Grant: Operating Grant

The tridecapeptide neurotensin (NT), inducing antinociception in the brain through interaction with two identified receptors subtypes, NTS1 and NTS2, presents great potential for the development of a new class of analgesics. However, because NT penetrates only poorly through the blood-brain barrier (BBB), its potential as a therapeutic agent is limited to spinal injections, thus with weak clinical outcomes. Angiochem is a pharmaceutical group focused on technologies to improve the BBB penetration of centrally active compounds. Our goal is to initiate collaboration with Angiochem to investigate the brain uptake and analgesic effects of a new chemical entity formed by the conjugation of NT to Angiopep-2, a 19-amino-acid peptide that crosses the BBB. Preliminary results of in-situ brain perfusions in mice demonstrated that the Angiopep-2-NT conjugate, ANG2002, efficiently penetrated the blood-brain barrier with a transport rate 10-fold higher than that of unconjugated NT. Through our collaboration, we intend to determine, by in vivo studies, if the systemically administered ANG2002 induces antinociceptive effects consistent with those of centrally administered NT in a variety of acute, inflammatory, and neuropathic pain models. Our expertise in pain neurophysiology will allow determining the potential of Angiochem's NT derivatives to address the reality of intractable chronic pain.