Dissection of NTSR2/calcium channel signaling as a non-opioid spinal analgesic mechanism for the treatment of high impact chronic pain - Project Summary: Spinal administration of analgesics such as opioids and local anesthetics via an implanted intrathecal drug delivery system have profound efficacy in some of the most severe high impact chronic pain conditions. Despite their profound efficacy, their use is limited primarily because of side effects such as tolerance, psychosis and motor block associated with drugs used in them (opioids, ziconotide, local anesthetics). Novel analgesics that take advantage of spinal pain processing, are safe to use in humans and have minimal motor block and tolerance can be revolutionary in the management of high impact chronic pain conditions. Contulakin-G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin has been shown to be safe in humans and in a small, pilot Phase1A study demonstrated analgesic effects in patients with spinal cord injury pain, a high impact chronic pain condition. These studies suggested a possibility of a novel, non-opioid, analgesic mechanism that is active in humans. Our preliminary studies in animal models of high impact chronic pain unraveled spinal neurotensin receptor 2 (NTSR2) and subsequent inhibition of voltage-gated calcium channels Cav2.3 and 2.2 as an opioid-independent spinal analgesic mechanism. Importantly, despite profound analgesia, NTSR2 activation was not associated with unwarranted side effects such as rapid tolerance or motor blockade. Despite clear translational relevance of NTSR2-Cav2.3/2.2 pathway, nothing is known about NTSR2 downstream signaling that leads to calcium channel inhibition, particularly so in sensory neurons. Aim 1 will evaluate detailed signaling following NTSR2 activation that leads to calcium channel inhibition in mouse sensory neurons. Aim 2 will assess the anatomical correlation and functional significance of NTSR2-Cav pathway in human sensory neurons and spinal cord. Aim 3 will evaluate in vivo significance of this pathway in models of high impact chronic pain with rigorous independent replication. If successful, proposed studies could unravel the signaling molecules involved in human-tested mechanism for the treatment of high impact chronic pain conditions. Moreover, this information can be utilized for further development of novel analgesics that are biased agonist of or directly engage this signaling pathway.
