Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression

This study evaluated its antihypersensitivity activity in the rat models of neuropathic and cancer pains and explored its underlying mechanisms. Subcutaneous injection of cumulative doses of lappaconitine produced dose-dependent mechanical antiallodynia and thermal antihyperalgesia in spina l nerve ligation-induced neuropathic rats. The cumulative dose–response analysis exhibited theirEmax values of 53.3 and 58.3% MPE, and ED50 values of 1.1 and 1.6  mg/kg. Single intrathecal lappaconitine dose in neuropathy also dose- and time-dependently blocked mechanical allodynia, with anEmax of 66.1% MPE and an ED50 of 0.8  μg. Its multiple twice-daily intrathecal administration over 7 days did not induce mechanical antiallodynic tolerance. Subcutaneous cumulative doses of lappaconitine also produced dose-dependent blockade of mechanical allodynia in the rat bone cancer pain model induced by tibia implantation of c ancer cells, with theEmax of 57.9% MPE and ED50 of 2.0  mg/kg. Furthermore, lappaconitine treatment stimulated spinal dynorphin A expression in neuropathic rats, and in primary cultures of microglia but not neurons or astrocytes. Intrathecal pretreatment with the specific microglia depletor liposome-encapsulated clodronate, dynorphin A antibody, and κ -opioid receptor antagonist GNTI totally suppressed intrathecal and subcutaneous lappaconitine-induced mechanical antiallodynia. This study suggests that lappaconitine exhibits antinociception through directly stimulatin...
Source: Psychopharmacology - Category: Psychiatry Source Type: research