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. 2005 Jan 10;144(3):400–404. doi: 10.1038/sj.bjp.0706086

Dextromethorphan differentially affects opioid antinociception in rats

Shiou-Lan Chen 1, Eagle Yi-Kung Huang 2, Lok-Hi Chow 1, Pao-Luh Tao 2,*
PMCID: PMC1576017  PMID: 15655510

Abstract

  1. Opioid drugs such as morphine and meperidine are widely used in clinical pain management, although they can cause some adverse effects. A number of studies indicate that N-methyl-D-aspartate (NMDA) receptors may play a role in the mechanism of morphine analgesia, tolerance and dependence. Being an antitussive with NMDA antagonist properties, dextromethorphan (DM) may have some therapeutic benefits when coadministered with morphine. In the present study, we investigated the effects of DM on the antinociceptive effects of different opioids. We also investigated the possible pharmacokinetic mechanisms involved.

  2. The antinociceptive effects of the μ-opioid receptor agonists morphine (5 mg kg−1, s.c.), meperidine (25 mg kg−1, s.c.) and codeine (25 mg kg−1, s.c.), and the κ-opioid agonists nalbuphine (8 mg kg−1, s.c.) and U-50,488H (20 mg kg−1, s.c.) were studied using the tail-flick test in male Sprague–Dawley rats. Coadministration of DM (20 mg kg−1, i.p.) with these opioids was also performed and investigated.

  3. The pharmacokinetic effects of DM on morphine and codeine were examined, and the free concentration of morphine or codeine in serum was determined by HPLC.

  4. It was found that DM potentiated the antinociceptive effects of some μ-opioid agonists but not codeine or κ-opioid agonists in rats. DM potentiated morphine's antinociceptive effect, and acutely increased the serum concentration of morphine. In contrast, DM attenuated the antinociceptive effect of codeine and decreased the serum concentration of its active metabolite (morphine).

  5. The pharmacokinetic interactions between DM and opioids may partially explain the differential effects of DM on the antinociception caused by opioids.

Keywords: Opioid drugs, dextromethorphan, antinociception

Introduction

The opioid drugs such as morphine, meperidine, etc. are still the most effective analgesic drugs used in the treatment of severe and chronic pain. There are three major types of opioid receptors, mu (μ), delta (δ) and kappa (κ), which are expressed in the brain and spinal cord. The opioid drugs act on the corresponding opioid receptors and produce their antinociceptive effects. However, side effects such as vomiting, pruritus, respiratory depression, tolerance and dependence have restricted their clinical use. Dextromethorphan (DM) is the dextrorotatory isomer of levomethorphan, but lacks opioid-like activity and is best known for its antitussive effects (Wang et al., 1977). DM has been demonstrated to have anticonvulsant (Ferkany et al., 1988) and neuroprotective properties through antagonizing the glycine and Mg2+ sites, as well as the phencyclidine-binding site on the N-methyl-D-aspartate (NMDA) receptor complex. DM has been shown to prevent the development of tolerance to the antinociceptive effects of morphine in rodents (Elliott et al., 1994a; Mao et al., 1996; Manning et al., 1996). DM also attenuated signs of naloxone-precipitated withdrawal in morphine-dependent rats (Mao et al., 1996; Manning et al., 1996). DM is a particularly attractive candidate for clinical use since it has been dispensed as a nonprescription drug for over 40 years and is known to have a wide margin of safety. It has been reported that coadministration of DM with morphine or methadone could potentiate their antinociceptive effects (Grass et al., 1996; Hoffmann & Wiesenfeld-Hallin, 1996; Bulka et al., 2002); however, the mechanism is not clear.

There are two major aims in the present study. One is to investigate the effects of DM on the antinociceptive effects of different opioids; the second is to investigate the possible pharmacokinetic mechanism involved.

Methods

Animals

Male Sprague–Dawley rats, weighing 350–400 g, were purchased from the National Experimental Animal Centre, Taipei, Taiwan. All rats were kept in an animal room with a 12 h light/dark cycle, at a temperature of 25±2°C and humidity of 55%. Standard diet and water were provided ad libitum. The animals were acclimated for at least 3 days before the experiments. The care of animals was carried out in accordance with institutional and international standards (Principles of Laboratory Animal Care, NIH) and the protocol has got approval from the Institutional Animal Care and Use Committee of National Defense Medical Center, Taiwan, R.O.C.

Determination of the antinociceptive effect of drugs

Selected doses of opioids with submaximal antinociceptive effect (morphine 5 mg kg−1, meperidine 25 mg kg−1, codeine 25 mg kg−1, nalbuphine 8 mg kg−1 or U-50,488H 20 mg kg−1) were administered to different groups of rats subcutaneously (s.c.). DM (20 mg kg−1; i.p.) was coadministered with the opioid in other comparative groups. Saline (1 ml kg−1; i.p.) was administered in control group. There were at least six rats in each group and different rats were used in each experiment. Drug-induced antinociception was evaluated using the tail-flick test (Amour & Smith, 1941). Using a tail-flick apparatus (Model: DS-20, Ugo Basile, Italy), tail-flick latency was recorded at 30, 60, 90, 120, 150, 180 min after drug administration. The intensity of the heat source was set to make the basal tail-flick latency to be controlled between 2.5 and 3.5 s for all animals (cutoff: 10 s). The area under the time–response curve (AUC) was calculated using the Trapezoidal and Simpson's rules. The AUC value was regarded as an index of the antinociceptive effect of the drug(s).

In vivo pharmacokinetic study

Individual rats were placed in a restrainer, and blood (0.5–1 ml) was collected from the tail vein at the 30, 60, 90, and 150 min after drug administration. The blood was collected from the same animal at different time points, and the animals were not used in the tail-flick test. The whole blood sample was centrifuged at 3000 × g for 10 min at 4°C. The serum was collected and filtered through Millipore Amicon Microcon YM-3 centrifugal filters (MW cut-off 3000) at 17,800 × g for 40 min at 4°C. The recovery rate of the filtration is 100%. The filtered sample was then injected into the high-performance liquid chromatography (HPLC) system for the measurement of free drug concentration. The free form of morphine was determined as described below in HPLC analysis.

High-performance liquid chromatography (HPLC analysis)

We used a HPLC method for the quantification of the morphine concentration in serum. Quantification was performed by HPLC-coupled electrochemical detection. Using linear regression, calibration curves (standard curves) were constructed and covered a wide range of concentrations (10–1000 nM). The samples were compared with the standard curves to determine their contents of drugs. The electrochemical chromatographic system consisted of a pump (LC-10AD, Shimadzu, Japan), a TSKgel ODS-80TM C18 column (Tosoh, Japan), and an electrochemical detector (ESA Coulochem II, Chelmsford, MA, U.S.A.) containing a 5020 guard cell and 5010 analytical cells. For the determination of the free form of morphine in serum, 20 μl samples were injected into the HPLC system. The voltages of the guard cell and analytical cells were set at 650 and 550 mV (detecting potential), respectively. The mobile phase (ESA MDTM mobile phase) consisted of 75 mM sodium dehydrogenate phosphate (monohydrate), 1.7 mM 1-octanesulfonic acid (sodium salt), 100 μl l−1 triethylamine, 25 μM EDTA, 10% acetonitrile, pH 3.00, which was delivered at a flow rate of 1.0 ml min−1.

Statistical analysis

The data were expressed as means±s.e.m. One-way ANOVA and Newman–Keuls test were used to analyze the data. A difference was considered to be significant at P<0.05 or P<0.01.

Chemicals

Morphine hydrochloride, meperidine, and codeine were purchased from the National Bureau of Controlled Drugs, National Health Administration, Taipei, Taiwan, R.O.C. Nalbuphine was purchased from Mallinckrodt Inc. (St Louis, Missouri, U.S.A.). U-50,488H was a gift from Dr Chen-Yu Cheng, who prepared it as described in our previous paper (Su et al., 1998). All other chemicals were supplied by Sigma (St Louis, MO, U.S.A.). The chemicals were all of analytical grade and the solvents were of HPLC grade.

Results

DM potentiated the antinociceptive effects of morphine and meperidine but not codeine or kappa-opioid agonists in rats

As shown in Figure 1, coadministration of DM (20 mg kg−1) acutely and significantly increased the antinociceptive effect of morphine (5 mg kg−1) (P<0.01). Similarly, coadministration of DM (20 mg kg−1) also significantly potentiated the antinociceptive effect of meperidine (mg kg−1). However, DM did not potentiate the antinociceptive effect of another μ-opioid agonist – codeine (25 mg kg−1) – and, in addition, it decreased codeine's effect. Conversely, DM did not affect the antinociceptive effect of the κ-opioid agonists: U-50,488H (20 mg kg−1) or nalbuphine (8 mg kg−1) (Figure 2). These results indicate that DM had differential effects on the antinociceptive effect of different opioid agonists in rats. Most interestingly, DM showed opposite effects on opioid agonists acting on the same μ-opioid receptors, such as morphine and codeine. In order to investigate whether pharmacokinetic mechanisms are involved, we carried out the following study in pharmacokinetics.

Figure 1.

Figure 1

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The effect of DM (20 mg kg−1, i.p.) on the antinociceptive effect of mu opioid agonists: morphine (M; 5 mg kg−1, s.c.); meperidine (Mep; 25 mg kg−1, s.c.) and codeine (C; 25 mg kg−1, s.c.). Values are means±s.e.m. ANOVA and Newman–Keuls test were used to analyze the data. **P<0.01 represents a significant difference between the opioid and opioid+DM groups.

Figure 2.

Figure 2

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The effect of DM (20 mg kg−1, i.p.) on the antinociceptive effect of kappa opioid agonists: U-50,488 (U-50; 20 mg kg−1, s.c.) and nalbuphine (Nal; 8 mg kg−1, s.c.). Values are means±s.e.m. ANOVA and Newman–Keuls test were used to analyze the data.

The effect of DM on the serum concentration of the free form of morphine

When DM was coadministered with morphine, the serum concentration of morphine (free form) was higher than in the morphine group after drug administration, as shown in Figure 3a and b. In contrast, when DM was coadministered with codeine, the serum concentration of morphine (the active metabolite of codeine) was lower than in the codeine group (Figure 4). These data indicate that DM increased the serum concentration of morphine and potentiated the antinociceptive effect of morphine (Figures 1 and 3). Conversely, DM decreased the serum concentration of morphine and therefore attenuated the antinociceptive effect of codeine (Figures 1 and 4).

Figure 3.

Figure 3

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The pharmacokinetic effect of dextromethorphan (DM; 20 mg kg−1, i.p.) on the morphine (M; 5 mg kg−1, s.c.). (a) Time course of the serum concentration of morphine (nM) after drug administration. (b) Area under curve (AUC) value of upper plot in (a). ANOVA and Newman–Keuls test were used to analyze the data. Values are means±s.e.m. *P<0.05, **P<0.01 represents a significant difference between the M and M+DM groups at the same time. ##P<0.01 represents a significant difference of AUC value between the M and M+DM groups.

Figure 4.

Figure 4

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The pharmacokinetic effect of dextromethorphan (DM; 20 mg kg−1, i.p.) on the codeine (C; 25 mg kg−1, s.c.). ANOVA and Newman-Keuls test were used to analyze the data. Values are means±s.e.m. **P<0.01 represents a significant difference between the C and C+DM groups at the same time.

Discussion

A number of studies indicate that NMDA receptor antagonists such as MK-801, LY274614 and ketamine can attenuate the development of morphine tolerance and dependence (Kest et al., 1993; Gutstein & Trujillo, 1993; Elliott et al., 1994b; Tiseo et al., 1994; Trujillo & Akil, 1994; Herman et al., 1995; Manning et al., 1996; Mao et al., 1996). However, MK-801 has been shown to have great toxicity to animals and cannot be used in clinical treatment. Owing to its NMDA antagonist action and lower toxic properties, DM has been used with morphine to test if DM could prevent the development of morphine tolerance and dependence. Studies have shown that DM can attenuate and reverse analgesic tolerance to morphine (Elliott et al., 1994a; Mao et al., 1996). On the other hand, recent animal studies have reported the potentiation of opioid antinociception by coadministration of NMDA receptor antagonists such as MK-801, ketamine and DM (Grass et al., 1996; Hoffmann & Wiesenfeld-Hallin, 1996; Zhu et al., 2003).

In the present study, we found that DM significantly potentiated the antinociceptive effects of certain μ-opioid agonists such as morphine or meperidine, but not the κ-opioid agonists U-50,488H or nalbuphine in rats. These results are consistent with the previous report that DM potentiates the antinociceptive effects of μ- but not κ-opioid agonists in a mouse model of acute pain (Allen et al., 2002; Baker et al., 2002). Morphine is a natural opiate that is metabolized mainly through glucuronidation by uridine diphosphate glucuronosyl transferase (UGT) 2B enzymes in the liver (Pritchard et al., 1994; Coffman et al., 1997; King et al., 2000). DM undergoes O-demethylation to dextrorphan and N-demethylation to 3-methoxymorphinan. The N-demethylation of DM to 3-methoxymorphinan is catalyzed primarily by cytochrome P450 3A (CYP3A) enzymes in the liver. The O-demethylation pathway to dextrorphan is catalyzed primarily by cytochrome P450 2D6 (CYP2D6) enzymes in the human liver (Dayer et al., 1988; Ladona et al., 1991; Jacqz-Aigrain & Cresteil, 1992; Jacqz-Aigrain et al., 1993).

As mentioned above, morphine and DM are metabolized in different metabolic pathways. How could DM increase the serum concentration of morphine? The exact mechanism is unknown. However, liver microsomal studies have shown inhibition of morphine-3-glucuronide (M3G) formation by DM (Wahlstrom et al., 1988) and this may play a role in the mechanism of DM to potentiate morphine antiniciceptive effect. On the other hand, in our other studies, we found that intrathecal DM also potentiated the antinociceptive effect of morphine at the spinal level, in addition to the potentiation by DM injected systemically (Chow et al., 2004). Therefore, apart from the pharmacokinetic factor, there must be some other mechanism(s) involved in the effects of DM in potentiating morphine antinociception.

Codeine is widely used for analgesia and cough suppression. Its analgesic effect is through its active metabolite morphine and therefore, codeine is classified as a μ-opioid agonist. In the present study, DM potentiated the antinociceptive effect of two μ-opioid agonists: morphine and meperidine, but not codeine. Why? Is the pharmacokinetic factor involved again in this case? We know that codeine is metabolized by CYP2D6 to the more potent drug morphine in human liver (Dayer et al., 1988; Ladona et al., 1991) but metabolized by CYP2D1 in rats (Cleary et al., 1994). DM is also a potent CYP2D1 substrate (Kerry et al., 1993; Tyndale et al., 1999) and has been shown to be an inhibitor of morphine formation from codeine (Mikus et al., 1991). Our results have shown that coadministration of DM with codeine decreases the serum morphine concentration, metabolized from codeine. This indicates that CYP2D1 inhibition by DM may result in a decrease in the analgesic effects of codeine in rats.

In summary, DM can differentially potentiate the antinociceptive effect of μ-opioid agonists in rats, and pharmacokinetic factor(s) may be one of the important mechanisms involved.

Acknowledgments

This study was supported by the grant from National Health Research Institutes, Taiwan, R.O.C. (NHRI-EX-92-8909BP) and was supported in part by the C.Y. Chai Foundation for Advancement of Education, Science and Medicine, Taiwan, R.O.C.

Abbreviations

AUC

area under the time–response curve

DM

dextromethorphan

HPLC

high-performance liquid chromatography

NMDA

N-methyl-D-aspartate

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