Morphine-3-Glucuronide’s Neuro-Excitatory Effects Are Mediated via Indirect Activation of N-Methyl-d-Aspartic Acid Receptors: Mechanistic Studies in Embryonic Cultured Hippocampal Neurones

Hemstapat, Ruedee; Monteith, Gregory R.; Smith, Deborah L.; Smith, M. T.

doi:10.1213/01.ane.0000059225.40049.99

Cited by 59 publications

(35 citation statements)

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“…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). In support of this latter assertion, Bartlett et al (1994) reported that some excitatory effects of M3G are attenuated by pretreatment with an anxiolytic agent (midazolam).…”

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confidence: 86%

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: 86%

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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“…M3G has been reported to have neuroexcitatory action [10][11][12][13][14][15][16], and this neuroexcitatory action of M3G reduces analgesia of MOR and M6G [17]. Moreover, in cultured hippocampal neurons it was reported that M3G indirectly activates the NMDA receptor resulting in increased cytosol calcium concentrations via a predominantly non-opioidergic mechanism [28,29]. Patients who receive large doses of systemically administered MOR have an elevated plasma concentration of M3G of the main metabolite, which is considered to be the cause of neuroexcitatory actions, such as allodynia or myoclonic jerks.…”

Section: Discussionmentioning

confidence: 99%

Relationship between plasma concentrations of morphine and its metabolites and pain in cancer patients

et al. 2010

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“…Many reports have explained that in cases where opioid levels are rapidly rising (as in intrathecal administration); opioid metabolites (example morphine-3-glucuronide) cause neuroexcitation and could induce hyperalgesia, as many patients reported increased pain at the sites of ongoing pain [19][20][21].…”

Section: Decreased Reuptake and Enhanced Nociceptive Responsementioning

confidence: 99%

Opioid-Induced Hyperalgesia

Youssef¹,

Pater²,

Shehata³

2015

J Pain Relief

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Morphine-3-Glucuronide’s Neuro-Excitatory Effects Are Mediated via Indirect Activation of N-Methyl-d-Aspartic Acid Receptors: Mechanistic Studies in Embryonic Cultured Hippocampal Neurones

Cited by 59 publications

References 34 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

Relationship between plasma concentrations of morphine and its metabolites and pain in cancer patients

Opioid-Induced Hyperalgesia

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