The Journal of neuroscience : the official journal of the Society for Neuroscience
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Comparative Study
Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons.
The endogenous dynorphin-κ opioid receptor (KOR) system encodes the dysphoric component of the stress response and controls the risk of depression-like and addiction behaviors; however, the molecular and neural circuit mechanisms are not understood. In this study, we report that KOR activation of p38α MAPK in ventral tegmental (VTA) dopaminergic neurons was required for conditioned place aversion (CPA) in mice. Conditional genetic deletion of floxed KOR or floxed p38α MAPK by Cre recombinase expression in dopaminergic neurons blocked place aversion to the KOR agonist U50,488. Selective viral rescue by wild-type KOR expression in dopaminergic neurons of KOR(-/-) mice restored U50,488-CPA, whereas expression of a mutated form of KOR that could not initiate p38α MAPK activation did not. Surprisingly, while p38α MAPK inactivation blocked U50,488-CPA, p38α MAPK was not required for KOR inhibition of evoked dopamine release measured by fast scan cyclic voltammetry in the nucleus accumbens. In contrast, KOR activation acutely inhibited VTA dopaminergic neuron firing, and repeated exposure attenuated the opioid response. This adaptation to repeated exposure was blocked by conditional deletion of p38α MAPK, which also blocked KOR-induced tyrosine phosphorylation of the inwardly rectifying potassium channel (GIRK) subunit Kir3.1 in VTA dopaminergic neurons. Consistent with the reduced response, GIRK phosphorylation at this amino terminal tyrosine residue (Y12) enhances channel deactivation. Thus, contrary to prevailing expectations, these results suggest that κ opioid-induced aversion requires regulation of VTA dopaminergic neuron somatic excitability through a p38α MAPK effect on GIRK deactivation kinetics rather than by presynaptically inhibiting dopamine release. ⋯ Kappa opioid receptor (KOR) agonists have the potential to be effective, nonaddictive analgesics, but their therapeutic utility is greatly limited by adverse effects on mood. Understanding how KOR activation produces dysphoria is key to the development of better analgesics and to defining how the endogenous dynorphin opioids produce their depression-like effects. Results in this study show that the aversive effects of κ receptor activation required arrestin-dependent p38α MAPK activation in dopamine neurons but did not require inhibition of dopamine release in the nucleus accumbens. Thus, contrary to the prevailing view, inhibition of mesolimbic dopamine release does not mediate the aversive effects of KOR activation and functionally selective κ opioids that do not activate arrestin signaling may be effective analgesics lacking dysphoric effects.
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For accurate diagnosis and prognostic prediction of acquired brain injury (ABI), it is crucial to understand the neurobiological mechanisms underlying loss of consciousness. However, there is no consensus on which regions and networks act as biomarkers for consciousness level and recovery outcome in ABI. Using resting-state fMRI, we assessed intrinsic functional connectivity strength (FCS) of whole-brain networks in a large sample of 99 ABI patients with varying degrees of consciousness loss (including fully preserved consciousness state, minimally conscious state, unresponsive wakefulness syndrome/vegetative state, and coma) and 34 healthy control subjects. Consciousness level was evaluated using the Glasgow Coma Scale and Coma Recovery Scale-Revised on the day of fMRI scanning; recovery outcome was assessed using the Glasgow Outcome Scale 3 months after the fMRI scanning. One-way ANOVA of FCS, Spearman correlation analyses between FCS and the consciousness level and recovery outcome, and FCS-based multivariate pattern analysis were performed. We found decreased FCS with loss of consciousness primarily distributed in the posterior cingulate cortex/precuneus (PCC/PCU), medial prefrontal cortex, and lateral parietal cortex. The FCS values of these regions were significantly correlated with consciousness level and recovery outcome. Multivariate support vector machine discrimination analysis revealed that the FCS patterns predicted whether patients with unresponsive wakefulness syndrome/vegetative state and coma would regain consciousness with an accuracy of 81.25%, and the most discriminative region was the PCC/PCU. These findings suggest that intrinsic functional connectivity patterns of the human posteromedial cortex could serve as a potential indicator for consciousness level and recovery outcome in individuals with ABI. ⋯ Varying degrees of consciousness loss and recovery are commonly observed in acquired brain injury patients, yet the underlying neurobiological mechanisms remain elusive. Using a large sample of patients with varying degrees of consciousness loss, we demonstrate that intrinsic functional connectivity strength in many brain regions, especially in the posterior cingulate cortex and precuneus, significantly correlated with consciousness level and recovery outcome. We further demonstrate that the functional connectivity pattern of these regions can predict patients with unresponsive wakefulness syndrome/vegetative state and coma would regain consciousness with an accuracy of 81.25%. Our study thus provides potentially important biomarkers of acquired brain injury in clinical diagnosis, prediction of recovery outcome, and decision making for treatment strategies for patients with severe loss of consciousness.
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Adaptive behaviors are built on the arbitrary linkage of sensory inputs to actions and goals. Although the sensorimotor and associative frontostriatal circuits are known to mediate arbitrary visuomotor mappings, the underlying corticocortico dynamics remain elusive. Here, we take a novel approach exploiting gamma-band neural activity to study the human cortical networks and corticocortical functional connectivity mediating arbitrary visuomotor mapping. Single-trial gamma-power time courses were estimated for all Brodmann areas by combing magnetoencephalographic and MRI data with spectral analysis and beam-forming techniques. Linear correlation and Granger causality analyses were performed to investigate functional connectivity between cortical regions. The performance of visuomotor associations was characterized by an increase in gamma-power and functional connectivity over the sensorimotor and frontoparietal network, in addition to medial prefrontal areas. The superior parietal area played a driving role in the network, exerting Granger causality on the dorsal premotor area. Premotor areas acted as relay from parietal to medial prefrontal cortices, which played a receiving role in the network. Link community analysis further revealed that visuomotor mappings reflect the coordination of multiple subnetworks with strong overlap over motor and frontoparietal areas. We put forward an associative account of the underlying cognitive processes and corticocortical functional connectivity. Overall, our approach and results provide novel perspectives toward a better understanding of how distributed brain activity coordinates adaptive behaviors. ⋯ In everyday life, most of our behaviors are based on the arbitrary linkage of sensory information to actions and goals, such as stopping at a red traffic light. Despite their automaticity, such behaviors rely on the activity of a large brain network and elusive interareal functional connectivity. We take a novel approach exploiting noninvasive recordings of human brain activity to reveal the cortical networks and corticocortical functional connectivity mediating visuomotor mappings. Parietal areas were found to play a driving role in the network, whereas premotor areas acted as relays from parietal to medial prefrontal cortices, which played a receiving role. Overall, our approach and results provide novel perspectives toward a better understanding of how distributed brain activity coordinates adaptive behaviors.
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The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. ⋯ These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. Significance statement: The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids.
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Proteinase cascades are part of the basic machinery of neuronal death pathways. Neuronal cathepsin B (CatB), a typical cysteine lysosomal protease, plays a critical role in neuronal death through lysosomal leakage or excessive autophagy. On the other hand, much attention has been paid to microglial CatB in neuronal death. ⋯ On the other hand, much attention has been also paid to the role of microglial cathepsin B in neuronal death. In this study, using in vivo and in vitro models of relevance to brain ischemia, we found a critical role of proteolytic relay through cathepsin B and cathepsin E in the neurotoxic polarization of microglia/macrophages, which is responsible for aggravation of hypoxia/ischemia-induced neuronal injury. These findings suggest orally active selective inhibitors of cathepsin B or cathepsin E as promising pharmacological agents for the treatment of ischemic brain injury.