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Toxins (Basel). 2018 Jan 15;10(1). pii: E43. doi: 10.3390/toxins10010043.

The Peptide PnPP-19, a Spider Toxin Derivative, Activates μ-Opioid Receptors and Modulates Calcium Channels.

Author information

1
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil. acnfreitas@gmail.0100com.
2
Toxicology and Pharmacology, KU Leuven, 3000 Leuven, Belgium. steve.peigneur@pharm.kuleuven.be.
3
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil. flavio.hpmacedo@gmail.com.
4
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
5
Arthritis Research UK Pain Centre, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. paul.millns@nottingham.ac.uk.
6
Cell Signaling Research Group, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. licimedeiros@gmail.com.
7
Cell Signaling Research Group, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. Maria.Arruda@nottingham.ac.uk.
8
Farmanguinhos, Fiocruz, Brazilian Ministry of Health, Rio de Janeiro 22775-903, Brazil. Maria.Arruda@nottingham.ac.uk.
9
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil. jadercruzytrio@gmail.com.
10
Cell Signaling Research Group, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. nicholas.holliday@nottingham.ac.uk.
11
Toxicology and Pharmacology, KU Leuven, 3000 Leuven, Belgium. jan.tytgat@pharm.kuleuven.be.
12
Arthritis Research UK Pain Centre, School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK. gareth.hathway@nottingham.ac.uk.
13
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil. melpg@icb.ufmg.br.

Abstract

The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin δ-CNTX-Pn1c (PnTx2-6), isolated from the venom of the spider Phoneutria nigriventer. Behavioural tests suggest that PnPP-19 induces antinociception by activation of CB1, μ and δ opioid receptors. Since the peripheral and central antinociception induced by PnPP-19 involves opioid activation, the aim of this work was to identify whether this synthetic peptide could directly activate opioid receptors and investigate the subtype selectivity for μ-, δ- and/or κ-opioid receptors. Furthermore, we also studied the modulation of calcium influx driven by PnPP-19 in dorsal root ganglion neurons, and analyzed whether this modulation was opioid-mediated. PnPP-19 selectively activates μ-opioid receptors inducing indirectly inhibition of calcium channels and hereby impairing calcium influx in dorsal root ganglion (DRG) neurons. Interestingly, notwithstanding the activation of opioid receptors, PnPP-19 does not induce β-arrestin2 recruitment. PnPP-19 is the first spider toxin derivative that, among opioid receptors, selectively activates μ-opioid receptors. The lack of β-arrestin2 recruitment highlights its potential for the design of new improved opioid agonists.

KEYWORDS:

Phoneutria nigriventer; antinociception; opioid receptor; spider toxin

PMID:
29342943
PMCID:
PMC5793130
DOI:
10.3390/toxins10010043
[Indexed for MEDLINE]
Free PMC Article

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