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 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.