Dextromethorphan, 3-methoxymorphinan, and dextrorphan have local anaesthetic effect on sciatic nerve blockade in rats
Introduction
Dextromethorphan, a dextrorotatory morphinan, has been used clinically as a cough suppressant for more than 40 years and is considered a drug with a good margin of safety (Bem and Peck, 1992, Carlsson et al., 2005, Duedahl et al., 2006, Weinbroum et al., 2000). Dextromethorphan was synthesized originally as a pharmacological alternative to morphine. However, in contrast to the levorotatory morphinans, dextromethorphan has little or no opioid activity (Weinbroum et al., 2000). Dextromethorphan has a complex pharmacology. In in vitro binding assays, dextromethorphan inhibits the N-methyl-d-aspartate (NMDA) glutamate and nicotine/neuronal nicotinic receptor channels, and the voltage-gated Ca2+ and Na+ channels (Carlsson et al., 2005, Damaj et al., 2005, Netzer et al., 1993, Trube and Netzer, 1994). Dextromethorphan has been used as an antitussive and proposed as a treatment for stroke, brain ischemia (Moses and Choi, 1991, Steinberg et al., 1993), seizure disorders (Fisher et al., 1990), morphine dependence (Glick et al., 2001, Mao et al., 1996), and acute or neuropathic pain (Carlsson et al., 2005; Duedahl et al., 2006, Joshi, 2005, Weinbroum et al., 2000). The NMDA receptor antagonist effects of dextromethorphan seem to be the primary rationale for these uses.
Although dextromethorphan has a long history of clinical uses with a good margin of safety, the pharmacologic effects with respect to its channel bindings were not well studied, e.g., the Na+ channel blockade. The Na+ channel blockade is an essential activity of the local anaesthetics (Fozzard et al., 2005, McLure and Rubin, 2005, Scholz, 2002). With this activity, local anaesthetics produce infiltrative cutaneous analgesia, peripheral nerve block, and spinal/epidural anaesthesia (McLure and Rubin, 2005). Because dextromethorphan has a Na+ channel blocking effect (Netzer et al., 1993), theoretically, it may have a local anaesthetic effect. However, this was never tested. The aim of the study was to evaluate whether dextromethorphan has a local anaesthetic effect. We focused on the sciatic nerve blockade. The potency and duration of action of dextromethorphan on sciatic nerve blockade in rats were evaluated. Two major metabolites of dextromethorphan — 3-methoxymorphinan and dextrorphan— (Mordecai et al., 1995) were also studied. Lidocaine, a commonly used local anaesthetic, was used as control. The effects of co-administration of dextromethorphan or its metabolites with lidocaine on sciatic nerve blockade were evaluated, too.
Section snippets
Animals
Experiments were performed on 200–250 g male Sprague–Dawley rats (the National Laboratory Animal Center, Taipei, Taiwan). Rats were housed in a climate controlled room maintained at 21 °C with approximately 50% relative humidity. Lighting was on a 12-h light–dark cycle (light on at 6:00 a.m.), with food and water available ad libitum up to the time of testing. The experiments protocols were approved by the animal investigation committee of Chi-Mei Medical Center, Tainan, Taiwan and conformed to
Time courses of sciatic nerve blockade
The time courses of sciatic nerve blockades in motor function, proprioception, and nociception by dextromethorphan, 3-methoxymorphinan, dextrorphan, and lidocaine were performed. Due to the similarities of the figures, only the figures obtained from dextromethorphan and lidocaine at a dose of 6.7 mg/kg are shown (Fig. 1). At the given dose, dextromethorphan produced 71 ± 16, 78 ± 17, and 83 ± 26% of blockades (% MPE) in motor function, proprioception, and nociception with durations of action of about
Discussion
In this study, the local anaesthetic effects of dextromethorphan and its metabolites — 3-methoxymorphinan and dextrorphan — on sciatic nerve blockades of motor function, proprioception and nociception were studied. We found that dextromethorphan and its metabolites produced dose-related local anaesthetic effects on sciatic nerve blockades of motor function, proprioception and nociception. Co-administration of dextromethorphan or its metabolites with lidocaine produced an additive effect on the
References (27)
- et al.
Comparative effects of dextromethorphan and dextrorphan on morphine, methamphetamine and nicotine self-administration in rats
Eur. J. Pharmacol.
(2001) - et al.
Protection of rat spinal cord from ischemia with dextrorphan and cycloheximide: effects on necrosis and apoptosis
J. Thorac. Cardiovasc. Surg.
(1997) - et al.
Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats
Pain
(1996) - et al.
Dextromethorphan blocks N-methyl-d-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons
Eur. J. Pharmacol.
(1993) Mechanisms of (local) anaesthetics on voltage-gated sodium and other ion channels
Br. J. Anaesth.
(2002)- et al.
Tricyclic antidepressants as long-acting local anesthetics
Pain
(2003) - et al.
Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan
Pharmacol. Biochem. Behav.
(1991) - et al.
Dextromethorphan. An overview of safety issues
Drug Saf.
(1992) - et al.
Analgesic effect of dextromethorphan in neuropathic pain
Acta Anaesthesiol. Scand.
(2005) - et al.
Effect of dextrometorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity
J. Pharmacol. Exp. Ther.
(2005)
A qualitative systematic review of peri-operative dextromethorphan in post-operative pain
Acta Anaesthesiol. Scand.
Dextromethorphan for treatment of complex partial seizures
Neurology
Mechanism of local anesthetic drug action on voltage-gated sodium channels
Curr. Pharm. Des.
Cited by (13)
Subcutaneous l-tyrosine elicits cutaneous analgesia in response to local skin pinprick in rats
2015, European Journal of PharmacologyThe use of carbetapentane for spinal anesthesia and use-dependent block of sodium currents
2013, European Journal of PharmacologyCitation Excerpt :Carbetapentane has been known as a non-opioid antitussive drug with anticonvulsant properties (Leander, 1989). Antitussive dextromethorphan has a local anesthetic effect (Chen et al., 2007, 2008; Hou et al., 2006). In the present study, we showed that intrathecal carbetapentane produced spinal/local anesthesia.
Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats
2013, Pharmacological ReportsCitation Excerpt :At each testing time, only one pinch was given to each of the four testing sites, and the time interval between stimulations at different sites was around 2 s. The nociceptive blockade was graded as 4 (normal or 0% MPE), 3 (25% MPE), 2 (50% MPE), 1 (75% MPE), and 0 (absent or 100% MPE) [1, 10]. After injecting the rats with four different doses of each drug (n = 8 for each dose of each drug) intrathecally, the dose-response curve was constructed.
Enrichment of new alkane oxidizing bacterial strains for human drug metabolite production
2009, Journal of Molecular Catalysis B: EnzymaticIsobolographic Analysis of Epinephrine With Bupivacaine, Dextromethorphan, 3-Methoxymorphinan, or Dextrorphan on Infiltrative Anesthesia in Rats: Dose-Response Studies
2008, Regional Anesthesia and Pain MedicineCitation Excerpt :Our study showed that 3MM produced a dose-dependent local anesthetic effect of cutaneous analgesia. The local anesthetic effect of 3MM in rat sciatic nerve block9 and spinal anesthesia11 has also been proven. In order to rule out the possibility of vehicle or systemic analgesic effect of the drugs, 2 control groups were used.