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

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 alpha 9 alpha 10 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 alpha 9 alpha 10 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 GABA(B) receptors has caused confusion over whether blockade of alpha 9 alpha 10 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 alpha 9 alpha 10 nAChRs, and was at least 1,000-fold more selective for alpha 9 alpha 10 nAChRs vs. all other molecular targets tested, including opioid and GABA(B) 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 alpha 9 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 alpha 9-containing nAChRs as the basis for the efficacy of RgIA4, and that alpha 9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain.