Repeated sinomenine administration alleviates chronic neuropathic pain-like behaviours in rodents without producing tolerance

• Spinally injured rats and sciatic nerve injured mice were used to study the effect of repeatedly administered sinomenine on hypersensitivity to mechanical and cold stimuli.
• Following repeated administration, the analgesic effect of sinomenine was increased, without development of tolerance.
• Sinomenine may be explored as a novel analgesic for treating some forms of chronic neuropathic pain in patients.

Background and aimsWe have previously reported that systemic administration of sinomenine produced antinociception in various experimental pain conditions in rodents, particularly in models of neuropathic pain. In the present study we assessed the effects of repeated administration of sinomenine in two rodent models of neuropathic pain in order to study the development of tolerance.MethodsThe analgesic effect of sinomenine was tested in female Sprague-Dawley rats that exhibited mechanical and cold hypersensitivity following ischaemic injury to the spinal cord and in male C57/BL6 mice that developed mechanical hypersensitivity after ischaemic injury to the sciatic nerve. Briefly, the animals were anaesthetized and injected i.v. with the photosensitizing dye erythrosine B. Vertebral segments T12 to T13 in rats or the sciatic nerve in mice were exposed and irradiated under an argon ion laser for 10 min or 45 s, respectively. In rats, mechanical hypersensitivity to pressure with von Frey hairs, the response to brushing and decreasing cold temperature were tested in the flanks or upper back areas. In mice, mechanical hypersensitivity on the hind paw to von Frey hairs and response to cold following a drop of acetone were measured. Sinomenine was administered i.p. in rats and p.o. in mice at 10:00 and 16:00, twice a day for 5 days. Response threshold before and 2 h after drug administration at 10.00 h was recorded.ResultsRepeated administration of sinomenine at 10 or 20 mg/kg twice a day, doses that have no analgesic effect as single injection, alleviated mechanical, but not cold allodynia in spinally injured rats and the effect was maintained during the 5 day treatment period with no signs of tolerance. Furthermore, the pre-drug response threshold was significantly elevated during repeated treatment with 20 mg/kg sinomenine. Sinomenine administered at 40 mg/kg twice a day for 5 days significantly reduced mechanical and cold alldoynia, elevated pre-drug response threshold without tolerance development in spinally injured rats. Similarly, sinomenine at 80 mg/kg twice a day for 5 days significantly reduced mechanical allodynia in mice with sciatic nerve injury and increased pre-drug response threshold with no sign of tolerance. The effect of sinomenine on response threshold persisted for days after termination of the 5 day drug administration.ConclusionsThe results suggest that repeated administration of simomenine produced an enhanced anti-allodynic effect without tolerance in rodent models of neuropathic pain.ImplicationsSinomenine may be tested as a novel analgesic in treating some forms of chronic neuropathic pain in patients.