Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice

Abstract

We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel (2mg/kg, i.p., once daily during 5 days) produced long-lasting (2-4 weeks) heat hyperalgesia (plantar test), mechanical allodynia (electronic Von Frey test) and cold allodynia (acetone drop method), with maximum effects observed on days 7, 10 and 10-14, respectively. Acute subcutaneous treatment with 1 or 3 microg/kg of TTX reduced the expression of mechanical allodynia, whereas higher doses (3 or 6 microg/kg) were required to reduce the expression of cold allodynia and heat hyperalgesia. In contrast, TTX (3 or 6 microg/kg, s.c.) did not affect the response to the same thermal and mechanical stimuli in control animals, which indicates that the antihyperalgesic and antiallodynic effects of TTX were not due to unspecific inhibition of the perception of these stimuli. Administration of TTX (6 microg/kg, s.c.) 30 min before each of the 5 doses of paclitaxel did not modify the development of heat hyperalgesia produced by the antineoplastic, but abolished the development of mechanical and cold allodynia. Coadministration of a lower dose of TTX (3 microg/kg) also prevented the development of mechanical allodynia. No signs of TTX-induced toxicity or motor incoordination were observed. These data suggest that low doses of TTX can be useful to prevent and treat paclitaxel-induced neuropathic pain, and that TTX-sensitive subtypes of sodium channels play a role in the pathogenesis of chemotherapy-induced neuropathic pain.

Effects of repeated milnacipran and fluvoxamine treatment on mechanical allodynia in a mouse paclitaxel-induced neuropathic pain model

“…These observations are consistent with those of other reports showing paclitaxel to induce mechanical allodynia in mice (4,19). The present study further demonstrated a significant attenuation of paclitaxel-induced mechanical allodynia by repeated milnacipran or fluvoxamine treatment.…”

“…to mice at doses of 0.5-2 mg/ kg, once per day for 5 consecutive days. Paclitaxel dosing was determined based on previous reports that used mice (4,19). Milnacipran hydrochloride or fluvoxamine maleate (Sigma Chemical Co., St. Louis, MO) was administered i.p.…”

Pain in cancer survivors

“…Capsaicin 0.025% cream, 8% patches or 5% lidocaine patches have all been shown to be efficacious in a variety of other peripheral neuropathies, 176,177 although robust evidence for their use in CIPN is lacking. A number of potential treatments are being evaluated, including topical menthol (an inactivator of nociceptor voltage-gated sodium channels), 178 tetrodotoxin (voltage-gated sodium channel inhibitor) 179 and the cannabinoid receptor agonists WIN55, 212-2 and AM1710. 180 …”

Chemotherapy-Induced Peripheral Neuropathy

“…Both voltage-and ligand-gated ion channels have been shown to play a role in chemotherapy-induced changes in nociceptive behaviors. Included in these are sodium channels, 137,234,235 calcium channels, 155,173,[236][237][238] ATP-gated channels, 239 acid-sensing channels, 239 and TRP channels, [240][241][242] although much controversy persists regarding which channels mediate different modalities of chemotherapy-induced behaviors. Gabapentin, which binds to the α 2 δ subunit of the calcium channel, 243 has been investigated in preclinical studies and found to have variable effects on nociceptive behaviors, depending on the class of chemotherapy administered.…”