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 1 g/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 (1 g/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 100 mg/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.

Introduction

Chronic neuropathic pain can be the consequence of many diseases (like diabetes, herpes zoster infection, cancer, etc.), and despite the fact that major advances have been made for treating this condition, therapy is far from being perfect. Thus, there is still a need for new therapeutic principles. Among the proposed targets for new drugs are Na⁺ channels in peripheral sensory neurons, especially Nav1.8 channels (Baker and Wood, 2001). Lai et al. (2002) showed that downregulation of Nav1.8 expression by antisense oligonucleotides suppressed behavioural changes in a rat model of neuropathic pain. Thus, Nav1.8 channel blockers might be promising analgesic agents, and might have a beneficial side effect profile due to sparing other Na⁺ channel subtypes. Unfortunately, most of the Na⁺ channel blockers available today do not preferentially block Nav1.8 channels, although some show efficacy for treating neuropathic pain (although with dose-limiting side effects, e.g. mexiletine; Jarvis and Coukell, 1998).

Ambroxol is a secretolytic compound which was introduced in Germany in 1979 for the treatment of respiratory diseases, and today it is available in more than 50 countries worldwide. In addition to its effects on the respiratory system, recent investigations showed that ambroxol is an effective blocker of neuronal Na⁺ channels (Weiser and Wilson, 2002). Interestingly, this drug inhibited tetrodotoxin (TTX)-resistant (Nav1.8) channels more effectively than TTX-sensitive subtypes. We therefore used this compound as a tool to investigate whether a Nav1.8-preferring Na⁺ channel blocker might be effective in animal models of chronic, neuropathic and inflammatory pain. Ambroxol's effects were compared with those of gabapentin, a drug widely used for the treatment of neuropathic pain. In addition, pharmacokinetic investigations were performed to ensure that clinically meaningful ambroxol plasma concentrations were achieved.