A spider derived peptide, PnPP-19, induces central antinociception mediated by opioid and cannabinoid systems

 

Daniela da Fonseca Pacheco^1, Ana Cristina Nogueira Freitas^2, Adriano Monteiro C. Pimenta^2, Igor Dimitri Gama Duarte^1, Maria Elena de Lima²

 

1 Departamento de Farmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brasil.

2 Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Av. Antônio Carlos, 6627, Belo Horizonte, MG CEP 31.270.901, Brasil.

 

ABSTRACT

Background

Some peptides purified from the venom of the spider Phoneutria nigriventer have been identified as potential sources of drugs for pain treatment. In this study, we characterized the antinociceptive effect of the peptide PnPP-19 on the central nervous system and investigated the possible involvement of opioid and cannabinoid systems in its action mechanism.

 

Methods

Nociceptive threshold to thermal stimulation was measured according to the tail-flick test in Swiss mice. All drugs were administered by the intracerebroventricular route.

 

Results

PnPP-19 induced central antinociception in mice in the doses of 0.5 and 1 μg. The non-selective opioid receptor antagonist naloxone (2.5 and 5 μg), μ-opioid receptor antagonist clocinnamox (2 and 4 μg), δ-opioid receptor antagonist naltrindole (6 and 12 μg) and CB₁ receptor antagonist AM251 (2 and 4 μg) partially inhibited the antinociceptive effect of PnPP-19 (1 μg). Additionally, the anandamide amidase inhibitor MAFP (0.2 μg), the anandamide uptake inhibitor VDM11 (4 μg) and the aminopeptidase inhibitor bestatin (20 μg) significantly enhanced the antinociception induced by a low dose of PnPP-19 (0.5 μg). In contrast, the κ-opioid receptor antagonist nor-binaltorphimine (10 μg and 20 μg) and the CB₂ receptor antagonist AM630 (2 and 4 μg) do not appear to be involved in this effect.

 

Conclusions

PnPP-19-induced central antinociception involves the activation of CB₁ cannabinoid, μ- and δ-opioid receptors. Mobilization of endogenous opioids and cannabinoids might be required for the activation of those receptors, since inhibitors of endogenous substances potentiate the effect of PnPP-19. Our results contribute to elucidating the action of the peptide PnPP-19 in the antinociceptive pathway.

 

Key words: Peptide PnPP-19; Central antinociception; Phoneutria nigriventer; μ-opioid receptor; δ-opioid receptor; CB1 receptor; CB2 receptor

 

Funding

Fellowships were awarded to authors by the following Brazilian agencies: the State of Minas Gerais Research Foundation (FAPEMIG), the Coordination for the Improvement of Higher Education Personnel (CAPES), the National Council for Scientific and Technological Development (CNPq) and the National Institute of Science and Technology on Toxins (INCTTOX). This work was also supported by the Edital Toxinologia CAPES no. 063/2010, Process no. 230.38.006280/2011-07, AUXPE Toxinologia 1810/2011.

 

Received: July 27, 2016.

Revised: November 30, 2016.

Accepted: December 21, 2016.

 

Correspondence: lima.mariaelena@gmail.com; melenalima@icb.ufmg.br

 

Authors’ contributions

ACNF and DFP performed the research, analyzed data and wrote the first draft of the manuscript. AMP, IDGD and MEL designed research, contributed with essential reagents or tools and reviewed the paper. All authors read and approved the final manuscript.

 

Competing interests

The authors declare that they have no competing interests.

 

Ethics approval

The algesimetric protocol was approved by the Committee for Ethics in Animal Experimentation (CETEA) of UFMG, under the protocol number 131/2014.