Over the past two decades, numerous tools have been developed to study the endocannabinoid system. Studies show the potential effectiveness of endocannabinoids for the relief of pain and neurological disorders. However, global targeting of the endocannabinoid system has also been associated with unwanted outcomes, including deleterious effects on cognitive and emotional functions, the development of tolerance and dependence, and withdrawal symptoms after drug cessation in humans. The main objective of the present study was to determine whether male mice develop tolerance to delta-9-tetrahydro-cannabinol (THC) and cannabinolic acid (CBNA)-induced antinociception with long-term treatment. Using behavioral tests of mechanical and thermal nociception, we found that systemic (intraperitoneal, i.p.) administration of THC and CBNA resulted in strong antinociception on the first day of the experiment. However, over the next four days, the behavior indices of antinociception to mechanical and thermal stimuli gradually decreased, indicating the development of tolerance following systemic administration of these drugs. Thus, the two main components of cannabis, THC and CBNA, are characterized by the development of tolerance in mice as a result of their repeated i.p. administration.