Oral administration of dextromethorphan does not produce neuronal vacuolation in the rat brain

Abstract

Dextromethorphan is a widely used antitussive agent, also showing increased recreational abuse. Dextromethorphan and its metabolite dextrorphan are non-competitive antagonists at the N-methyl-d-aspartate (NMDA) receptor ion channel. Single doses of some NMDA receptor antagonists produce neuropathologic changes in neurons of the retrosplenial/posterior cingulate cortices (RS/PC), characterized by vacuolation or neurodegeneration. To determine whether dextromethorphan produces these characteristic lesions, dextromethorphan was administered orally either as a single dose of 120 mg/kg to female rats, or daily for 30 days at doses of 5–400 mg/(kg day) to male rats and 5–120 mg/(kg day) to female rats. Brains were examined microscopically for evidence of neuronal vacuolation (4–6 h postdose) and neurodegeneration (∼24 or 48 h postdose). Administration of dextromethorphan at 120 mg/(kg day) in females, and at ≥150 mg/(kg day) in males produced marked behavioral changes, indicative of neurologic effects. Mortality occurred at the highest doses administered. There were no detectable neuropathologic changes following single or repeated oral administration of dextromethorphan at any dose. Administration of MK-801 (9 mg/kg) produced both cytoplasmic vacuolation and neuronal degeneration in neurons of the RS/PC cortex. Thus characteristic neuropathologic changes found with more potent NMDA receptor antagonists do not occur following single or repeated oral administration of dextromethorphan.

Introduction

Dextromethorphan (3 methoxy-17-methylmorphinan monohydrate) is the d-isomer of levorphanol, a codeine analog. Dextromethorphan is used worldwide as an antitussive agent in cough and cold medications in at least 125 products. Because of its ready accessibility, recreational abuse of dextromethorphan has been increasing in recent years, although accurate statistics are not available.

Dextromethorphan and its primary metabolite dextrorphan act as channel blockers at the N-methyl-d-aspartate (NMDA) receptor and are generally classified as non-competitive, low affinity antagonists (Franklin and Murray, 1992, Roth et al., 1996). Dextromethorphan is rapidly demethylated in vivo to dextrorphan which has higher NMDA receptor binding affinity than dextromethorphan (Sun and Wessinger, 2004). Therefore dextrorphan likely contributes to the in vivo activity of dextromethorphan. Neither dextromethorphan nor dextrorphan has significant in vivo opioid activity.

Several NMDA receptor antagonists have been associated with a specific neuropathologic lesion following acute exposure in rats. The lesion (occasionally referred to as the “Olney lesion”) is characterized by neuronal vacuolation in the retrosplenial/posterior cingulated cortices (RS/PC) (Olney et al., 1989). The effect has been described for both non-competitive antagonists (ketamine, tiletamine, phencyclidine and MK-801) and the competitive antagonists (2-amino, 5-phosphonopentanoate [AP5], 3-(2-carboxypiperazin-4-yl)propyl-l-phosphonoic acid [CPP]) (Olney et al., 1989, Fix, 1994, Fix et al., 1995a, Fix et al., 1996, Fix et al., 2000, Auer and Coulter, 1994). The time-and dose-dependent nature of the lesion has been most extensively studied using the prototypical NMDA antagonist, MK-801. At low single doses neuronal vacuolation is readily reversible and limited to the RS/PC. Vacuolation is observed most prominently at 4–8 h after dosing, but is not apparent by 24 h (Olney et al., 1989). The vacuolar changes are also not sustained with repeated dosing (up to 4 days) of MK-801, suggesting the rapid development of cellular tolerance (Olney et al., 1989). At higher doses, irreversible neuronal necrosis occurs with associated reactive gliosis (Fix et al., 1995b), and disseminated changes involving additional corticolimbic structures (Horváth et al., 1997, Wozniak et al., 1998) have been described.

The neuropathologic effects of dextromethorphan and/or dextrorphan have not been well characterized. Therefore, the studies reported here were conducted to determine if oral administration of dextromethorphan to rats produces these characteristic findings after single or repeated administration at doses up to a maximally tolerated dose. Oral administration was used in these studies because this is the route of human therapeutic use and most common route of recreational abuse.