• Juan-Fernando Padín, Marcos Maroto, José Manuel Entrena, Javier Egea, Eulàlia Montell, Josep Vergés, Manuela G López, Enrique J Cobos, and Antonio G García.
• Instituto-Fundación Teófilo Hernando, C/ Faraday 7, Parque Científico del Campus de Cantoblanco, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Avda. Arzobispo Morcillo 4, Madrid, Spain; Departamento de Ciencias Médicas (Farmacología), Facultad de Medicina, Universidad de Castilla-La Mancha, Ciudad Real, Spain. Electronic address: fernando.padin@uclm.es.
• J Pain. 2023 Jan 1; 24 (1): 688368-83.

AbstractNeuropathic 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.Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

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