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Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Romero, Haylie K. ; Christensen, Sean B. ; Di Cesare Mannelli, Lorenzo ; Gajewiak, Joanna ; Ramachandra, Renuka ; Elmslie, Keith S. ; Vetter, Douglas E. ; Ghelardini, Carla ; Iadonato, Shawn P. ; Mercado, Jose L. ; Olivera, Baldomera M. ; McIntosh, J. Michael

Proceedings of the National Academy of Sciences - PNAS, 2017-03, Vol.114 (10), p.E1825-E1832 [Periódico revisado por pares]

United States: National Academy of Sciences

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Título:
Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain
Autor: Romero, Haylie K. ; Christensen, Sean B. ; Di Cesare Mannelli, Lorenzo ; Gajewiak, Joanna ; Ramachandra, Renuka ; Elmslie, Keith S. ; Vetter, Douglas E. ; Ghelardini, Carla ; Iadonato, Shawn P. ; Mercado, Jose L. ; Olivera, Baldomera M. ; McIntosh, J. Michael
Assuntos: Analgesics, Opioid - adverse effects ; Animals ; Biological Sciences ; Cancer Pain - chemically induced ; Cancer Pain - drug therapy ; Cancer Pain - genetics ; Cancer Pain - pathology ; Humans ; Hyperalgesia - chemically induced ; Hyperalgesia - drug therapy ; Hyperalgesia - genetics ; Hyperalgesia - pathology ; Ligands ; Mice ; Mice, Knockout ; Neuralgia - chemically induced ; Neuralgia - drug therapy ; Neuralgia - genetics ; Neuralgia - pathology ; Nicotinic Antagonists - administration & dosage ; Organoplatinum Compounds - adverse effects ; Peptides - administration & dosage ; PNAS Plus ; Receptors, GABA-B - genetics ; Receptors, Nicotinic - genetics ; Receptors, Nicotinic - metabolism
É parte de: Proceedings of the National Academy of Sciences - PNAS, 2017-03, Vol.114 (10), p.E1825-E1832
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Contributed by Baldomero M. Olivera, January 25, 2017 (sent for review December 1, 2016; reviewed by Michael E. Adams and Frank Porreca)
Author contributions: L.D.C.M., J.G., R.R., K.S.E., C.G., and J.M.M. designed research; H.K.R., S.B.C., L.D.C.M., J.G., and R.R. performed research; D.E.V. contributed new reagents/analytic tools; H.K.R., S.B.C., L.D.C.M., J.G., R.R., K.S.E., C.G., B.M.O., and J.M.M. analyzed data; and H.K.R., S.B.C., L.D.C.M., J.G., R.R., K.S.E., D.E.V., C.G., S.P.I., J.L.M., B.M.O., and J.M.M. wrote the paper.
Reviewers: M.E.A., University of California, Riverside; and F.P., The University of Arizona Health Sciences Center.
Descrição: Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial.Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioidmechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABAB receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABAB receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain.
Editor: United States: National Academy of Sciences
Idioma: Inglês

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Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

Romero, Haylie K. ; Christensen, Sean B. ; Di Cesare Mannelli, Lorenzo ; Gajewiak, Joanna ; Ramachandra, Renuka ; Elmslie, Keith S. ; Vetter, Douglas E. ; Ghelardini, Carla ; Iadonato, Shawn P. ; Mercado, Jose L. ; Olivera, Baldomera M. ; McIntosh, J. Michael

United States: National Academy of Sciences

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