ABSTRACT
Dopamine receptor antagonists are commonly used to counter the adverse effects of opioids such as hallucinations, delusions and emesis. However, most of these agents themselves have side effects, including extrapyramidal symptoms. Here, we investigated the effect of the dopamine system stabilizer aripiprazole on morphine-induced dopamine-related actions in mice. Morphine-induced hyperlocomotion and reward were significantly suppressed by either the dopamine receptor antagonist prochlorperazine or aripiprazole. Catalepsy was observed with a high dose of prochlorperazine, but not with an even higher dose of aripiprazole. The increased level of dialysate dopamine in the nucleus accumbens stimulated by morphine was significantly decreased by pretreatment with aripiprazole. These results suggest that the co-administration of aripiprazole may be useful for reducing the severity of morphine-induced dopamine-related side effects.
Subject(s)
Analgesics, Opioid/adverse effects , Antipsychotic Agents/pharmacology , Morphine/adverse effects , Piperazines/pharmacology , Quinolones/pharmacology , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Aripiprazole , Catalepsy/chemically induced , Dopamine/metabolism , Dopamine Antagonists/administration & dosage , Dopamine Antagonists/adverse effects , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Hyperkinesis/chemically induced , Male , Mice , Mice, Inbred ICR , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Piperazines/administration & dosage , Piperazines/adverse effects , Prochlorperazine/administration & dosage , Prochlorperazine/adverse effects , Prochlorperazine/pharmacology , Quinolones/administration & dosage , Quinolones/adverse effects , Reward , Severity of Illness IndexABSTRACT
It has often been proposed that opioid addiction does not arise as a consequence of opioid treatment for pain. Recently, we demonstrated that activated protein kinase C (PKC) in the spinal cord associated with chronic pain-like hyperalgesia suppressed the morphine-induced rewarding effect in mice. In the present study, we investigated whether a gene deletion for an endogenous mu-opioid peptide beta-endorphin could affect pain-like behavior and the suppression of the morphine-induced rewarding effect by the direct activation of PKC in the spinal cord. We found that activation of spinal PKC by intrathecal (i.t.) treatment with phorbol 12,13-dibutyrate (PDBu), a specific PKC activator, caused thermal hyperalgesia, pain-like behaviors and suppression of the morphine-induced rewarding effect. This suppression of morphine reward was eliminated in mice that lacked beta-endorphin. In contrast, thermal hyperalgesia and pain-like behaviors were not affected in beta-endorphin knockout mice. These results suggest that the activation of PKC in the spinal cord may play an essential role in the suppression of the morphine-induced rewarding effect in mice with neuropathic pain through the constant release of beta-endorphin.
Subject(s)
Brain/drug effects , Morphine Dependence/enzymology , Pain/enzymology , Protein Kinase C/metabolism , Spinal Cord/drug effects , beta-Endorphin/genetics , Animals , Brain/metabolism , Brain/physiopathology , Enzyme Activation/genetics , Enzyme Activators/pharmacology , Female , Hyperalgesia/chemically induced , Hyperalgesia/enzymology , Hyperalgesia/genetics , Injections, Spinal , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Morphine/pharmacology , Morphine Dependence/genetics , Morphine Dependence/physiopathology , Narcotics/pharmacology , Neural Inhibition/drug effects , Neural Inhibition/genetics , Pain/genetics , Pain/physiopathology , Reward , Spinal Cord/enzymologyABSTRACT
In the previous study, we reported that exposure to bisphenol-A induced the potentiation of dopamine receptor functions in the mouse limbic area, resulting in supersensitivity to methamphetamine-induced pharmacological actions. The present study was undertaken to investigate whether prenatal exposure to bisphenol-A could produce morphological change in dopaminergic neuron and the pattern of expression of genes regulating the dopaminergic neuron development. Here we found that prenatal and neonatal exposures to bisphenol-A increased the tyrosine hydroxylase- and dopamine transporter-like immunoreactivities in the adult mouse limbic area. The present molecular biological study shows that chronic bisphenol-A treatment produced a significant decrease in the dopaminergic neuron development factors, sonic hedgehog and glial cell line-derived neurotrophic factor, which were also decreased by prenatal exposure to bisphenol-A. These results suggest that chronic exposure to bisphenol-A could disrupt the dopaminergic neurotransmission in the process of dopaminergic neuron development.