Cannabinoid–improgan cross-tolerance: Improgan is a cannabinomimetic analgesic lacking affinity at the cannabinoid CB1 receptor

Improgan is a non-opioid analgesic which does not act at known histamine or cannabinoid receptors. Because improgan antinociception is blocked by low doses of a cannabinoid CB1 antagonist, the present experiments determined if development of cannabinoid tolerance in mice would alter improgan antinociception. Twice-daily injections of Δ9-tetrahydrocannabinol (THC, 10 mg/kg, s.c.) for 3.5 days induced 47–54% and 42–56% reductions in cannabinoid (WIN 55,212-2, 20 μg, i.c.v.) and improgan (30 μg, i.c.v.) antinociception, respectively, as compared with responses from vehicle-treated groups. Because improgan lacks cannabinoid-like side effects in rats, and does not act directly on cannabinoid CB1 receptors, the finding that development of cannabinoid tolerance reduces improgan antinociception suggests that this drug may release endocannabinoids, or activate novel cannabinoid sites. Either possibility offers the potential for developing new types of analgesics.