RESUMEN
Sleep disturbance has been reported to be one of the most frequent symptoms in patients suffered from severe pain. Benzodiazepines are effective and reduce anxiety in the hours after use, but the induced sleep tends to be less than ideal in quality, with increased Stages I-II and reduces Stages III-IV sleep. In the present study, we investigated sleep disturbance under a neuropathic pain-like state in mice using electroencephalogram (EEG)/electromyogram (EMG). In a model of neuropathic pain, sciatic nerve ligation caused a marked decrease in the latency of paw withdrawal in response to a thermal stimulus only on the ipsilateral side. Under this condition, sciatic nerve-ligated animals showed a statistically significant increase in wakefulness and a decrease in non-rapid eye movement (NREM) sleep during the light phase. Mirtazapine (MTZ) is an antidepressant, which is considered to enhance noradrenergic and serotonergic neurotransmission via antagonistic action at central α2-adrenergic autoreceptors and heteroreceptors. In the present binding study, MTZ showed higher affinity for histamine H1 and serotonin 5-HT(2A/2C) receptors than other receptors, including α2-adrenergic receptor, in the mouse brain tissue. The thermal hyperalgesia and sleep disturbance following nerve ligation were almost completely alleviated by MTZ. These findings suggest that MTZ may improve the quality of sleep as well as control pain in patients with neuropathic pain mainly through histamine H1- and serotonin 5-HT2-receptor antagonistic actions.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Mianserina/análogos & derivados , Neuralgia/tratamiento farmacológico , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Masculino , Mianserina/uso terapéutico , Ratones , Ratones Endogámicos ICR , Mirtazapina , Neuralgia/complicaciones , Dimensión del Dolor , Receptores Histamínicos H1/metabolismo , Nervio Ciático/efectos de los fármacos , Nervio Ciático/lesiones , Nervio Ciático/fisiología , Trastornos del Sueño-Vigilia/etiología , Vigilia/efectos de los fármacosRESUMEN
BACKGROUND: The use of opioids for pain management is often associated with nausea and vomiting. Although conventional antipsychotics are often used to counter emesis, they can be associated with extrapyramidal symptoms. However, chronic pain can induce sleep disturbance. The authors investigated the effects of the atypical antipsychotic olanzapine on morphine-induced emesis and the sleep dysregulation associated with chronic pain. METHODS: A receptor binding assay was performed using mouse whole brain tissue. The emetic response in ferrets was evaluated by counting retching and vomiting behaviors. Catalepsy in mice was evaluated by placing both of their forepaws over a horizontal bar. Released dopamine was measured by an in vivo microdialysis study. Sleep disturbance in mice in a neuropathic pain-like state was assayed by electroencephalogram and electromyogram recordings. RESULTS: Olanzapine showed high affinity for muscarinic M1 receptor in brain tissue. Olanzapine decreased morphine-induced nausea and vomiting in a dose-dependent manner. However, olanzapine at a dose that had an antiemetic effect (0.03 mg/kg) did not induce catalepsy or hyperglycemia. In addition, olanzapine at this dose had no effect on the morphine-induced release of dopamine or inhibition of gastrointestinal transit. Finally, olanzapine inhibited thermal hyperalgesia and completely alleviated the sleep disturbance induced by sciatic nerve ligation. CONCLUSION: These findings suggest that olanzapine may be useful for the treatment of morphine-induced emesis and as an adjunct for the treatment of neuropathic pain associated with sleep disturbance.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Morfina/uso terapéutico , Neuralgia/tratamiento farmacológico , Analgésicos Opioides/efectos adversos , Animales , Antipsicóticos/farmacocinética , Glucemia/metabolismo , Química Encefálica/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/psicología , Clozapina/farmacocinética , Dopamina/metabolismo , Quimioterapia Combinada , Electroencefalografía/efectos de los fármacos , Electromiografía/efectos de los fármacos , Tránsito Gastrointestinal/efectos de los fármacos , Hiperalgesia/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Microdiálisis , Morfina/efectos adversos , Neuralgia/complicaciones , Olanzapina , Manejo del Dolor , Receptores de Serotonina/metabolismo , Ciática/prevención & control , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Trastornos del Sueño-Vigilia/etiología , Vómitos/inducido químicamente , Vómitos/prevención & controlRESUMEN
Despite the importance of prefrontal cortical dopamine in modulating reward, little is known about the implication of the specific subregion of prefrontal cortex in opioid reward. We investigated the role of neurons projecting from the ventral tegmental area (VTA) to the anterior cingulate cortex (ACG) in opioid reward. Microinjection of the retrograde tracer fluorogold (FG) into the ACG revealed several retrogradely labelled cells in the VTA. The FG-positive reactions were noted in both tyrosine hydroxylase (TH)-positive and -negative VTA neurons. The released levels of dopamine and its major metabolites in the ACG were increased by either the electrical stimulation of VTA neurons or microinjection of a selective µ-opioid receptor (MOR) agonist, (D-Ala²,N-MePhe4,Gly-ol5) enkephalin (DAMGO), into the VTA. MOR-like immunoreactivity was seen in both TH-positive and -negative VTA neurons projecting to the ACG. The conditioned place preference induced by intra-VTA injection of DAMGO was significantly attenuated by chemical lesion of dopaminergic terminals in the ACG. The depletion of dopamine in the ACG induced early extinction of µ-opioid-induced place preference. The levels of phosphorylated DARPP32 (Thr34) and phosphorylated CREB (Ser133) were increased in the ACG of rats that had maintained the morphine-induced place preference, whereas the increases of these levels induced by morphine were blocked by pre-treatment of a selective dopamine D1 receptor antagonist SCH23390. These findings suggest that VTA-ACG transmission may play a crucial role in the acquisition and maintenance of µ-opioid-induced place preference. The activation of DARPP32 and CREB through dopamine D1 receptors in the ACG could be implicated in the maintenance of µ-opioid-induced place preference.