Hemopressin is an inverse agonist of CB₁ cannabinoid receptors

To date, the endogenous ligands described for cannabinoid receptors have been derived from membrane lipids. To identify a peptide ligand for CB₁ cannabinoid receptors, we used the recently described conformation-state sensitive antibodies and screened a panel of endogenous peptides from rodent brain or adipose tissue. This led to the identification of hemopressin (PVNFKFLSH) as a peptide ligand that selectively binds CB₁ cannabinoid receptors. We find that hemopressin is a CB₁ receptor-selective antagonist, because it is able to efficiently block signaling by CB₁ receptors but not by other members of family A G protein-coupled receptors (including the closely related CB₂ receptors). Hemopressin also behaves as an inverse agonist of CB₁ receptors, because it is able to block the constitutive activity of these receptors to the same extent as its well characterized antagonist, rimonabant. Finally, we examine the activity of hemopressin in vivo using different models of pain and find that it exhibits antinociceptive effects when administered by either intrathecal, intraplantar, or oral routes, underscoring hemopressin's therapeutic potential. These results represent a demonstration of a peptide ligand for CB₁ cannabinoid receptors that also exhibits analgesic properties. These findings are likely to have a profound impact on the development of novel therapeutics targeting CB₁ receptors.