Lanthionine synthetase C-like protein 1 (LanCL1): a therapeutic target for neuropathic pain

Since the discovery of the mammalian lanthionine synthetase C-like (LanCL) proteins, there has been considerable interest in identifying their functions. Using LAT8881, a novel peptide ligand for LanCL1, we confirm a key role for LanCL1 in chronic neuropathic sensitisation, with little effect on inflammatory hypersensitivity or physiological nociception. LAT8881 reversed mechanical allodynia in multiple rodent neuropathic models, including chronic constriction injury, where it suppressed spontaneous ectopic firing in vivo at the dorsal root ganglion (DRG), wind-up, and spontaneous activity in wide dynamic range neurons in the dorsal horn. It also induced membrane potential hyperpolarisation and suppressed spontaneous and primary-afferent-mediated excitatory events in ex vivo spinal cords. To identify protein targets of LAT8881, a photoaffinity conjugate of the active metabolite was used to pull down LanCL1 as the binding target in the spinal cord. This was validated with siRNA knockdown of LanCL1 in DRG, which blocked LAT8881 activity. Immunohistochemical analysis revealed a functional reorganisation of LanCL1 in neuropathic models, with reduced cytosolic expression in the DRG and increased expression in satellite glia. These findings establish LanCL1 as a critical mediator of neuropathic hypersensitivity and a prime target for clinical translation.