title: Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain.
abstract: 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 nonopioid mechanism 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 GABABreceptors 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 GABABreceptors. 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.
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112.
authors.forename: Haylie K
authors.initials: HK
authors.lastname: Romero
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112.
authors.forename: Sean B
authors.initials: SB
authors.lastname: Christensen
authors.affiliation: Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, 50139 Florence, Italy.
authors.forename: Lorenzo
authors.identifier: 0000-0001-8374-4432
authors.initials: L
authors.lastname: Di Cesare Mannelli
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gajewiak
authors.affiliation: Department of Pharmacology, Kirksville College of Osteopathic Medicine, A. T. Still University, Kirksville, MO 63501.
authors.forename: Renuka
authors.initials: R
authors.lastname: Ramachandra
authors.affiliation: Department of Pharmacology, Kirksville College of Osteopathic Medicine, A. T. Still University, Kirksville, MO 63501.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Elmslie
authors.affiliation: Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS 39216.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vetter
authors.affiliation: Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, 50139 Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Kineta, Inc., Seattle, WA 98109-5208.
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Iadonato
authors.affiliation: Kineta, Inc., Seattle, WA 98109-5208.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Mercado
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112; mcintosh.mike@gmail.com olivera@biology.utah.edu.
authors.forename: Baldomera M
authors.initials: BM
authors.lastname: Olivera
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112; mcintosh.mike@gmail.com olivera@biology.utah.edu.|George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT 84108.|Department of Psychiatry, University of Utah, Salt Lake City, UT 84132.
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects; D000818:Animals; D000072716:Cancer Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D018733:Nicotinic Antagonists / Q000008:administration & dosage; D009944:Organoplatinum Compounds / Q000009:adverse effects; D000077150:Oxaliplatin; D010455:Peptides / Q000008:administration & dosage*; D018080:Receptors, GABA-B / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; C493739:CHRNA10 protein, human; C498540:CHRNA9 protein, human; D008024:Ligands; D018733:Nicotinic Antagonists; D009944:Organoplatinum Compounds; D010455:Peptides; D018080:Receptors, GABA-B; D011978:Receptors, Nicotinic; D000077150:Oxaliplatin
keywords: alpha9; chemotherapy; nicotinic; pain