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
Graphical Abstract
Key words
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References
- The delta opioid receptor in pain control.Handb Exp Pharmacol. 2018; 247: 147-177
- Lengths of the C-terminus and interconnecting loops impact stability of spider-derived gating modifier toxins.Toxins (Basel). 2017; 9: 248
- Subtype-selective small molecule inhibitors reveal a fundamental role for nav1.7 in nociceptor electrogenesis, axonal conduction and presynaptic release.PLoS One. 2016; 11e0152405
- Sensory neuron-derived NaV1.7 contributes to dorsal horn neuron excitability.Sci Adv. 2020; 6: eaax4568
- 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
- The role of voltage-gated sodium channels in pain signaling.Physiol Rev. 2019; 99: 1079-1151
- Painful and painless channelopathies.Lancet Neurol. 2014; 13: 587-599
- Engineering antibody reactivity for efficient derivatization to generate nav1.7 inhibitory gptx-1 peptide-antibody conjugates.ACS Chem Biol. 2017; 12: 2427-2435
- 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
- Prolonged morphine treatment targets delta opioid receptors to neuronal plasma membranes and enhances delta-mediated antinociception.J Neurosci. 2001; 21: 7598-7607
- Integration of transcriptome resequencing and quantitative proteomics analyses of collagenase VII-induced intracerebral hemorrhage in mice.Front Genet. 2020; 11551065
- 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
- Opioid receptor signalling mechanisms.Clin Exp Pharmacol Physiol. 1999; 26: 493-499
- Woods CG: An SCN9A channelopathy causes congenital inability to experience pain.Nature. 2006; 444: 894-898
- Voltage-gated sodium channels: structure, function, pharmacology, and clinical indications.J Med Chem. 2015; 58: 7093-7118
- Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.Sci Rep. 2017; 7: 40883
- Analgesic effects of GpTx-1, PF-04856264 and CNV1014802 in a mouse model of nav1.7-mediated pain.Toxins (Basel). 2016; 8: 78
- Delta opioid receptor-mediated analgesia is not altered in preprotachykinin A knockout mice.Eur J Neurosci. 2010; 32: 1921-1929
- [des-Arg(1)]-Proctolin: A novel NEP-like enzyme inhibitor identified in Tityus serrulatus venom.Peptides. 2016; 80: 18-24
- 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
- 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
- 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
- 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
- Inflammatory pain is enhanced in delta opioid receptor-knockout mice.Eur J Neurosci. 2008; 27: 2558-2567
- Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.Clin Genet. 2007; 71: 311-319
- Biased signaling by endogenous opioid peptides.Proc Natl Acad Sci U S A. 2020; 117: 11820-11828
- Synergistic regulation of serotonin and opioid signaling contributes to pain insensitivity in Nav1.7 knockout mice.Sci Signal. 2017; 10: eaah4874
- Sodium channels and venom peptide pharmacology.Adv Pharmacol. 2017; 79: 67-116
- Nerve growth factor-induced hyperexcitability of rat sensory neuron in culture.Biomed Res. 2005; 26: 123-130
- 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
- Peptide-membrane interactions affect the inhibitory potency and selectivity of spider toxins protx-ii and gptx-1.ACS Chem Biol. 2019; 14: 118-130
- Voltage gated sodium channels as therapeutic targets for chronic pain.J Pain Res. 2019; 12: 2709-2722
- A central mechanism of analgesia in mice and humans lacking the sodium channel NaV1.7.Neuron. 2021; 109: 1497-1512.e6
- Enkephalins, dynorphins, and beta-endorphin in the rat dorsal horn: an immunofluorescence colocalization study.J Comp Neurol. 2009; 517: 51-68
- 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
- Pain without nociceptors? Nav1.7-independent pain mechanisms.Cell Rep. 2014; 6: 301-312
- Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons.Nat Commun. 2012; 3: 791
- Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7.Nat Commun. 2015; 6: 8967
- Synergism between fentanyl and tramadol in tonic inflammatory pain: the orofacial formalin test.Inflammation. 2012; 35: 1132-1137
- Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.PLoS One. 2018; 13e0196791
- 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
- 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
- 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
- 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
- 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
- Development of a spontaneously active dorsal root ganglia assay using multiwell multielectrode arrays.J Neurophysiol. 2016; 115: 3217-3228
- Characterization of voltage-dependent calcium channel blocking peptides from the venom of the tarantula Grammostola rosea.Toxicon. 2011; 58: 265-276
- Selective ligands and drug discovery targeting the voltage-gated sodium channel Nav1.7.Handb Exp Pharmacol. 2018; 246: 271-306
- Analgesia linked to Nav1.7 loss of function requires micro- and delta-opioid receptors.Wellcome Open Res. 2018; 3: 101
- Dissociation of the opioid receptor mechanisms that control mechanical and heat pain.Cell. 2009; 137: 1148-1159
- 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
- Selective voltage-gated sodium channel peptide toxins from animal venom: pharmacological probes and analgesic drug development.ACS Chem Neurosci. 2018; 9: 187-197
- 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
- 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
- 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
- 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
- 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
Article info
Publication history
Published online: December 28, 2022
Accepted:
December 21,
2022
Received in revised form:
December 17,
2022
Received:
July 14,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Disclosures: This study was supported by the National Natural Science Foundation of China [grant numbers: Nos. 81973159, 81903430], the Funds for Fundamental Research Creative Groups of Gansu Province [grant number: 20JR5RA310], the Fundamental Research Funds for the Central Universities [grant number: lzujbky-2021-pd05], the Changjiang Scholars Programme of China (Young Scholar), and the Natural Science Foundation of Gansu Province [grant number: 22JR5RA545].
Conflict of Interest: The authors have no conflicts of interest to declare.
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© 2022 by United States Association for the Study of Pain, Inc.
