Anandamides: tolerance and cross-tolerance to delta 9-tetrahydrocannabinol

In this study we examined whether tolerance develops to chronic exposure to anandamides [20:4, n-6 (ANA) and 20:3, n-6 (HLEA)] two of the recently discovered endogenous cannabinoid receptor ligands in brain. Tolerance to ANA and cross-tolerance to delta 9-tetrahydrocannabinol (delta 9-THC) was examined in female Sabra or C57BL/6 mice which had received daily injections (i.p.) of low (0.001-1 mg/kg) or high doses (20 mg/kg) of ANA or HLEA for 2 weeks. Twenty four h after the last injection, the mice were challenged with 20 mg/kg ANA or delta 9-THC. Animals were subjected to a series of tests frequently used to assess cannabinoid-induced effects. The results indicated that the high dose, but not the low doses of anandamides produced tolerance to ANA and cross-tolerance to delta 9-THC for motor activity in an open field, catalepsy on a ring, hypothermia and analgesia on a hot plate. One week after the last ANA treatment, tolerance was not present anymore. No tolerance to ANA was observed for reduced defecation in the open field, a measure of intestinal hypomotility. This phenomenon may possibly be attributed to a difference between activities produced through different types of cannabinoid receptors.