Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer , in models of thermal, chemical and incisional pain in mice

Abstract

Venom-derived peptides constitute a unique source of drug prototypes for the pain management. Many of them can modulate voltage-gated calcium channels that are central in the processing of pain sensation. PhTx3-4 is a peptide isolated from Phoneutria nigriventer venom, which blocks high voltage-activated calcium channels with low specificity, thereby leading to neuroprotection in models of ischemia in vitro. The aim of the present work was evaluating the potential of intrathecal PhTx3-4 in the reversal of different nociceptive states in mice, furthermore assessing the potential of PhTx3-4 in triggering motor side effects. We found that bellow 100 pmol/site, PhTx3-4 did not cause major motor side effects. By comparison, ω-conotoxin MVIIA and ω-conotoxin MVIIC triggered motor side effects at the doses of 10 and 100 pmol/site, respectively. Also, PhTx3-4 (30 pmol/site) caused no significant alterations in the forced locomotor activity test (rotarod) and in the exploratory activity test (versamax). In a model of inflammatory persistent pain (formalin test), PhTx3-4 reversed nociceptive behavior both pre or post-administered, although this effect was observed only at the inflammatory phase of the test and not at the neurogenic phase. Comparatively, ω-conotoxin MVIIC was effective only when post-administered in the formalin test. Nonetheless, PhTx3-4 treatment was devoid of action in acute nociceptive thermal model (hotplate test), whereas morphine showed efficacy in this test. Efficacy of PhTx3-4 in the formalin test was associated with inhibition of formalin-induced glutamate release in the cerebrospinal fluid. PhTx3-4, but not ω-conotoxin MVIIC, reversed NMDA-induced nociceptive behavior indicating a putative role of PhTx3-4 at ionotropic glutamate receptors. Finally, we observed efficacy of PhTx3-4 in ameliorating mechanical hypersensitivity induced by paw incision, a post-operative and more clinically relevant pain model. Taken together, our data show that PhTx3-4 possesses antinociceptive effect in different models of pain in mice, suggesting that this toxin may serve as drug prototype for pain control.

An overview of Phoneutria nigriventer spider venom using combined transcriptomic and proteomic approaches

“…Sequences from this group were classified in the omega-agatoxin superfamily: Tx1 family and Type II/III omega-agatoxin family. ω-ctenitoxin-Pn3a (UniProt: P81790) is a calcium channel blocker and shows neuroprotective properties [ 9 ] and antinociceptive activity [ 11 ]. U20-ctenitoxin-Pn1a (UniProt: P84093) is also a predicted calcium channel inhibitor toxin and μ-ctenitoxin-Pn1a (UniProt: P17727) is a potent sodium channel inhibitor [ 96 , 97 ].…”

“…nigriventer venom is a complex mixture of enzymes, proteinaceous and non-proteinaceous neurotoxins [ 5 ], which act on ion channels (sodium, calcium and potassium) and chemical receptors of vertebrate and invertebrate neuromuscular systems (review in:[ 6 ]). Several of these venom toxins have been shown as promising models for pharmaceutical and biotechnological applications, with specific effects, such as penile erection [ 7 ], neuronal protection, cell death decrease after induced ischemia in hippocampal and retinal tissues [ 8 , 9 ], anti-arrhythmogenic effect on isolated heart and ventricular myocytes [ 10 ], antinociceptive effects in mice and rats [ 11 – 14 ] and insecticidal action [ 15 , 16 ], among others.…”

δ-Ctenitoxin-Pn1a, a Peptide from Phoneutria nigriventer Spider Venom, Shows Antinociceptive Effect Involving Opioid and Cannabinoid Systems, in Rats

“…The antinociceptive potential of animal toxins has been subject of several investigations that demonstrate the antinociceptive effect of venoms and many of their derivative peptides [ 5 , 6 , 12 , 43 , 44 , 45 , 46 ]. Our results show the analgesic effect of δ-CNTX-Pn1a in inflammatory, neuropathic and nociceptive in vivo pain models.…”

“…Indeed, peptides derived from animal venoms, including scorpions, spiders, amphibians, snakes and marine organisms, have been explored as antinociceptive agents. Many of them selectively inhibit voltage-activated Ca 2+ and Na + channels, acid-sensitive ion channels or glutamate ionotropic receptors [ 8 , 9 , 10 , 11 , 12 ] (for a review please refer to [ 3 , 5 , 6 , 7 , 13 , 14 ]). A successful example is the drug (Prialt ® ) derived from ω-conotoxin MVIIA, a peptide from Conus magus snail venom, known to have a pronounced analgesic effect resulting from the inhibition of voltage-activated Ca 2+ channels [ 15 , 16 ].…”

Animal Venom Components: New Approaches for Pain Treatment

“…For example, some antinociceptive spider toxins induce antinociception by affecting glutamatergic neurotransmission, blocking ASIC channels, activating opioid and cannabinoid pathways, inhibiting P2X3 receptors, among others [5,[21][22][23]. Recently, many toxins from the spider Phoneutria nigriventer have been studied by the group of Gomez [20,[24][25][26][27][28] and by our group [15,[21][22][23][24], which have highlighted the great potential of these molecules as analgesic models.…”