Grant: Project Grant

The neurotensin (NT) peptide, inducing pain relief in the brain through interaction with two identified receptor subtypes, NTS1 and NTS2, presents great potential for the development of a new class of analgesic drugs. However, because NT penetrates only poorly through the blood-brain barrier (BBB), its potential as a therapeutic agent remained limited to spinal injections, thus with weak clinical outcomes. Our goal is therefore to develop brain-penetrant NT analogs exhibiting improved analgesia to side effect ratios. For this purpose, we propose to increase the brain uptake of chemically-modified NT analogs by their conjugation to the Angiopep-2 carrier peptide that crosses the BBB through its binding to the LRP1 receptor, akin to a Trojan horse. Specifically, we will determine if these fusion molecules retain their ability to bind the BBB LRP1 receptor and NTS1/NTS2 receptors and are effectively transported across the BBB. We will also evaluate if these new NT conjugates achieve therapeutic brain concentrations after systemic delivery. To this aim, we will screen the new brain-penetrating NT entities for their analgesic activity in response to different noxious stimulus modalities in a variety of acute, inflammatory, and neuropathic pain models. Knowing that the analgesic action of NT is independent of the endogenous opioid system, and may even act synergistically with morphine to reduce pain, this project may lead to the development of a new class of non-opioid pain relief medications.