To date, the endogenous ligands described for cannabinoid receptors have been derived from membrane lipids. To identify a peptide ligand for CB 1 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 CB 1 cannabinoid receptors. We find that hemopressin is a CB 1 receptor-selective antagonist, because it is able to efficiently block signaling by CB 1 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 CB 1 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 CB 1 cannabinoid receptors that also exhibits analgesic properties. These findings are likely to have a profound impact on the development of novel therapeutics targeting CB 1 receptors.

N-type calcium channels are essential mediators of spinal nociceptive transmission. The core subunit of the N-type channel is encoded by a single gene, and multiple N-type channel isoforms can be generated by alternate splicing. In particular, cell-specific inclusion of an alternatively spliced exon 37a generates a novel form of the N-type channel that is highly enriched in nociceptive neurons and, as we show here, downregulated in a neuropathic pain model. Splice isoform-specific small interfering RNA silencing in vivo reveals that channels containing exon 37a are specifically required for mediating basal thermal nociception and for developing thermal and mechanical hyperalgesia during inflammatory and neuropathic pain. In contrast, both N-type channel isoforms (e37a-and e37b-containing) contribute to tactile neuropathic allodynia. Hence, exon 37a acts as a molecular switch that tailors the channels toward specific roles in pain.

The protease inhibitor Elafin prevents intestinal inflammation in mouse models of colitis and might be developed as a therapeutic agent for inflammatory bowel disease.