| First Author | Romero HK | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 10 | Pages | E1825-E1832 |
| PubMed ID | 28223528 | Mgi Jnum | J:241645 |
| Mgi Id | MGI:5903330 | Doi | 10.1073/pnas.1621433114 |
| Citation | Romero HK, et al. (2017) Inhibition of alpha9alpha10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain. Proc Natl Acad Sci U S A 114(10):E1825-E1832 |
| abstractText | 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 alpha9alpha10 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 alpha9alpha10 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 alpha9alpha10 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 alpha9alpha10 nAChRs, and was at least 1,000-fold more selective for alpha9alpha10 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 alpha9 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 alpha9-containing nAChRs as the basis for the efficacy of RgIA4, and that alpha9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain. |
