Midazolam attenuates the antinociception induced by d-serine or morphine at the supraspinal level in rats

Ito, Kenji; Yoshikawa, Masanobu; Maeda, Miho; Jin, Xing Lu; Takahashi, Shigeru; Matsuda, Mitsumasa; Tamaki, Raita; Kobayashi, Hiroyuki; Suzuki, Toshiyasu; Hashimoto, Atsushi

doi:10.1016/j.ejphar.2008.02.068

Cited by 12 publications

(10 citation statements)

References 35 publications

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“…Indeed, controversial evidence exists regarding the analgesic versus hyperalgesic effect of midazolam in both human subjects and rodents (Clavier et al, 1992; Kontinen et al, 2000; Lim et al, 2006; Niv et al, 1988; Rattan et al, 1991; Shih et al, 2008; Tatsuo et al, 1999; Yanez et al, 1990). At higher doses, midazolam has a predominantly hyperalgesic effect, possibly due to its supraspinal effect (Ito et al, 2008; Niv et al 1988). In this study, we used a low midazolam dose (2 mg/kg) which by itself did not cause any abnormal motor function (e.g., gait abnormality).…”

Section: Discussionmentioning

confidence: 99%

“…Benzodiazepines have been reported to both potentiate and attenuate morphine analgesia (Ito et al, 2008; Mantegazza et al, 1982). For example, intrathecal administration of midazolam potentiated morphine anti-nociception, whereas administration of midazolam intracerebroventricularly or into the dorsal raphe-periaqueductal gray area reduced the anti-nociceptive effect of morphine (Ito et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…For example, intrathecal administration of midazolam potentiated morphine anti-nociception, whereas administration of midazolam intracerebroventricularly or into the dorsal raphe-periaqueductal gray area reduced the anti-nociceptive effect of morphine (Ito et al, 2008). Systemic midazolam has been shown to inhibit the anti-nociceptive effect of opioids, which is at least partially reversed by bicuculline (a GABA antagonist) injected into the periaqueductal gray area (Mantegazza et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

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Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury

Song¹,

Wang

Zuo

et al. 2014

Brain Research

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Midazolam and morphine are often used in pediatric intensive care unit (ICU) for analgesia and sedation. However, how these two drugs interact behaviorally remains unclear. Here, we examined whether 1) co-administration of midazolam with morphine would exacerbate morphine tolerance and morphine-induced hyperactive behaviors, and 2) protein kinase C (PKC) would contribute to these behavioral changes. Male rats of 3 to 4 weeks old were exposed to a hindpaw burn injury. In Experiment 1, burn-injured young rats received once daily saline or morphine (10 mg/kg, subcutaneous, s.c.), followed 30 min later by either saline or midazolam (2 mg/kg, intraperitoneal, i.p.), for 14 days beginning 3 days after burn injury. In Experiment 2, young rats with burn injury were administered with morphine (10 mg/kg, s.c.), midazolam (2 mg/kg, i.p.), and chelerythrine chloride (a non-specific PKC inhibitor 10 nmol, intrathecal) for 14 days. For both experiments, cumulative morphine anti-nociceptive dose-response (ED50) was tested and hyperactive behaviors such as jumping and scratching were recorded. Following 2 weeks of each treatment, ED50 dose was significantly increased in rats receiving morphine alone as compared with rats receiving saline or midazolam alone. The ED50 dose was further increased in rats receiving both morphine and midazolam. Co-administration of morphine and midazolam also exacerbated morphine-induced hyperactive behaviors. Expression of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptor and PKCγ in the spinal cord dorsal horn (immunohistochemistry; Western blot) was upregulated in burn-injured young rats receiving morphine alone or in combination with midazolam, and chelerythrine prevented the development of morphine tolerance. These results indicate that midazolam exacerbated morphine tolerance through a spinal NMDA/PKC-mediated mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury

Song¹,

Wang

Zuo

et al. 2014

Brain Research

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“…Intracerebral administered D-serine is effective in several pain models [50, 51] although the effects of D-serine on pain responsiveness might greatly differ depending on the brain region where it is administered (see [52] for an example of potentiation of the pain response by D-serine). However, there is a significant amount of research showing that NMDA receptor antagonists might be also useful for treating pain [53], so the mechanism of action by which D-serine has reported analgesic effects is not well understood.…”

Section: Other Therapeutic Indications For Daao Inhibitorsmentioning

confidence: 99%

The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors

Smith¹,

Uslaner²,

Hutson³

2010

Open Med Chem J

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D-amino acid oxidase (DAAO) is a flavoenzyme that degrades D-amino acids through the process of oxidative deamination. DAAO regulation of D-amino acid levels has been associated with several physiological processes ranging from hormone secretion to synaptic transmission and cognition. Recent genetic studies have identified a mutation on chromosome 13 in schizophrenia patients that encodes two gene products (G30 and G72) that are associated with DAAO. Furthermore, DAAO expression and enzyme activity has been reported to be increased in post mortem brain tissue samples from patients with schizophrenia compared to healthy controls. D-serine, a D-amino acid that is regulated by DAAO, is a potent, endogenous co-agonist of the N-methyl-D-aspartic acid (NMDA) receptor. Because NMDA receptor dysfunction is thought to be involved in the positive (psychotic), negative and cognitive symptoms in schizophrenia, there has been much interest in developing potent and selective DAAO inhibitors for the treatment of this disease. Several research reports have been published that describe the synthesis and biological effects of novel, selective, small molecule inhibitors of DAAO. Many of these compounds have been shown, when given systemically, to increase D-serine concentrations in the blood and brain. However, the efficacy of these compounds in behavioral assays that measure antipsychotic potential and pro-cognitive effects in laboratory animals has been inconsistent. This article highlights and reviews research advances for DAAO inhibitors published in peer reviewed journals.

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“…The use of morphine-midazolam (M/M) combination in painful conditions is based on the well-known relationship between anxiety and pain. [16,17] Despite animal studies suggesting the possibility of increased nociception with the use of midazolam, [18] the bulk of clinical studies have either reported better pain control, [16,19,20] or no significant effect. [21][22][23] This study aimed to compare M/M combination with MS in pain control of patients suffering from isolated traumatic fracture of extremities.…”

Section: Introductionmentioning

confidence: 99%

Comparison of morphine–midazolam versus morphine injection for pain relief in patients with limb fractures - a clinical trial

Majidi

Dinpanah

Ashoori

et al. 2015

Ulus Travma Acil Cerrahi Derg

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Midazolam attenuates the antinociception induced by d-serine or morphine at the supraspinal level in rats

Cited by 12 publications

References 35 publications

Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury

Midazolam exacerbates morphine tolerance and morphine-induced hyperactive behaviors in young rats with burn injury

The Therapeutic Potential of D-Amino Acid Oxidase (DAAO) Inhibitors

Comparison of morphine–midazolam versus morphine injection for pain relief in patients with limb fractures - a clinical trial

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