Neuroscience
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The transient receptor potential ankyrin type-1 (TRPA1) channels have been proposed as a potential target for migraine therapy. Yet the role of cortical TRPA1 channels in migraine mechanism has not been fully understood. Cortical spreading depression (CSD) is known as an underlying cause of migraine aura. ⋯ Consistent to TRPA1 deactivation, the prolonged CSD latency was observed by an anti-CGRP antibody in the mouse brain slice, which was reversed by exogenous CGRP. We conclude that cortical TRPA1 is critical in regulating cortical susceptibility to CSD, which involves CGRP. The data strongly suggest that deactivation of TRPA1 channels and blockade of CGRP would have therapeutic benefits in preventing migraine with aura.
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Exposure to both sustained and intermittent hypoxia for as little as a day produces sustained augmentation of carotid chemoreceptor sensitivity; however, the molecular basis for this chemoreflex plasticity remains uncertain. We previously reported that NMDA receptor-dependent glutamatergic signaling in rat carotid body played a role in altered hypoxic sensitivity after exposure to cyclic intermittent hypoxia (CIH). Here we found that mRNAs of multiple AMPA and Kainate glutamate receptors were expressed in rat carotid body. ⋯ In addition, our results showed that multiple of vesicular glutamate transporters (VGLUTs) and excitatory amino acid transporters (EAATs) were expressed in the rat carotid body, indicating that glutamate might be as a neurotransmitter stored, released and uptake in the carotid body. Finally, we found that mRNAs of GluA1, GluA2 and GluA3 as well as PSD-95-like membrane-associated granulate kinase family members, PSD-95, PSD-93, and SAP97, were expressed in human carotid body. Our data suggest AMPA receptor-dependent glutamatergic signaling is present in the carotid body and might be involved in the carotid chemoreceptor response to hypoxia.
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Accumulated evidences suggest important roles of glial GAP-junctions in pain. However, only a few studies have explored the role of neuronal GAP-junctions or electrical synapses in neuropathic pain (NP). Therefore, the present study explores the role of connexin 36 (Cx36) in NP using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model in rat. ⋯ Altogether, our findings demonstrated that Cx36 play an important role in mechanical allodynia by coupling GABA cells. Increasing cell coupling by enhancing Cx36 expression favors neuropathic pain while disrupting this coupling alleviates it. This mechanism may constitute a novel target for the treatment of orofacial mechanical allodynia.
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Neuroligin 2 is a synaptic cell adhesion molecule that is mainly located in inhibitory synapses and is crucial in the regulation of synapse function through protein-protein interactions. However, researchers have not clearly determined whether neuroligin 2 is involved in the development of postoperative pain. In the current study, Western blot, immunofluorescence staining and co-immunoprecipitation were used to examine the critical role of neuroligin 2 in postoperative pain hypersensitivity. ⋯ Additionally, at 3 h after plantar incision, the amount of PSD-95 that was co-immunoprecipitated with neuroligin 2 antibody was significantly increased in the ipsilateral dorsal horn, as compared to that of the control group. Intrathecal pretreatment of siRNA-targeting neuroligin 2 to reduce the neuroligin 2 expression in the spinal cord significantly inhibited the pain hypersensitivity and reduced the synaptic targeting of GluR1 in ipsilateral dorsal horns. Our study indicates that the incision-induced interaction between neuroligin 2 and PSD-95 and subsequent synaptic targeting of GluR1 in ipsilateral dorsal horns contribute to postoperative pain hypersensitivity.