fang
    Correspondence
    Address reprint requests to Quan Fang PhD, Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, 199 Donggang West Road, Lanzhou, 730000, China.
    Affiliations
    Key Laboratory of Preclinical Study for New Drugs of Gansu Province, and Institute of Physiology, School of Basic Medical Sciences, and State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou University, Lanzhou, PR China
    Search for articles by this author
Published:December 28, 2022DOI:https://doi.org/10.1016/j.jpain.2022.12.012

      Highlights

      • GpTx-1-71 attenuates CFA-induced inflammatory hypersensitivity in rats.
      • Endogenous enkephalin is essential for GpTx-1-71-induced anti-hyperalgesia.
      • Sodium is crucial for the functional linkage between NaV1.7 and enkephalin systems.

      Abstract

      Venom-derived NaV1.7 channel blockers have promising prospects in pain management. The 34-residue tarantula peptide GpTx-1 is a potent NaV1.7 channel blocker. Its powerful analog [Ala5, Phe6, Leu26, Arg28]GpTx-1 (GpTx-1-71) displayed excellent NaV1.7 selectivity and analgesic properties in mice. The current study aimed to elucidate the anti-hyperalgesic activities of GpTx-1-71 in inflammatory pain and reveal the underlying mechanisms. Our results demonstrated that intrathecal and intraplantar injections of GpTx-1-71 dose-dependently attenuated CFA-induced inflammatory hypersensitivity in rats. Moreover, GpTx-1-71-induced anti-hyperalgesia was significantly reduced by opioid receptor antagonists and the enkephalin antibody and diminished in proenkephalin (Penk) gene knockout animals. Consistently, GpTx-1-71 treatment increased the enkephalin level in the spinal dorsal horn and promoted the Penk transcription and enkephalin release in primary dorsal root ganglion (DRG) neurons, wherein sodium played a crucial role in these processes. Mass spectrometry analysis revealed that GpTx-1-71 mainly promoted the secretion of Met-enkephalin but not Leu-enkephalin from DRG neurons. In addition, the combination of subtherapeutic Met-enkephalin and GpTx-1-71 produced synergistic anti-hyperalgesia in CFA-induced inflammatory hypersensitivity. These findings suggest that the endogenous enkephalin pathway is essential for GpTx-1-71-induced spinal and peripheral analgesia in inflammatory pain.

      Perspective

      This article presents a possible pharmacological mechanism underlying NaV1.7 blocker-induced analgesia in inflammatory pain, which helps us to better understand and develop venom-based painkillers for incurable pain.

      Graphical abstract

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abdallah K
        • Gendron L
        The delta opioid receptor in pain control.
        Handb Exp Pharmacol. 2018; 247: 147-177
        • Agwa AJ
        • Huang YH
        • Craik DJ
        • Henriques ST
        • Schroeder CI
        Lengths of the C-terminus and interconnecting loops impact stability of spider-derived gating modifier toxins.
        Toxins (Basel). 2017; 9: 248
        • Alexandrou AJ
        • Brown AR
        • Chapman ML
        • Estacion M
        • Turner J
        • Mis MA
        • Wilbrey A
        • Payne EC
        • Gutteridge A
        • Cox PJ
        • Doyle R
        • Printzenhoff D
        • Lin Z
        • Marron BE
        • West C
        • Swain NA
        • Storer RI
        • Stupple PA
        • Castle NA
        • Hounshell JA
        • Rivara M
        • Randall A
        • Dib-Hajj SD
        • Krafte D
        • Waxman SG
        • Patel MK
        • Butt RP
        • Stevens EB
        Subtype-selective small molecule inhibitors reveal a fundamental role for nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release.
        PLoS One. 2016; 11e0152405
        • Alles SRA
        • Nascimento F
        • Lujan R
        • Luiz AP
        • Millet Q
        • Bangash MA
        • Santana-Varela S
        • Zhou X
        • Cox JJ
        • Okorokov AL
        • Beato M
        • Zhao J
        • Wood JN
        Sensory neuron-derived NaV1.7 contributes to dorsal horn neuron excitability.
        Sci Adv. 2020; 6: eaax4568
        • Antunes bras J
        • Becker C
        • Bourgoin S
        • Lombard M
        • Cesselin F
        • Hamon M
        • Pohl M
        Met-enkephalin is preferentially transported into the peripheral processes of primary afferent fibres in both control and HSV1-driven proenkephalin A overexpressing rats.
        Neuroscience. 2001; 103: 1073-1083
        • Bennett DL
        • Clark AJ
        • Huang J
        • Waxman SG
        • Dib-Hajj SD
        The role of voltage-gated sodium channels in pain signaling.
        Physiol Rev. 2019; 99: 1079-1151
        • Bennett DL
        • Woods CG
        Painful and painless channelopathies.
        Lancet Neurol. 2014; 13: 587-599
        • Biswas K
        • Nixey TE
        • Murray JK
        • Falsey JR
        • Yin L
        • Liu H
        • Gingras J
        • Hall BE
        • Herberich B
        • Holder JR
        • Li H
        • Ligutti J
        • Lin MJ
        • Liu D
        • Soriano BD
        • Soto M
        • Tran L
        • Tegley CM
        • Zou A
        • Gunasekaran K
        • Moyer BD
        • Doherty L
        • Miranda LP
        Engineering antibody reactivity for efficient derivatization to generate nav1.7 inhibitory gptx-1 peptide-antibody conjugates.
        ACS Chem Biol. 2017; 12: 2427-2435
        • Black JA
        • Frezel N
        • Dib-Hajj SD
        • Waxman SG
        Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn.
        Mol Pain. 2012; 8: 82
        • Cahill CM
        • Morinville A
        • Lee MC
        • Vincent JP
        • Collier B
        • Beaudet A
        Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances delta-mediated antinociception.
        J Neurosci. 2001; 21: 7598-7607
        • Cao F
        • Guo Y
        • Zhang Q
        • Fan Y
        • Liu Q
        • Song J
        • Zhong H
        • Yao S
        Integration of transcriptome resequencing and quantitative proteomics analyses of collagenase VII-induced intracerebral hemorrhage in mice.
        Front Genet. 2020; 11551065
        • Chen C
        • Xu B
        • Shi X
        • Zhang M
        • Zhang Q
        • Zhang T
        • Zhao W
        • Zhang R
        • Wang Z
        • Li N
        • Fang Q
        GpTx-1 and [Ala5, Phe6, Leu26, Arg28]GpTx-1, two peptide NaV1.7 inhibitors: analgesic and tolerance properties at the spinal level.
        Br J Pharmacol. 2018; 175: 3911-3927
        • Connor M
        • Christie MD
        Opioid receptor signalling mechanisms.
        Clin Exp Pharmacol Physiol. 1999; 26: 493-499
        • Cox JJ
        • Reimann F
        • Nicholas AK
        • Thornton G
        • Roberts E
        • Springell K
        • Karbani G
        • Jafri H
        • Mannan J
        • Raashid Y
        • Al-Gazali L
        • Hamamy H
        • Valente EM
        • Gorman S
        • Williams R
        • McHale DP
        • Wood JN
        • Gribble FM
        Woods CG: An SCN9A channelopathy causes congenital inability to experience pain.
        Nature. 2006; 444: 894-898
        • de Lera Ruiz M
        • Kraus RL
        Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications.
        J Med Chem. 2015; 58: 7093-7118
        • Deuis JR
        • Dekan Z
        • Wingerd JS
        • Smith JJ
        • Munasinghe NR
        • Bhola RF
        • Imlach WL
        • Herzig V
        • Armstrong DA
        • Rosengren KJ
        • Bosmans F
        • Waxman SG
        • Dib-Hajj SD
        • Escoubas P
        • Minett MS
        • Christie MJ
        • King GF
        • Alewood PF
        • Lewis RJ
        • Wood JN
        • Vetter I
        Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.
        Sci Rep. 2017; 7: 40883
        • Deuis JR
        • Wingerd JS
        • Winter Z
        • Durek T
        • Dekan Z
        • Sousa SR
        • Zimmermann K
        • Hoffmann T
        • Weidner C
        • Nassar MA
        • Alewood PF
        • Lewis RJ
        • Vetter I
        Analgesic effects of GpTx-1, PF-04856264 and CNV1014802 in a mouse model of nav1.7-mediated pain.
        Toxins (Basel). 2016; 8: 78
        • Dubois D
        • Gendron L
        Delta opioid receptor-mediated analgesia is not altered in preprotachykinin A knockout mice.
        Eur J Neurosci. 2010; 32: 1921-1929
        • Duzzi B
        • Cajado-Carvalho D
        • Kuniyoshi AK
        • Kodama RT
        • Gozzo FC
        • Fioramonte M
        • Tambourgi DV
        • Portaro FV
        • Rioli V
        [des-Arg(1)]-Proctolin: A novel NEP-like enzyme inhibitor identified in Tityus serrulatus venom.
        Peptides. 2016; 80: 18-24
        • Fan H
        • Gong N
        • Li TF
        • Ma AN
        • Wu XY
        • Wang MW
        • Wang YX
        The non-peptide GLP-1 receptor agonist WB4-24 blocks inflammatory nociception by stimulating beta-endorphin release from spinal microglia.
        Br J Pharmacol. 2015; 172: 64-79
        • Fang JQ
        • Du JY
        • Liang Y
        • Fang JF
        Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats.
        Mol Pain. 2013; 9: 13
        • Freitas AC
        • Pacheco DF
        • Machado MF
        • Carmona AK
        • Duarte ID
        • de Lima ME
        PnPP-19, a spider toxin peptide, induces peripheral antinociception through opioid and cannabinoid receptors and inhibition of neutral endopeptidase.
        Br J Pharmacol. 2016; 173: 1491-1501
        • Gallantine EL
        • Meert TF
        A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80.
        Basic Clin Pharmacol Toxicol. 2005; 97: 39-51
        • Gaveriaux-Ruff C
        • Karchewski LA
        • Hever X
        • Matifas A
        • Kieffer BL
        Inflammatory pain is enhanced in delta opioid receptor-knockout mice.
        Eur J Neurosci. 2008; 27: 2558-2567
        • Goldberg YP
        • MacFarlane J
        • MacDonald ML
        • Thompson J
        • Dube MP
        • Mattice M
        • Fraser R
        • Young C
        • Hossain S
        • Pape T
        • Payne B
        • Radomski C
        • Donaldson G
        • Ives E
        • Cox J
        • Younghusband HB
        • Green R
        • Duff A
        • Boltshauser E
        • Grinspan GA
        • Dimon JH
        • Sibley BG
        • Andria G
        • Toscano E
        • Kerdraon J
        • Bowsher D
        • Pimstone SN
        • Samuels ME
        • Sherrington R
        • Hayden MR
        Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.
        Clin Genet. 2007; 71: 311-319
        • Gomes I
        • Sierra S
        • Lueptow L
        • Gupta A
        • Gouty S
        • Margolis EB
        • Cox BM
        • Devi LA
        Biased signaling by endogenous opioid peptides.
        Proc Natl Acad Sci U S A. 2020; 117: 11820-11828
        • Isensee J
        • Krahe L
        • Moeller K
        • Pereira V
        • Sexton JE
        • Sun X
        • Emery E
        • Wood JN
        • Hucho T
        Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.
        Sci Signal. 2017; 10: eaah4874
        • Israel MR
        • Tay B
        • Deuis JR
        • Vetter I
        Sodium channels and venom peptide pharmacology.
        Adv Pharmacol. 2017; 79: 67-116
        • Kitamura N
        • Konno A
        • Kuwahara T
        • Komagiri Y
        Nerve growth factor-induced hyperexcitability of rat sensory neuron in culture.
        Biomed Res. 2005; 26: 123-130
        • Kornecook TJ
        • Yin R
        • Altmann S
        • Be X
        • Berry V
        • Ilch CP
        • Jarosh M
        • Johnson D
        • Lee JH
        • Lehto SG
        • Ligutti J
        • Liu D
        • Luther J
        • Matson D
        • Ortuno D
        • Roberts J
        • Taborn K
        • Wang J
        • Weiss MM
        • Yu V
        • Zhu DXD
        • Fremeau RT
        • Moyer BD
        Pharmacologic characterization of AMG8379, a potent and selective small molecule sulfonamide antagonist of the voltage-gated sodium channel nav1.7.
        J Pharmacol Exp Ther. 2017; 362: 146-160
        • Lawrence N
        • Wu B
        • Ligutti J
        • Cheneval O
        • Agwa AJ
        • Benfield AH
        • Biswas K
        • Craik DJ
        • Miranda LP
        • Henriques ST
        • Schroeder CI
        Peptide-membrane interactions affect the inhibitory potency and selectivity of spider toxins protx-ii and gptx-1.
        ACS Chem Biol. 2019; 14: 118-130
        • Ma RSY
        • Kayani K
        • Whyte-Oshodi D
        • Whyte-Oshodi A
        • Nachiappan N
        • Gnanarajah S
        • Mohammed R
        Voltage gated sodium channels as therapeutic targets for chronic pain.
        J Pain Res. 2019; 12: 2709-2722
        • MacDonald DI
        • Sikandar S
        • Weiss J
        • Pyrski M
        • Luiz AP
        • Millet Q
        • Emery EC
        • Mancini F
        • Iannetti GD
        • Alles SRA
        • Arcangeletti M
        • Zhao J
        • Cox JJ
        • Brownstone RM
        • Zufall F
        • Wood JN
        A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7.
        Neuron. 2021; 109: 1497-1512.e6
        • Marvizon JC
        • Chen W
        • Murphy N
        Enkephalins, dynorphins, and beta-endorphin in the rat dorsal horn: an immunofluorescence colocalization study.
        J Comp Neurol. 2009; 517: 51-68
        • McDonnell A
        • Collins S
        • Ali Z
        • Iavarone L
        • Surujbally R
        • Kirby S
        • Butt RP
        Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy.
        Pain. 2018; 159: 1465-1476
        • Minett MS
        • Falk S
        • Santana-Varela S
        • Bogdanov YD
        • Nassar MA
        • Heegaard AM
        • Wood JN
        Pain without nociceptors? Nav1.7-independent pain mechanisms.
        Cell Rep. 2014; 6: 301-312
        • Minett MS
        • Nassar MA
        • Clark AK
        • Passmore G
        • Dickenson AH
        • Wang F
        • Malcangio M
        • Wood JN
        Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons.
        Nat Commun. 2012; 3: 791
        • Minett MS
        • Pereira V
        • Sikandar S
        • Matsuyama A
        • Lolignier S
        • Kanellopoulos AH
        • Mancini F
        • Iannetti GD
        • Bogdanov YD
        • Santana-Varela S
        • Millet Q
        • Baskozos G
        • MacAllister R
        • Cox JJ
        • Zhao J
        • Wood JN
        Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7.
        Nat Commun. 2015; 6: 8967
        • Miranda HF
        • Noriega V
        • Zepeda RJ
        • Sierralta F
        • Prieto JC
        Synergism between fentanyl and tramadol in tonic inflammatory pain: the orofacial formalin test.
        Inflammation. 2012; 35: 1132-1137
        • Moyer BD
        • Murray JK
        • Ligutti J
        • Andrews K
        • Favreau P
        • Jordan JB
        • Lee JH
        • Liu D
        • Long J
        • Sham K
        • Shi L
        • Stocklin R
        • Wu B
        • Yin R
        • Yu V
        • Zou A
        • Biswas K
        • Miranda LP
        Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.
        PLoS One. 2018; 13e0196791
        • Mueller A
        • Starobova H
        • Morgan M
        • Dekan Z
        • Cheneval O
        • Schroeder CI
        • Alewood PF
        • Deuis JR
        • Vetter I
        Antiallodynic effects of the selective NaV1.7 inhibitor Pn3a in a mouse model of acute postsurgical pain: evidence for analgesic synergy with opioids and baclofen.
        Pain. 2019; 160: 1766
        • Murray JK
        • Biswas K
        • Holder JR
        • Zou A
        • Ligutti J
        • Liu D
        • Poppe L
        • Andrews KL
        • Lin FF
        • Meng SY
        • Moyer BD
        • McDonough SI
        • Miranda LP
        Sustained inhibition of the NaV1.7 sodium channel by engineered dimers of the domain II binding peptide GpTx-1.
        Bioorg Med Chem Lett. 2015; 25: 4866-4871
        • Murray JK
        • Ligutti J
        • Liu D
        • Zou A
        • Poppe L
        • Li H
        • Andrews KL
        • Moyer BD
        • McDonough SI
        • Favreau P
        • Stocklin R
        • Miranda LP
        Engineering potent and selective analogues of GpTx-1, a tarantula venom peptide antagonist of the NaV1.7 sodium channel.
        J Med Chem. 2015; 58: 2299
        • Murray JK
        • Long J
        • Zou A
        • Ligutti J
        • Andrews KL
        • Poppe L
        • Biswas K
        • Moyer BD
        • McDonough SI
        • Miranda LP
        Single residue substitutions that confer voltage-gated sodium ion channel subtype selectivity in the nav1.7 inhibitory peptide gptx-1.
        J Med Chem. 2016; 59: 2704-2717
        • Nassar MA
        • Stirling LC
        • Forlani G
        • Baker MD
        • Matthews EA
        • Dickenson AH
        • Wood JN
        Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain.
        Proc Natl Acad Sci U S A. 2004; 101: 12706-12711
        • Newberry K
        • Wang S
        • Hoque N
        • Kiss L
        • Ahlijanian MK
        • Herrington J
        • Graef JD
        Development of a spontaneously active dorsal root ganglia assay using multiwell multielectrode arrays.
        J Neurophysiol. 2016; 115: 3217-3228
        • Ono S
        • Kimura T
        • Kubo T
        Characterization of voltage-dependent calcium channel blocking peptides from the venom of the tarantula Grammostola rosea.
        Toxicon. 2011; 58: 265-276
        • Payandeh J
        • Hackos DH
        Selective ligands and drug discovery targeting the voltage-gated sodium channel Nav1.7.
        Handb Exp Pharmacol. 2018; 246: 271-306
        • Pereira V
        • Millet Q
        • Aramburu J
        • Lopez-Rodriguez C
        • Gaveriaux-Ruff C
        • Wood JN
        Analgesia linked to Nav1.7 loss of function requires micro- and delta-opioid receptors.
        Wellcome Open Res. 2018; 3: 101
        • Scherrer G
        • Imamachi N
        • Cao YQ
        • Contet C
        • Mennicken F
        • O'Donnell D
        • Kieffer BL
        • Basbaum AI
        Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.
        Cell. 2009; 137: 1148-1159
        • Siebenga P
        • van Amerongen G
        • Hay JL
        • McDonnell A
        • Gorman D
        • Butt R
        • Groeneveld GJ
        Lack of Detection of the Analgesic Properties of PF-05089771, a Selective Nav1.7 Inhibitor, Using a Battery of Pain Models in Healthy Subjects.
        Clin Transl Sci. 2020; 13: 318-324
        • Wu Y
        • Ma H
        • Zhang F
        • Zhang C
        • Zou X
        • Cao Z
        Selective voltage-gated sodium channel peptide toxins from animal venom: pharmacological probes and analgesic drug development.
        ACS Chem Neurosci. 2018; 9: 187-197
        • Xu B
        • Zhang M
        • Shi X
        • Zhang R
        • Chen D
        • Chen Y
        • Wang Z
        • Qiu Y
        • Zhang T
        • Xu K
        • Zhang X
        • Liedtke W
        • Wang R
        • Fang Q
        The multifunctional peptide DN-9 produced peripherally acting antinociception in inflammatory and neuropathic pain via mu- and kappa-opioid receptors.
        Br J Pharmacol. 2020; 177: 93-109
        • Zhang M
        • Xu B
        • Li N
        • Liu H
        • Shi X
        • Zhang Q
        • Shi Y
        • Xu K
        • Xiao J
        • Chen D
        • Zhu H
        • Sun Y
        • Zhang T
        • Zhang R
        • Fang Q
        Synthesis and biological characterization of cyclic disulfide-containing peptide analogs of the multifunctional opioid/neuropeptide ff receptor agonists that produce long-lasting and nontolerant antinociception.
        J Med Chem. 2020; 63: 15709-15725
        • Zhang M
        • Xu B
        • Li N
        • Zhang R
        • Zhang Q
        • Shi X
        • Xu K
        • Xiao J
        • Chen D
        • Niu J
        • Shi Y
        • Fang Q
        Development of multifunctional and orally active cyclic peptide agonists of opioid/neuropeptide ff receptors that produce potent, long-lasting, and peripherally restricted antinociception with diminished side effects.
        J Med Chem. 2021; 64: 13394-13409
        • Zhang P
        • Bi RY
        • Gan YH
        Glial interleukin-1beta upregulates neuronal sodium channel 1.7 in trigeminal ganglion contributing to temporomandibular joint inflammatory hypernociception in rats.
        J Neuroinflammation. 2018; 15: 117
        • Zhang R
        • Xu B
        • Zhang Q
        • Chen D
        • Zhang M
        • Zhao G
        • Xu K
        • Xiao J
        • Zhu H
        • Niu J
        • Li N
        • Fang Q
        Spinal administration of the multi-functional opioid/neuropeptide FF agonist BN-9 produced potent antinociception without development of tolerance and opioid-induced hyperalgesia.
        Eur J Pharmacol. 2020; 880173169