Antinociceptive effect of Brazilian armed spider venom toxin Tx3–3 in animal models of neuropathic pain

Venoms peptides have produced exceptional sources for drug development to treat pain. In this study we examined the antinociceptive and side effects of Tx3–3, a peptide toxin isolated from Phoneutria nigriventer venom, which inhibits high-voltage-dependent calcium channels (VDCC), preferentially P/Q and R-type VDCC. We tested the effects of Tx3–3 in animal models of nociceptive (tail-flick test), neuropathic (partial sciatic nerve ligation and streptozotocin-induced diabetic neuropathy), and inflammatory (intraplantar complete Freund's adjuvant) pain. In the tail-flick test, both intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of Tx3–3 in mice caused a short-lasting effect (ED50 and 95% confidence intervals of 8.8 [4.1–18.8] and 3.7 [1.6–8.4] pmol/site for i.t. and i.c.v. injection, respectively), without impairing motor functions, at least at doses 10–30 times higher than the effective dose. By comparison, ω-conotoxin MVIIC, a P/Q and N-type VDCC blocker derived from Conus magus venom, caused significant motor impairment at doses close to efficacious dose in tail flick test. Tx3–3 showed a long-lasting antinociceptive effect in neuropathic pain models. Intrathecal injection of Tx3–3 (30 pmol/site) decreased both mechanical allodynia produced by sciatic nerve injury in mice and streptozotocin-induced allodynia in mice and rats. On the other hand, i.t. injection of Tx3–3 did not alter inflammatory pain. Taken together, our data show that Tx3–3 shows prevalent antinociceptive effects in the neuropathic pain models and does not cause adverse motor effects at antinociceptive efficacious doses, suggesting that this peptide toxin holds promise as a novel therapeutic agent for the control of neuropathic pain. The Brazilian armed spider Tx3–3, a new P/Q and R-type calcium channel blocker, effectively alleviates allodynia in animal neuropathic pain models.