• Laurent Martin, Mohab Ibrahim, Kimberly Gomez, Jie Yu, Song Cai, Lindsey A Chew, Shreya S Bellampalli, Aubin Moutal, Tally Largent-Milnes, Frank Porreca, Rajesh Khanna, Baldomero M Olivera, and Amol Patwardhan.
• Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ. Bellampalli is now with the Mayo Clinic School of Medicine, Rochester, MN, United States.
• Pain. 2022 Sep 1; 163 (9): 175117621751-1762.

AbstractIntrathecal application of contulakin-G (CGX), a conotoxin peptide and a neurotensin analogue, has been demonstrated to be safe and potentially analgesic in humans. However, the mechanism of action for CGX analgesia is unknown. We hypothesized that spinal application of CGX produces antinociception through activation of the presynaptic neurotensin receptor (NTSR)2. In this study, we assessed the mechanisms of CGX antinociception in rodent models of inflammatory and neuropathic pain. Intrathecal administration of CGX, dose dependently, inhibited thermal and mechanical hypersensitivities in rodents of both sexes. Pharmacological and clustered regularly interspaced short palindromic repeats/Cas9 editing of NTSR2 reversed CGX-induced antinociception without affecting morphine analgesia. Electrophysiological and gene editing approaches demonstrated that CGX inhibition was dependent on the R-type voltage-gated calcium channel (Cav2.3) in sensory neurons. Anatomical studies demonstrated coexpression of NTSR2 and Cav2.3 in dorsal root ganglion neurons. Finally, synaptic fractionation and slice electrophysiology recordings confirmed a predominantly presynaptic effect. Together, these data reveal a nonopioid pathway engaged by a human-tested drug to produce antinociception.Copyright © 2022 International Association for the Study of Pain.

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