Cannabinoid withdrawal syndrome is reduced in pre-proenkephalin knock-out mice

The functional interactions between the endogenous cannabinoid and opioid s ystems were evaluated in pre-proenkephalin-deficient mice. Antinociception induced in the tail-immersion test by acute Delta9-tetrahydrocannabinol was reduced in mutant mice, whereas no difference between genotypes was observ ed in the effects induced on body temperature, locomotion, or ring cataleps y. During a chronic treatment with Delta9-tetrahydrocannabinol, the develop ment of tolerance to the analgesic responses induced by this compound was s lower in mice lacking enkephalin. In addition, cannabinoid withdrawal syndr ome, precipitated in Delta9-tetrahydrocannabinol-dependent mice by the inje ction of SR141716A, was significantly attenuated in mutant mice. These resu lts indicate that the endogenous enkephalinergic system is involved in the antinociceptive responses of Delta9-tetrahydrocannabinol and participates i n the expression of cannabinoid abstinence.