Aim: In light of the antinociceptive activity of the short‐chain neurotoxin, cobrotoxin, and other acetylcholine antagonists, the antinociceptive activity and mechanisms of cobratoxin (CTX), a long‐chain postsynaptic α‐neurotoxin, was investigated in rodent pain models. Methods: CTX was administered intraperito‐neally (30,45, 68 μg/kg), intra‐cerebral ventricularly (4.5 μg/kg) or microinjected into periaqueductal gray (PAG; 4.5 μg/kg). The antinociceptive action was tested using the hot‐plate and acetic acid writhing tests in mice and rats. The involvement of the cholinergic system and opioid system in CTX‐induced analgesia was examined by pretreatment of animals withatropine (0.5 mg/kg, im; or 10 mg/kg, ip) or naloxone (1 and 5 mg/kg, ip). The effect of CTX on motor activity was tested using the Animex test. Results: CTX exhibited a dose‐dependent analgesic action in mice as determined by both the hot‐plate and acetic acid writhing tests. The peak effect of analgesia was seen 3 h after administration. In the mouse acetic acid writhing test, the intra‐cerebral ventricular administration of CTX at 4.5 μg/kg (1/12th of a systemic dose)produced marked analgesic effects. Microinjection of CTX (4.5 μg/kg) into the PAG region did not elicit an analgesic action in rats in the hot‐plate test. Atropine at 0.5 mg/kg (im) and naloxone at 1 and 5 mg/kg (ip) both failed to block the analgesic effects of CTX, but atropine at 10 mg/kg (ip) did antagonize the analgesia mediated by CTX in the mouse acetic acid writhing test. Acetylsalicylic acid (300 mg/kg) did not enhance the analgesic effects of CTX. At the highest effective dose of 68 μg/kg the neurotoxin did not change the spontaneous mobility of mice. Conclusion: CTX has analgesic effects, which are mediated in the central nervous system though not through the PAG. The central cholinergic system but not opioid system appears to be involved in the antinociceptive action of CTX.

Aim: Cobratoxin (CTX), the long-chain α-neurotoxin from Thailand cobra venom, has been demonstrated to have analgesic action in rodent pain models. The present study evaluated the anti-inflammatory and anti-nociceptive effects of CTX on adjuvant arthritis (AA) in rats. Methods: Arthritis was induced by injection of complete Freund's adjuvant (CFA) in rats. Paw swelling and hyperalgesia of AA rats were measured at various times after CFA administration. Tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-2 (IL-2) and interleukin-10 (IL-10) levels in serum were determined with ELISA. Histopathological changes in synoviocytes were examined under a microscope. Involvement of the cholinergic system in the effects of CTX was examined by pretreatment of animals with the α 7 nicotinic receptor (α 7 -nAChR) antagonist methyllycaconitine (MLA). Results: CFA induced marked paw swelling and reduced thresholds of mechanical and cold-induced paw withdrawal. The levels of TNF-α, IL-1 and IL-2 in the serum of AA rats were increased, whereas the level of IL-10 was decreased. Histopathological examination of synoviocytes showed pronounced inflammation and accumulation of collagen. The administration of CTX (17.0 µg/kg, ip) significantly reduced paw swelling and mechanical and thermal hyperalgesia. CTX also reduced the production of TNF-α, IL-1, and IL-2 but increased the production of IL-10 and altered pathohistological changes. The analgesic and anti-inflammatory efficacy of CTX was significantly reduced by MLA (3 mg/kg, sc). Conclusion: These results indicate that CTX has a beneficial effect on CFA-induced arthritis by modulating the production of inflammatory cytokines. α 7 -nAChR appears to mediate the anti-nociceptive and anti-inflammatory actions of CTX.

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