Differential anti-neuropathic pain effects of tetrodotoxin in sciatic nerve- versus infraorbital nerve-ligated rats - Behavioral, pharmacological and immunohistochemical investigations

Several voltage-gated sodium channels are expressed in primary sensory neurons where they control excitability and participate in the generation and propagation of action potentials. Peripheral nerve injury-induced alterations in both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels have been proposed to contribute to neuropathic pain caused by such lesion. We herein investigated whether the blockade of TTX-sensitive channels could reduce pain-related behaviors and evoked c-Fos immunoreactivity in rats with neuropathic pain produced by chronic unilateral constriction injury to either the sciatic nerve or the infraorbital nerve. Acute as well as subchronic administration of TTX (1-6 μg/kg s.c.) was found to suppress for up to 3 h allodynia and hyperalgesia in sciatic nerve-ligated rats. In contrast, TTX was only moderately effective in rats with ligated infraorbital nerve. In sciatic nerve-ligated rats, TTX administration prevented the increased c-Fos immunoreactivity occurring in the dorsal horn of the lumbar cord and some supraspinal areas in response to light mechanical stimulation of the nerve-injured hindpaw. The anti-allodynia/antihyperalgesia caused by TTX in these neuropathic rats was promoted by combined treatment with naloxone (0.5 mg/kg s.c.) but unaffected by the 5-HT_1B receptor antagonist F11648 (0.5 mg/kg s.c.) and the α₂-adrenergic receptor antagonist idazoxan (0.5 mg/kg i.v.). In contrast, the anti-allodynic and anti-hyperalgesic effects of TTX were significantly attenuated by co-administration of morphine (3 mg/kg s.c.) or the cholecystokinin₂-receptor antagonist CI-1015 (0.1 mg/kg i.p.). These results indicate that TTX alleviates pain-related behaviors in sciatic nerve-lesioned rats through mechanisms that involve complex interactions with opioidergic systems.