The conotoxin Contulakin-G reverses hypersensitivity observed in rodent models of cancer-induced bone pain without inducing tolerance or motor disturbance.

Autor:	Martin LF; Departments of Pharmacology.; Anesthesiology, and.; Comprehensive Center for Pain and Addiction, College of Medicine, The University of Arizona, Tucson, AZ, United States., Almuslim M; Departments of Pharmacology.; Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia., Ismail KA; Anesthesiology, and., Ibrahim MM; Departments of Pharmacology.; Anesthesiology, and.; Comprehensive Center for Pain and Addiction, College of Medicine, The University of Arizona, Tucson, AZ, United States., Moutal A; Department of Pharmacology and Physiology, School of Medicine, Saint Louis University, St. Louis, MO, United States., Cheng K; Departments of Pharmacology., Stratton HJ; Departments of Pharmacology., Price TJ; Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, United States., Vanderah TW; Departments of Pharmacology.; Anesthesiology, and.; Comprehensive Center for Pain and Addiction, College of Medicine, The University of Arizona, Tucson, AZ, United States., Olivera BM; Department of Biology, University of Utah, Salt Lake City, UT, United States., Khanna R; Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL, United States.; Pain and Addiction Therapeutics (PATH) Collaboratory, College of Medicine, University of Florida, Gainesville, FL, United States., Patwardhan A; Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, TX, United States.; Peter O'Donnell Jr. Brain Institute, Dallas, TX, United States.
Jazyk:	angličtina
Zdroj:	Pain [Pain] 2024 Sep 19. Date of Electronic Publication: 2024 Sep 19.
DOI:	10.1097/j.pain.0000000000003391
Abstrakt:	Abstract: As the incidence and survival rates of patients with cancer continues to grow, an increasing number of people are living with comorbidities, which often manifests as cancer-induced bone pain (CIBP). The majority of patients with CIBP report poor pain control from currently available analgesics. A conotoxin, Contulakin-G (CGX), has been demonstrated to be an antinociceptive agent in postsurgical and neuropathic pain states via a neurotensin receptor 2 (NTSR2)-mediated pathway. However, the efficacy and side effect profile of CGX have never been assessed in CIBP. Here, we evaluated CGX's antinociceptive potential in a rodent model of CIBP. We hypothesized that CGX engages the NTSR2 pathway, providing pain relief with minimal tolerance and motor side effects. Our results demonstrated that CGX intrathecal injection in mice with CIBP attenuated both spontaneous pain behaviors and evoked mechanical hypersensitivity, regardless of their sex. Furthermore, the antinociceptive effect of CGX was dependent upon expression of NTSR2 and the R-type voltage-gated calcium channel (Cav2.3); gene editing of these targets abolished CGX antinociception without affecting morphine antinociception. Examination of the side effect profile of CGX demonstrated that, unlike morphine, chronic intrathecal infusion maintained antinociception with reduced tolerance in rats with CIBP. Moreover, at antinociceptive doses, CGX had no impact on motor behavior in rodents with CIBP. Finally, RNAScope and immunoblotting analysis revealed expression of NTSR2 in both dorsal and ventral horns, while Cav2.3 was minimally expressed in the ventral horn, possibly explaining the sensory selectivity of CGX. Together, these findings support advancing CGX as a potential therapeutic for cancer pain. (Copyright © 2024 International Association for the Study of Pain.)
Databáze:	MEDLINE
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