Background and aims We 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. Methods The
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 10min or 45s, 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 2h after
drug administration
at 10.00h was recorded. Results Repeated administration of
sinomenine at 10 or 20mg/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 20mg/kg
sinomenine.
Sinomenine administered at 40mg/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 80mg/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. Conclusions The results suggest that repeated administration of simomenine produced an enhanced anti-allodynic effect without tolerance in rodent models of
neuropathic pain. Implications
Sinomenine may be tested as a novel
analgesic in treating some forms of chronic
neuropathic pain in patients.