Antisense oligodeoxynucleotide treatment to the brain cannabinoid receptor inhibits antinociception

Studies using agonists from at least three major cannabinoid ligand groups suggest the mediation of several distinct effects (e.g. psychotropic, analgesia, and antiemetic) by the recently cloned CB1 cannabinoid receptor. However, other studies suggest the presence of multiple cannabinoid receptors and at least one other receptor (CB2) has been cloned. The present investigation was undertaken to determine whether one of the potential therapeutic actions of cannabinoids (i.e. antinociception) is mediated by the CB1 receptor using the antisense oligodeoxynucleotide 'knock-down' approach. Synthetic oligodeoxynucleotides complementary to the 5' end of the coding region of the mouse CB1 receptor mRNA were administered to mice by the intracerebroventricular (i.c.v.) route twice daily for 3 days. Mismatch oligodeoxynucleotides of similar sequence, but containing six mismatched positions out of the 18 nucleotides within the oligodeoxynucleotide were administered to other mice. Treatment with antisense oligodeoxynucleotides, but not mismatched oligodeoxynucleotides, greatly inhibited the antinociceptive response of the cannabinoid agonist CP-55,940. Untreated mice and those treated with mismatched oligodeoxynucleotides showed similar, full response antinociception after CP-55,940 administration. The data provides strong evidence that the CB1 receptor-ligand interaction is essential for the antinociceptive effect.