The synthetic peptide, PnPP-15, derived from the PnTx2-6 toxin of the spider Phoneutria nigriventer, induces peripheral antinociception involving neprilysin, opioid, and cannabinoid systems

• Published in: Pharmacological Research - Reports Vol. 2; p. 100012
• Main Authors: Ferreira, Renata Cristina Mendes, Lima-Batista, Edleusa Marques, Freitas, Ana Cristina Nogueira, Mariano, Xavier Maia, Machado, Marcelo Ferreira Marcondes, An, Dongchen, Carmona, Adriana Karaoglanovic, Peigneur, Steve, Lima, William Gustavo, Carvalho, Brener Cunha, Tagliati, Carlos Alberto, Tytgat, Jan, Duarte, Igor Dimitri Gama, Lima, Maria Elena de
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.03.2024
• Subjects: Analgesia; Cannabinoid system, neprilysin; Opioid system; Phoneutria nigriventer; PnPP-15; PnPP-15; Analgesia; Cannabinoid system, neprilysin; Phoneutria nigriventer; Opioid system
• ISSN: 2950-2004
• DOI: 10.1016/j.prerep.2024.100012

The PnTx2–6 toxin is isolated from the Phoneutria nigriventer spider venom. The synthetic peptide PnPP-19 is derived from this toxin and induces antinociception. When topically applied, it is cleaved by proteases generating a 15 amino acid residues peptide, PnPP-15. PnPP-15 showed an antinociceptive effect in neuropathic pain developed by streptozotocin-induced diabetic mice. The present work aimed to investigate if PnPP-15 is also effective against the inflammatory pain induced by PGE2. We also evaluated its cytotoxicity in vitro and studied its possible action mechanism in the pain pathway. The nociceptive threshold was assessed using the mechanical paw pressure test. Paw tissue was collected for protein extraction and western blot analyses. The FRET enzymatic assay measured neprilysin activity. The two-electrode voltage clamp technique measured evoked electrical currents in Xenopus laevis oocytes. Cytotoxicity was measured using multiple cell lines. PnPP-15 has peripheral antinociceptive activity via µ-opioid and CB1 cannabinoid receptors and inhibits neprilysin. In addition, it induced direct activation of mu-opioid receptors expressed in Xenopus laevis oocytes. PnPP-15 was not cytotoxic against mammalian kidney, liver, heart, nerve, or lung cells. This work demonstrated the antinociceptive effect of PnPP-15 in an inflammatory pain model, suggesting its use as a possible tool for developing new analgesic drugs. [Display omitted] •PnPP-15 induces peripheral antinociception in an inflammatory pain model.•PnPP-15 induces peripheral antinociception through the opioid system.•PnPP-15 induces peripheral antinociception through the cannabinoid system.