title: Ambroxol, a Nav1.8-preferring Na(+) channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain.
abstract: Neuropathic pain affects many patients, and treatment today is far from being perfect. Nav1.8 Na(+) channels, which are expressed by small fibre sensory neurons, are promising targets for novel analgesics. Na(+) channel blockers used today, however, show only limited selectivity for this channel subtype, and can cause dose-limiting side effects. Recently, the secretolytic ambroxol was found to preferentially inhibit Nav1.8 channels. We used this compound as a tool to investigate whether a Nav1.8-preferring blocker can suppress symptoms of chronic, neuropathic and inflammatory pain in animal models. The drug was tested in the formalin paw model, two models of mononeuropathy, and a model of monoarthritis in rats. Ambroxol's effects were compared with those of gabapentin. Ambroxol at a dose of 1g/kg had to be administered to rats to achieve the plasma levels that are reached in clinical use (for the treatment of infant and acute respiratory distress syndrome). Ambroxol (1g/kg) was only weakly effective in models for acute pain, but effectively reduced pain symptoms in all other models; in some cases it completely reversed pain behaviour. In most cases the effects were more pronounced than those of gabapentin (at 100mg/kg). These data show that a Nav1.8-preferring Na(+) channel blocker can effectively suppress pain symptoms in a variety of models for chronic, neuropathic and inflammatory pain at plasma levels, which can be achieved in the clinic.
authors.affiliation: Department of CNS Research, Boehringer Ingelheim Pharma GmbH and Co KG, D-88397 Biberach, Germany.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Gaida
authors.forename: Klaus
authors.initials: K
authors.lastname: Klinder
authors.forename: Kirsten
authors.initials: K
authors.lastname: Arndt
authors.forename: Thomas
authors.initials: T
authors.lastname: Weiser
mesh_terms: D000551:Ambroxol / Q000494:pharmacology*; D000588:Amines / Q000494:pharmacology; D000700:Analgesics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003251:Constriction, Pathologic / Q000517:prevention & control / Q000523:psychology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005557:Formaldehyde; D000077206:Gabapentin; D007249:Inflammation / Q000150:complications* / Q000523:psychology; D008026:Ligation; D008297:Male; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020426:Sciatic Neuropathy / Q000150:complications* / Q000523:psychology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D005557:Formaldehyde; D000551:Ambroxol; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin