The role of nucleus accumbens dopamine signaling in the development of morphine tolerance in neuropathic pain
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Background: There is converging evidence that indicates that the nucleus accumbens (NAc) plays a substantial role in pain modulation and analgesic drug responses. Here, the role of the NAc dopaminergic signaling in the development of morphine tolerance in a rat neuropathic pain model was explored. Methods: Morphine tolerance was induced by twice daily administration of intrathecal morphine in spinal nerveligated animals. The extracellular dopamine level in the NAc was measured by microdialysis study and the effects of dopaminergic receptor agonists microinjected into the NAc on morphine analgesic tolerance were evaluated behaviorally. Using immunohistochemical techniques, dopaminergic fiber expression in the NAc was assessed. Additionally, the effects of microglial inhibitor minocycline on the extracellular dopamine level in the NAc and the development of morphine tolerance were investigated. Results: Microdialysis study demonstrated that the extracellular level of dopamine in the NAc was decreased in morphine tolerant animals. A dopaminergic D1- or D2-like receptor agonist pretreated into the NAc improved analgesic response to morphine in the tolerant animals. By pretreating a microglial inhibitor minocycline with daily morphine administration, the level of extracellular dopamine in the NAc was partially recovered and the development of morphine tolerance was attenuated. Conclusions: These observations indicate that the decreased dopaminergic neurotransmission in the NAc induced by microglial activation plays a significant role in the development of morphine tolerance. By delineating how alterations in dopamine transmission and related neuroadaptations within the NAc contribute to diminished opioid efficacy, future studies may identify novel molecular and cellular targets for therapeutic intervention.
Abstract
Background: There is converging evidence that indicates that the nucleus accumbens (NAc) plays a substantial role in pain modulation and analgesic drug responses. Here, the role of the NAc dopaminergic signaling in the development of morphine tolerance in a rat neuropathic pain model was explored. Methods: Morphine tolerance was induced by twice daily administration of intrathecal morphine in spinal nerveligated animals. The extracellular dopamine level in the NAc was measured by microdialysis study and the effects of dopaminergic receptor agonists microinjected into the NAc on morphine analgesic tolerance were evaluated behaviorally. Using immunohistochemical techniques, dopaminergic fiber expression in the NAc was assessed. Additionally, the effects of microglial inhibitor minocycline on the extracellular dopamine level in the NAc and the development of morphine tolerance were investigated. Results: Microdialysis study demonstrated that the extracellular level of dopamine in the NAc was decreased in morphine tolerant animals. A dopaminergic D1- or D2-like receptor agonist pretreated into the NAc improved analgesic response to morphine in the tolerant animals. By pretreating a microglial inhibitor minocycline with daily morphine administration, the level of extracellular dopamine in the NAc was partially recovered and the development of morphine tolerance was attenuated. Conclusions: These observations indicate that the decreased dopaminergic neurotransmission in the NAc induced by microglial activation plays a significant role in the development of morphine tolerance. By delineating how alterations in dopamine transmission and related neuroadaptations within the NAc contribute to diminished opioid efficacy, future studies may identify novel molecular and cellular targets for therapeutic intervention.