High-performance liquid chromatography-mass spectrometry-mass spectrometry analysis of morphine and morphine metabolites and its application to a pharmacokinetic study in male Sprague–Dawley rats

Zheng, Ming; McErlane, Keith M.; Ong, May

doi:10.1016/s0731-7085(97)00094-0

Cited by 60 publications

(29 citation statements)

References 40 publications

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“…As shown in Figure 1, both 5.6 and 10 mg/kg morphine produced time-dependent anxiolyticlike effects after acute treatment, with peak effects at 2 hr following 5.6 mg/kg morphine and at 4 hr following 10 mg/kg morphine. One possible interpretation of the delay in onset of anxiolytic-like effect is that it is mediated by a build-up of morphine metabolites, which in the rat consist primarily of morphine-3-glucuronide (M3G; Christrup, 1997;Shang et al, 2006;Zheng et al, 1998). However, several pieces of evidence argue against this interpretation.…”

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confidence: 99%

“…First, M3G levels in plasma and CSF are higher at 2 hr after injection of 10-15 mg/kg of morphine (Barjavel et al, 1995;Shang et al, 2006) than they are at 4 hr post-injection, yet the anxiolytic-like effects observed after acute administration of 10 mg/kg morphine peaked at 4 hr, and were absent at 2 hr. Second, the lower dose of morphine (5.6 mg/kg) produces anxiolytic-like effects at 2 hr post-treatment where the higher dose of 10 mg/kg is without effect, yet plasma levels of M3G at 2 hr post-injection are significantly higher with 10 mg/kg than 5.6 mg/kg of morphine (Barjavel et al, 1995;Zheng et al, 1998). Finally, we are unaware of any reports in the literature of M3G producing anxiolytic-like effects, but there are a number of reports that central administration of this morphine metabolite elicits an excitatory reaction characterized by explosive motor behavior, touch-evoked agitation, myoclonic jerks, and wetdog shakes, behaviors that the rat is most likely to experience as aversive rather than anxiolytic (Bartlett et al, 1994;Hemstapat et al, 2003;Labella et al, 1979;Smith and Smith, 1998).…”

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confidence: 99%

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Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Zhang

Schulteis

2008

Pharmacology Biochemistry and Behavior

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Pretreatment with a single moderate dose of morphine (e.g. 5.6-10 mg/kg) 4-24 hr prior to challenge with an opioid antagonist such as naloxone results in reliable expression of behaviors that resemble aversive or emotional consequences of withdrawal from chronic opioid exposure, including suppression of operant responding, elevations in brain reward thresholds, and conditioned place aversion. Repeated daily or weekly treatment with these same morphine doses results in a progressive increase in naloxone potency to elicit these withdrawal signs. The current study sought to determine whether increased anxiety-like behavior during withdrawal from chronic opioid dependence is also seen after acute morphine exposure, and progresses with repeated intermittent treatment. Male Wistar rats were handled and injected with either vehicle or morphine for 4 consecutive days. Three injection regimens were employed: Morphine Naive (4 vehicle injections), Acute Morphine (3 vehicle injections, 4th injection 5.6 or 10 mg/kg morphine), or Repeat Morphine (all 4 injections with 5.6 or 10 mg/kg morphine). Acute pretreatment with 5.6 mg/kg or 10 mg/kg morphine resulted in timedependent increases in exploration of the open arms of the plus maze in naloxone-naive rats when rats were tested at 2, 4 or 8 hr after the final pretreatment injection, with the effects at the higher dose appearing later (4 hr) than after the lower dose (2 hr). This pattern of results, in combination with a separate study which confirmed a significant anxiolytic-like effect of a low dose of morphine (0.56 mg/kg) administered 15 min prior to test, suggested that low residual morphine levels in the plasma remaining at 2-4 hr after 5.6 and 10 mg/kg morphine may be sufficient to elicit anxiolytic-like effects. Repeat treatment with either dose of morphine resulted in a further increase in the magnitude and duration of this anxiolytic-like effect. These effects had dissipated by 8 hr post-morphine, and therefore precipitation of withdrawal by one of several doses of naloxone (0.10-3.3 mg/kg) was assessed in separate cohorts of rats 8 hr after the final pretreatment under Morphine Naïve, Acute Morphine, or Repeat Morphine conditions. Naloxone resulted in a significant dose-dependent expression of anxiety-like behavior with no effects on general activity after Acute Morphine pretreatment at either 5.6 or 10 mg/kg morphine. A further significant shift in naloxone potency was observed after Repeat Morphine pretreatment at the 10 mg/kg but not the 5.6 mg/kg dose. Thus, anxiety-like behavior is a prominent feature of the negative emotional consequences of naloxoneprecipitated withdrawal from acute opioid dependence.

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confidence: 99%

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confidence: 99%

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Zhang

Schulteis

2008

Pharmacology Biochemistry and Behavior

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“…A number of studies reported on identification and quantification of morphine and related metabolites in biological samples by flowinjection ESI-MS [1], LC/ESI-MS [1][2][3][4][5][6][7] or CE/ESI-MS [8,9], mostly from a forensic point of view. Frequently fragmentation by CID is described and applied as LC/MS/MS.…”

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confidence: 99%

Electrospray tandem mass spectrometric investigations of morphinans

Raith

Neubert

Poeaknapo

et al. 2003

J. Am. Soc. Mass Spectrom.

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In this study positive ESI tandem mass spectra of the [M ϩ H] ϩ ions of morphinan alkaloids obtained using an ion trap MS were compared with those from a triple quadrupole MS. This allows to assess the differences of the tandem-in-time versus the tandem-in-space principle, often hampering the development of ESI MS/MS libraries. Fragmentation pathways and possible fragment ion structures were discussed. In order to obtain elemental composition, accurate mass measurements were performed. According to the MS/MS fragmentation pathway, the investigated compounds can be grouped into 4 subsets: (1) morphine and codeine, (2) morphinone, codeinone, and neopinone, (3) thebaine and oripavine, (4) -7] or CE/ESI-MS [8,9], mostly from a forensic point of view. Frequently fragmentation by CID is described and applied as LC/MS/MS. Two reviews highlight the field [10,11]. Some systematic approaches to the setup of libraries have been undertaken, including data for morphine and codeine [12][13][14]. However, none of these studies compared data of ion trap and triple quad systems. Most of the morphinan type substances have been investigated before by electron impact ionization MS [15][16][17]. Tandem MS instrumentation and the principles of operation have been extensively discussed in the literature [18]. In contrast to magnetic sector instruments, triple quadrupole, quadrupole ion trap, and quadrupole time-of-flight are all considered to perform low collision energy fragmentation. Nevertheless, the obtained tandem mass spectra can look remarkably different. Although the structure elucidation potential of CID was early recognized [19], the setup of ESI-MS/MS libraries was hampered by lacking reproducibility. This article provides comparable ion trap and triple quadrupole MS/MS data of all discussed substances. Accurate mass data of selected morphinans were obtained by quadrupole time-of-flight and FT-ICR mass spectrometry, respectively.

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“…A subsequent study (Zheng et al, 1998) improved the use of LC-ESP tandem mass spectrometry, and obtained sensitivities 5±20 fold higher than those in the previous study for morphine and its glucuronide metabolites. In this case, MS-MS analysis was applied to overcome the effect of possible matrix interference, which could lower the sensitivity of SIM analysis.…”

Section: Electrospray Interfacementioning

confidence: 83%

The role of liquid chromatography-mass spectrometry in the determination of heroin and related opioids in biological fluids

Pichini

Altieri

Pellegrini

et al. 1999

Mass Spectrom. Rev.

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High-performance liquid chromatography-mass spectrometry-mass spectrometry analysis of morphine and morphine metabolites and its application to a pharmacokinetic study in male Sprague–Dawley rats

Cited by 60 publications

References 40 publications

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Withdrawal from acute morphine dependence is accompanied by increased anxiety-like behavior in the elevated plus maze

Electrospray tandem mass spectrometric investigations of morphinans

The role of liquid chromatography-mass spectrometry in the determination of heroin and related opioids in biological fluids

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