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The lateral parabrachial nucleus (LPBN) is known to relay noxious information to the amygdala for processing affective responses. However, it is unclear whether the LPBN actively processes neuropathic pain characterized by persistent hyperalgesia with aversive emotional responses. Here we report that neuropathic pain-like hypersensitivity induced by common peroneal nerve (CPN) ligation increases nociceptive stimulation-induced responses in glutamatergic LPBN neurons. Optogenetic activation of GABAergic LPBN neurons does not affect basal nociception, but alleviates neuropathic pain-like behavior. Optogenetic activation of glutamatergic or inhibition of GABAergic LPBN neurons induces neuropathic pain-like behavior in naïve mice. Inhibition of glutamatergic LPBN neurons alleviates both basal nociception and neuropathic pain-like hypersensitivity. Repetitive pharmacogenetic activation of glutamatergic or GABAergic LPBN neurons respectively mimics or prevents the development of CPN ligation-induced neuropathic pain-like hypersensitivity. These findings indicate that a delicate balance between excitatory and inhibitory LPBN neuronal activity governs the development and maintenance of neuropathic pain.
Learn More >A better understanding of neural pain processing and of the development of pain over time, is critical to identify objective measures of pain and to evaluate the effect of pain alleviation therapies. One issue is, that the brain areas known to be related to pain processing are not exclusively responding to painful stimuli, and the neuronal activity is also influenced by other brain areas. Functional connectivity reflects synchrony or covariation of activation between groups of neurons. Previous studies found changes in connectivity days or weeks after pain induction. However, less in known on the temporal development of pain. Our objective was therefore to investigate the interaction between the anterior cingulate cortex (ACC) and primary somatosensory cortex (SI) in the hyperacute (minute) and sustained (hours) response in an animal model of neuropathic pain. Intra-cortical local field potentials (LFP) were recorded in 18 rats. In 10 rats the spared nerve injury model was used as an intervention. The intra-cortical activity was recorded before, immediately after, and three hours after the intervention. The interaction was quantified as the calculated correlation and coherence. The results from the intervention group showed a decrease in correlation between ACC and SI activity, which was most pronounced in the hyperacute phase but a longer time frame may be required for plastic changes to occur. This indicated that both SI and ACC are involved in hyperacute pain processing.
Learn More >To determine whether high school start time is associated with headache frequency in adolescents with migraine.
Learn More >Dorsal root ganglion stimulation (DRG-S) involves the electrical modulation of the somata of afferent neural fibers to treat chronic pain. DRG-S has demonstrated clinical efficacy at frequencies lower than typically used with spinal cord stimulation (SCS). In a clinical study, we found that the frequency of DRG-S can be tapered to a frequency as low as 4 Hz with no loss of efficacy. This review discusses possible mechanisms of action underlying effective pain relief with very low-frequency DRG-S.
Learn More >Itch is an unpleasant and aversive somatosensory experience. These negative emotions significantly affect mental health in chronic itch patients. Therefore, it is important to understand the brain mechanism of negative emotions due to itch. The amygdala is an important hub of network to regulate negative emotions due to itch. However, the exact network remains unknown. Thus, using functional magnetic resonance imaging, we investigated what network the amygdala constitutes for processing itch in human brains. Twenty-five healthy subjects participated in the present study. Brain activity during electrical itch stimuli was measured by using functional magnetic resonance imaging. The amygdala exhibited increased functional connectivity during itch stimuli with key brain regions of the serotonergic system responsible for negative emotions (the medial habenula, median raphe nucleus) and the memory system to consolidate emotional experiences (the parahippocampus, perirhinal cortex). These systems may become therapeutic targets to prevent or reduce diminished mental health commonly seen in chronic itch patients.
Learn More >Neural precursor cell-expressed developmentally downregulated protein 4-2 (Nedd4-2) is a member of the E3 ubiquitin ligase family that is highly expressed in sensory neurons and involved in pain modulation via downregulation of ion channels in excitable membranes. Ubiquitination involving Nedd4-2 is regulated by adenosine monophosphate-activated protein kinase (AMPK), which is impaired in the dorsal root ganglion (DRG) neurons of db/db mice. AMPK negatively regulates the expression of transient receptor potential ankyrin 1 (TRPA1), a recognised pain sensor expressed on the membrane of DRG neurons, consequently relieving mechanical allodynia in db/db mice. Herein, we studied the involvement of Nedd4-2 in painful diabetic neuropathy and observed that Nedd4-2 negatively regulated diabetic mechanical allodynia. Nedd4-2 was co-expressed with TRPA1 in mouse DRG neurons. Nedd4-2 was involved in TRPA1 ubiquitination, this ubiquitination, as well as Nedd4-2-TRPA1 interaction, was decreased in db/db mice. Moreover, Nedd4-2 levels were decreased in db/db mice, while an abnormal intracellular distribution was observed in short-term high glucose-cultured DRG neurons. AMPK activators not only restored Nedd4-2 distribution but also increased Nedd4-2 expression. These findings demonstrate that Nedd4-2 is a potent regulator of TRPA1, and that the abnormal expression of Nedd4-2 in DRG neurons contributes to diabetic neuropathic pain.
Learn More >Anterolateral system neurons relay pain, itch, and temperature information from the spinal cord to pain-related brain regions, but the differentiation of these neurons and their specific contribution to pain perception remain poorly defined. Here, we show that most mouse spinal neurons that embryonically express the autonomic-system-associated Paired-like homeobox 2A (Phox2a) transcription factor innervate nociceptive brain targets, including the parabrachial nucleus and the thalamus. We define the Phox2a anterolateral system neuron birth order, migration, and differentiation and uncover an essential role for Phox2a in the development of relay of nociceptive signals from the spinal cord to the brain. Finally, we also demonstrate that the molecular identity of Phox2a neurons is conserved in the human fetal spinal cord, arguing that the developmental expression of Phox2a is a prominent feature of anterolateral system neurons.
Learn More >Chronic itch represents an incapacitating burden on patients suffering from a spectrum of diseases. Despite recent advances in our understanding of the cells and circuits implicated in the processing of itch information, chronic itch often presents itself without an apparent cause. Here, we identify a spinal subpopulation of inhibitory neurons defined by the expression of Ptf1a, involved in gating mechanosensory information self-generated during movement. These neurons receive tactile and motor input and establish presynaptic inhibitory contacts on mechanosensory afferents. Loss of Ptf1a neurons leads to increased hairy skin sensitivity and chronic itch, partially mediated by the classic itch pathway involving gastrin-releasing peptide receptor (GRPR) spinal neurons. Conversely, chemogenetic activation of GRPR neurons elicits itch, which is suppressed by concomitant activation of Ptf1a neurons. These findings shed light on the circuit mechanisms implicated in chronic itch and open novel targets for therapy developments.
Learn More >To compare spatial pain modulation capabilities between adolescents with and without migraine.
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