The Role of α<sub>2</sub>‐Adrenoceptors in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice

Homayoun, Houman; Khavandgar, Simin; Dehpour, Ahmad Reza

doi:10.1046/j.1528-1157.2002.49701.x

Cited by 36 publications

(10 citation statements)

References 58 publications

(93 reference statements)

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“…While this was also the case for the majority of high-dose responses, there were several instances in which the responses were insensitive to the naloxone treatment, implying possible nonopiate involvement in such cases, a suggestion supported by Homayoun et al (2002), who noted an opiate-α-adrenoceptor interaction that modulates the effects of morphine on chemically induced seizures in mice. In fact, pretreatment with the α 2 -adrenoceptor agonist clonidine inhibited the anticonvulsant effect of morphine in the PTZ mouse seizure model while potentiating its proconvulsant effect.…”

Section: Generalizability Of Opioid Biphasic Responsementioning

confidence: 81%

Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses

Calabrese

2008

Critical Reviews in Toxicology

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Considerable evidence has emerged that hormetic-like biphasic dose-response relationships are common in the biomedical sciences. Consequently, this article assesses dose-response relationships of agents known to modulate epileptic-like seizure thresholds in screening tests with animal models. Biphasic dose responses have been commonly reported as measured by changes in seizure threshold concentrations across a broad dose-response continuum of chemically diverse agents that act via different receptor-based mechanisms. Despite such differences in chemical structure and modes of actions, the quantitative features of these dose responses are quite similar, being consistent with the hormetic dose-response model with respect to the magnitude and width of the stimulatory responses. The hormetic responses were also independent of the animal model employed as well as type of seizure-related endpoint measured. These findings support the generalizability of the hormetic dose-response concept and may have important implications for the discovery of antiseizure drugs and their clinical evaluation.

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Section: Generalizability Of Opioid Biphasic Responsementioning

confidence: 81%

Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses

Calabrese

2008

Critical Reviews in Toxicology

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“…There is also evidence that the opioid system plays a role in seizure suppression in a variety of experimental models of epilepsy (Nandhu, Naijil, Smijin, Jayanarayanan, & Paulose, ; Tortella, ). Other studies have also reported that morphine exerts biphasic and dose‐dependent anti‐ and pro‐convulsant effects in the clonic seizure experimental model induced by the GABA transmission blocker PTZ (Homayoun, Khavandgar, & Dehpour, ; Lauretti, Ahmed, & Pleuvry, ). In the present study, neonatal morphine administration showed a long‐term, anti‐convulsant effect.…”

Section: Discussionmentioning

confidence: 91%

The long‐term effects of neonatal morphine administration on the pentylenetetrazol seizure model in rats: The role of hippocampal cholinergic receptors in adulthood

Saboory

Gholami

Zare

et al. 2013

Developmental Psychobiology

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Early life exposure to opiates may affect neuropathological conditions, such as epilepsy, during adulthood. We investigated whether neonatal morphine exposure affects pentylenetetrazol (PTZ)-induced seizures in adulthood. Male rats were subcutaneously injected with morphine or saline on postnatal days 8-14. During adulthood, each rat was assigned to 1 of the following 10 sub-groups: saline, nicotine (0.1, 0.5, or 1 μg), atropine (0.25 or 1 μg), oxotremorine M (0.1 or 1 μg), or mecamylamine (2 or 8 μg). An intrahippocampal infusion of the indicated compound was administered 30 min before seizure induction (80 mg/kg PTZ). Compared with the saline/oxotremorine (1 μg), saline/saline, and morphine/saline groups, the morphine/oxotremorine (1 μg) group showed a significantly increased latency to the first epileptic behavior. The duration of tonic-clonic seizures was significantly lower in the morphine/oxotremorine (1 μg) group compared to the saline/saline and morphine/saline groups. The severity of seizure was significantly decreased in the morphine/atropine (1 μg) group than in the saline/atropine (1 μg). Seizure severity was also decreased in the morphine/mecamylamine (2 μg) group than in the saline/mecamylamine (2 μg) group. Latency for death was significantly lower in the morphine/mecamylamine (2 μg) group compared with the saline/mecamylamine (2 μg) group. Mortality rates in the morphine/atropine (1 μg) and morphine/mecamylamine (2 μg) groups were significantly lower than those in the saline/atropine (1 μg) and saline/mecamylamine (2 μg) groups, respectively. Chronic neonatal morphine administration attenuated PTZ-induced seizures, reduced the mortality rate, and decreased the impact of the hippocampal cholinergic system on seizures and mortality rate in adult rats. Neonatal morphine exposure induces changes to μ-receptors that may lead to activation of GABAergic neurons in the hippocampus. This pathway may explain the anti-convulsant effects of morphine observed in our study.

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“…In experiment 2, animals received subcutaneous (s.c.) injections of different doses of morphine, 45 min before the determination of seizure threshold. This protocol was adapted, based on our previous studies (35,36), and allows the appearance of maximal modulatory effects of morphine on this model of seizures. Control animals received the same volume of saline solution.…”

Section: Methodsmentioning

confidence: 99%

Sex and Estrus Cycle Differences in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice

et al. 2004

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Summary:Purpose: To evaluate the effects of sex and estrus cycle on biphasic anticonvulsant and proconvulsant modulation of seizure threshold by morphine.Methods: The threshold for the clonic seizures (CST) induced by acute intravenous administration of γ -aminobutyric acid (GABA)-antagonist pentylenetetrazole (PTZ) was assessed in male and female mice. Estrus cycle was assessed by vaginal smears. The effect of removing circulating sex hormones was assessed by gonadectomy.Results: At baseline, diestrus females had a higher CST compared with males and estrus females. Morphine at lower doses (0.5-3 mg/kg) had a significant anticonvulsant effect in males and estrus females compared with that in vehicle-treated controls, whereas female mice in diestrus phase showed a relative subsensitivity to this effect. Morphine at higher doses (30 and 60 mg/kg) significantly decreased CST in males and diestrus females, with less relative effect in estrus mice. In both phases, morphine exerted stronger effects in males compared with females. Ovariectomy brought the baseline CST to the male level and resulted in significant expression of both phases of morphine effect but did not abolish the sex difference in responsiveness to morphine.Conclusions: The biphasic modulation of seizure threshold is subject to both constitutive sex differences in sensitivity to morphine and hormonal fluctuations during the estrus cycle.

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The Role of α₂‐Adrenoceptors in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice

Cited by 36 publications

References 58 publications

Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses

Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses

The long‐term effects of neonatal morphine administration on the pentylenetetrazol seizure model in rats: The role of hippocampal cholinergic receptors in adulthood

Sex and Estrus Cycle Differences in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice

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The Role of α2‐Adrenoceptors in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice

Cited by 36 publications

References 58 publications

Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses

Modulation of the Epileptic Seizure Threshold: Implications of Biphasic Dose Responses

The long‐term effects of neonatal morphine administration on the pentylenetetrazol seizure model in rats: The role of hippocampal cholinergic receptors in adulthood

Sex and Estrus Cycle Differences in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice

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The Role of α₂‐Adrenoceptors in the Modulatory Effects of Morphine on Seizure Susceptibility in Mice