Mechanism of intrathecal Contulakin-G induced analgesia without motor block

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Effective treatment of high-impact pain patients is one the major stated goals of the National Pain Strategy. Although implanted intrathecal drug delivery system that takes advantage of spinal pain processing mechanisms is highly effective in most intractable pain patients, their use is limited primarily because of the 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 pain. Contulakin-G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin has been shown to be safe in humans and a small, pilot Phase1A study demonstrated its analgesic effect. Prior published studies and our preliminary data demonstrate that intrathecal CGX is analgesic in various intractable pain conditions with minimal tolerance and motor block. However, the mechanism behind the analgesia without motor block and the receptor signaling pathway elicited by CGX is not known. Our preliminary data suggest that CGX activates neurotensin receptor 2 (NT2) to inhibit the R-type voltage gated calcium channels (VGCC). Interestingly, although NT2 is present in both sensory and motor neurons, R-type VGCC expression is more selective in pain neurons and possibly some motor neurons. In this project, we propose to test an innovative hypothesis that spinal CGX produces analgesia without motor block is secondary to CGX activation of neurotensin receptor 2 (NT2) leading to inhibition of R-type VGCC in sensory but not motor neurons. We propose to study the central hypothesis both in vitro (SA1) and in vivo (SA2). We incorporate cutting edge scientific tools such as CRISPR-Cas9 editing and proximity ligation assay coupled with highly validated in vitro and in vivo assays to address these questions. The proposed studies test a novel hypothesis with high translational significance and they also serve as a career development mechanism for a highly trained, interventional pain physician and pharmacologist who is mentored by accomplished pain scientists with a strong pedigree of successful mentees. Data from these studies will not only form the basis of a subsequent R01 application and allow the applicant to be an independently funded clinician scientist but have the potential to lead to clinical advancement of a nonopioid drug in a patient population that desperately needs relief.