Analgesic effects of 1',1' dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice

The metabolic pathway leading to carboxylic acid derivatives of cannabinoids was discovered more than twenty years ago. While these compounds showed no cannabimimetic activity, subsequent work documented several biological responses both in vitro and in vivo for the THC acids. These include inhibition of eicosanoid synthesis, antiedema effects, antagonism to PAF actions, inhibition of leucocyte adhesion and anti nociception. In this report we present data further characterizing the analgesic properties of the title substance which is a potent synthetic member of this group. CT3 was effective in the mouse hot plate assay at 48 degrees C showing an ED-50 of 4.31 (3.37-5.83) mg/kg when administered i.v (10% Cremophor EL in saline). When given by gavage in peanut oil, it resulted in 30-40% MPE (maximum possible effect) at 10 mg/kg with the effect persisting for up to 5 hours. A more potent response was observed in the mouse p-phenylquinone writhing test. When given i.v., it showed an ED-50 of 1.24 (0.84-1.75) mg/kg. However, no activity was found with oral administration either in peanut oil or Cremophor EL. At 10 mg/kg i.v., a 100% inhibition of the writhing response was seen. The mouse formalin antinociception test was also studied in animals that received CT3 (4.64 mg/kg) i.v. using three behavioral parameters for activity. The drug showed decreases in each category when compared with vehicle/formalin treated mice. The formalin effect showed a typical two phase, time related, response in which CT3 caused a 64% reduction in the early phase and a 48% reduction in the late phase in a composite score of nociception. Interestingly, it did not alter motor function in the rota rod procedure at 4.64 mg/kg i.v.