Potentiated Opioid Analgesia in Norepinephrine Transporter Knock-Out Mice

Bohn, Laura M.; Xu, Fei; Gainetdinov, Raul R.; Caron, Marc G.

doi:10.1523/jneurosci.20-24-09040.2000

Cited by 104 publications

(72 citation statements)

References 41 publications

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“…In b-arr2 + / + mice, neither of the JNK inhibitors altered the analgesic profile of morphine, which showed a comparable dose-response curve to previous publications (Sora et al, 1997;Bohn et al, 2000). In contrast, both SP6 and BI78D3, reversed the enhanced analgesic effect of morphine in b-arr2À/À mice to wild-type levels (Figure 2a and b).…”

Section: Jnk Inhibition Reverses Behavioral Phenotypes Of Morphine Insupporting

confidence: 74%

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Mittal

Tan

Egbuta

et al. 2012

Neuropsychopharmacol

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The altered behavioral effects of morphine, but not most other mu agonists, in mice lacking b-arrestin 2, suggest that this scaffolding protein regulates the signaling cascade of this commonly used analgesic. One of the cascades that could be regulated by b-arrestin 2 is cJun-N-terminal kinase (JNK), which binds with b-arrestin 2 and modulates the analgesic effects of morphine. Using neurons lacking b-arrestin 2 (b-arr2À/À) to examine this interaction, we found that b-arr2À/À neurons show altered intracellular distribution of JNK and cJun, and that morphine, but not fentanyl, increased the nuclear localization of the phosphorylated, therefore activated, form of cJun, a JNK target in dorsal root ganglia neurons. This suggests that deleting b-arrestin 2 affects the JNK cascade. We therefore examined whether some of the behavioral phenotypes of mice lacking b-arrestin 2 could be a result of altered JNK signaling. Indeed, two different JNK inhibitors reversed the enhanced analgesic effect of morphine, a known phenotype of b-arr2À/À mice, to + / + levels. Both the reduced locomotor effect of morphine and the psychomotor sensitization to repeated morphine administration in b-arr2À/À mice were also returned to + / + levels by inhibiting JNK. In contrast, the behavioral effects of fentanyl were neither genotype-dependent nor affected by JNK inhibition. Furthermore, a PKC inhibitor had a similar effect as inhibiting JNK in reducing the enhanced analgesic effect of morphine in b-arr2À/À mice to + / + levels. In summary, removing b-arrestin 2 reveals mu receptor activation of the JNK cascade in a ligand-specific manner explaining several behavioral phenotypes of b-arr2À/À mice.

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Section: Jnk Inhibition Reverses Behavioral Phenotypes Of Morphine Insupporting

confidence: 74%

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Mittal

Tan

Egbuta

et al. 2012

Neuropsychopharmacol

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“…Antiepileptic drugs show efficacy against these syndromes [9,1] further suggesting a common mechanism linking these pathological states [12,13,25]. The increased resistance of NET-KO mice to convulsant insults (present study) together with the increased nociceptive threshold [4], and the antidepressant-like phenotype [32] described in these mutants are consistent with this hypothesis, and indicate that the NET may be an effective target for the treatment of such complex disorders. Dose-response curves for the convulsant effects of cocaine and threshold doses of cocaine for the induction of seizures in NET-WT, NET-HT and NET-KO mice.…”

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confidence: 83%

Genetic deletion of the norepinephrine transporter decreases vulnerability to seizures

Kamiński

Shippenberg

Witkin

et al. 2005

Neuroscience Letters

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Norepinephrine (NE) has been reported to modulate neuronal excitability and act as endogenous anticonvulsant. In the present study we used NE transporter knock-out mice (NET-KO), which are characterized by high levels of extracellular NE, to investigate the role of endogenous NE in seizure susceptibility. Seizure thresholds for cocaine (i.p.), pentylenetetrazol (i.v.) and kainic acid (i.v.) were compared in NET-KO, heterozygous (NET-HT) and wild type (NET-WT) female mice. The doseresponse curve for cocaine-induced convulsions was significantly shifted to the right in NET-KO mice, indicating higher seizure thresholds. The threshold doses of pentylenetetrazol that induced clonic and tonic seizures were also significantly higher in NET-KO when compared to NET-WT mice. Similarly, NET-KO mice displayed higher resistance to convulsions engendered by kainic acid. For all drugs tested, the response of NET-HT mice was always intermediate. These data provide further support for a role of endogenous NE in the control of seizure susceptibility. KeywordsPentylenetetrazol; Kainic acid; Cocaine; Norepinephrine transporter; Seizures; Knock-out mice Norepinephrine (NE), released from neurons in the CNS, has been implicated in the modulation of seizure susceptibility. Inhibition of NE neurotransmission was reported to exacerbate seizures [5,21], while enhancement of NE neurotransmission appears to have anticonvulsant effects [18]. More recently, studies in mice lacking NE due to the genetic deletion of the enzyme dopamine beta-hydroxylase showed an increased susceptibility to seizures in the mutants [27] further supporting the hypothesis that NE might act as an endogenous modulator of convulsive seizures (for reviews see [28,7]). However, a fundamental question remains as to whether an elevation of extracellular levels of endogenous NE has an opposite effect. The recent generation of mice lacking the NE transporter (NET-KO), offered the opportunity to explore this question since extracellular NE levels are 100% higher in these animals compared to wild-type litter mates (NET-WT) [32]. Therefore, in the present study we have compared the susceptibility of NET-KO, heterozygous (NET-HT) and NET-WT mice to seizures induced by three distinct convulsant agents, i.e. cocaine, pentylenetetrazol and kainic acid.

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“…This was performed as described previously (Bohn et al, 2000). Latency to respond to warm water (501C) was measured to assess the nociceptive response; this was defined as the removal of the tail from the warm water.…”

Section: Measurement Of Nociceptive Responsesmentioning

confidence: 99%

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

Zhang

Huang

Masood

et al. 2007

Neuropsychopharmacol

159

143

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Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression-and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4BÀ/À). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4BÀ/À mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4BÀ/À mice. Compared to PDE4B + / + littermates, PDE4BÀ/À mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light-dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4BÀ/À mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4BÀ/À mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4BÀ/À mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior.

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Potentiated Opioid Analgesia in Norepinephrine Transporter Knock-Out Mice

Cited by 104 publications

References 41 publications

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Evidence that Behavioral Phenotypes of Morphine in β-arr2−/− Mice Are Due to the Unmasking of JNK Signaling

Genetic deletion of the norepinephrine transporter decreases vulnerability to seizures

Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

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