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.
