Molecular brain
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Spinal glia, particularly microglia and astrocytes, are of the utmost importance in the development and maintenance of chronic pain. A recent study from our laboratory revealed that gabapentin, a recommended first-line treatment for multiple neuropathic conditions, could also efficiently antagonize thermal hyperalgesia evoked by complete Freund's adjuvant (CFA)-induced monoarthritis (MA). In the present study, we investigated whether the spinal glia are involved in the anti-hyperalgesic effect of gabapentin and how this event occurs. ⋯ Here we provide the first evidence that gabapentin diminishes CX3CL1 signaling and spinal microglia activation induced by joint inflammation. We also show that the VGCC α2/δ-1 subunits might be involved in these events.
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Postsynaptic density (PSD)-95-like membrane-associated guanylate kinases (PSD-MAGUKs) are scaffold proteins in PSDs that cluster signaling molecules near NMDA receptors. PSD-MAGUKs share a common domain structure, including three PDZ (PDZ1/2/3) domains in their N-terminus. While multiple domains enable the PSD-MAGUKs to bind various ligands, the contribution of each PDZ domain to synaptic organization and function is not fully understood. Here, we focused on the PDZ1/2 domains of PSD-95 that bind NMDA-type receptors, and studied the specific roles of the ligand binding of these domains in the assembly of PSD proteins, synaptic properties of hippocampal neurons, and behavior, using ligand binding-deficient PSD-95 cDNA knockin (KI) mice. ⋯ These findings reveal that PSD-95 including its ligand binding of the PDZ1/2 domains controls the synaptic clustering of PSD-MAGUKs and AMPA receptors, which may have an essential role in regulating hippocampal synaptic transmission, plasticity, and hippocampus-dependent behavior.
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The Notch signaling pathway has been shown to be involved in the development of the nervous system. Recent studies showed that Notch receptors and ligands are also expressed in the nervous system of adult animals. However, whether the Notch signaling pathway has a function in adults is not fully understood. The present study is designed to investigate the function of the Notch signaling pathway in nociceptive transmission, especially during neuropathic pain in adult rats. ⋯ These results suggest that the Notch signaling pathway participates in the induction and maintenance of neuropathic pain, which indicates that the Notch pathway maybe a potential drug target for neuropathic pain treatment.
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Trigeminal neuropathic pain attacks can be excruciating for patients, even after being lightly touched. Although there are rodent trigeminal nerve research models to study orofacial pain, few models have been applied to studies in mice. A mouse trigeminal inflammatory compression (TIC) model is introduced here which successfully and reliably promotes vibrissal whisker pad hypersensitivity. ⋯ A simple, effective, and reproducible chronic mouse model mimicking clinical orofacial neuropathic pain (Type 2) is induced by placing chromic gut suture between the infraorbital nerve and the maxillary bone. The method produces mild inflammatory compression with significant continuous mechanical allodynia persisting at least 10 weeks and cold allodynia measureable at 4 weeks.
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The most frequent pain in patients with metastatic breast and prostate cancer is bone pain, which can be severe and difficult to treat. The mechanisms underlying this pain remain unclear. Here we investigated the role of c-jun N-terminal kinase (JNK) pathway in the spinal cord in cancer-induced bone pain (CIBP). ⋯ Taken together, our results demonstrated for the first time that JNK activation in the spinal cord is required in the maintenance of CIBP. Inhibition of the spinal JNK pathway may provide a new therapy for CIBP management.