Small Synthetic Hyaluronan Disaccharide BIS014 Mitigates Neuropathic Pain in Mice Padín, Juan-Fernando Entrena Fernández, José Manuel Cobos del Moral, Enrique José Compound BIS014 Neuropathic pain TRPV1 Hyaluronan disaccharide Hyaluronic Analgesic drugs Antiallodynic drugs Supplementary data Supplementary data related to this article can be found at https://doi.org/10.1016/j.jpain.2022.07.014. Neuropathic pain (NP) is a challenging condition to treat, as the need for new drugs to treat NP is an unmet goal. We investigated the analgesic potential of a new sulfated disaccharide compound, named BIS014. Oral administration (p.o.) of this compound induced ameliorative effects in formalin-induced nociception and capsaicin-induced secondary mechanical hypersensitivity in mice, but also after partial sciatic nerve transection (spared nerve injury), chemotherapy (paclitaxel)-induced NP, and diabetic neuropathy induced by streptozotocin. Importantly, BIS014, at doses active on neuropathic hypersensitivity (60 mg/kg/p.o.), did not alter exploratory activity or motor coordination (in the rotarod test), unlike a standard dose of gabapentin (40 mg/kg/p.o.) which although inducing antiallodynic effects on the NP models, it also markedly decreased exploration and motor coordination. In docking and molecular dynamic simulation studies, BIS014 interacted with TRPV1, a receptor involved in pain transmission where it behaved as a partial agonist. Additionally, similar to capsaicin, BIS014 increased cytosolic Ca2+ concentration ([Ca2+]c) in neuroblastoma cells expressing TRPV1 receptors; these elevations were blocked by ruthenium red. BIS014 did not block capsaicin-elicited [Ca2+]c transients, but inhibited the increase in the firing rate of action potentials in bradykinin-sensitized dorsal root ganglion neurons stimulated with capsaicin. Perspective: We report that the oral administration of a new sulfated disaccharide compound, named BIS014, decreases neuropathic pain from diverse etiology in mice. Unlike the comparator gabapentin, BIS014 does not induce sedation. Thus, BIS014 has the potential to become a new efficacious non-sedative oral medication for the treatment of neuropathic pain. 2022-11-11T09:47:16Z 2022-11-11T09:47:16Z 2022 journal article Article in press The Journal of Pain, Vol 00, No 00 (), 2022: pp 1−16 [https://doi.org/10.1016/j.jpain.2022.07.014] https://hdl.handle.net/10481/77916 10.1016/j.jpain.2022.07.014 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier