Grant: Project Grant

Chronic pain is a serious public health problem affecting more than 30% of Canadians during their lifetime. To date, conventional opioids remain the standard of care for pain management, despite concerns about their safety and effectiveness. Paradoxically, the over-prescription of opioids for pain management following surgery and the increasing use of highly potent opioids appearing on the illicit drug market have fueled the current opioid crisis. There is therefore an urgent need to develop non-opioid medications with an effective, safe, and non-addictive pharmacotherapeutic profile to relieve pain for Canadian patients. The neurotensin (NT) peptide and its analogs exert potent and long-lasting opioid-independent analgesia by interacting with NTS2 receptors. However, as NT penetrates only poorly through the blood-brain barrier (BBB), its potential as a therapeutic agent remained limited to spinal injections, with poor clinical outcomes. Our goal is therefore to develop brain-penetrant NTS2 analogs with a better analgesia/side-effect ratio. To this end, we propose to increase brain uptake of chemically-modified NTS2 analogs by their conjugation to the shuttle peptide Angiopep-2, which crosses the BBB by binding to the LRP1 receptor, akin to a Trojan horse. Specifically, we will determine if these fusion molecules retain their ability to bind to the LRP1 and NTS2 receptors and whether they are effectively transported across the BBB. We will also evaluate if these new NT conjugates reach therapeutic brain concentrations after systemic delivery. We will thus screen the new brain-penetrating NT entities for their analgesic activity in response to different noxious stimulus modalities in acute, inflammatory, and neuropathic pain models. Knowing that the analgesic action of NT is independent of the endogenous opioid system and can even act synergistically with morphine to reduce pain, this project could lead to the development of a new class of non-opioid analgesics.