ABSTRACT
Pain and learning memory have striking similarities in synaptic plasticity. Activation of the N-methyl-D-aspartic acid receptors 2B subunits (NR2B-NMDAs) is responsible for the hippocampal LTP in memory formation. In our previous studies, we found the significant enhancement of CA1 hippocampal long-term potentiation (LTP) induced by high-frequency stimulation (HFS) in rats with chronic visceral pain. However, it is unclear whether the NR2B-NMDAs are required for the LTP in chronic visceral pain. In this study, a rat model with irritable bowel syndrome (IBS) was established by colorectal distention (CRD). The sensitivity of visceral pain and HFS-induced LTP at SC-CA1 synapses were significantly enhanced in IBS-like rats (p<0.05). In addition, hippocampal NR2B protein levels significantly increased in IBS-like rats (p<0.05). To test whether NR2B-NMDAs are responsible for the LTP, effects of Ro 25-6981, a selective antagonist of NR2B-NMDAs, on field potential in CA1 region were investigated in vitro. Our results demonstrated that Ro 25-6981 dose-dependently inhibited the facilitation of CA1 LTP in IBS-like rats. The plausible activation mechanism of hippocampal NR2B-NMDAs in the LTP enhancement was further explored. Western blot data indicated that expression of tyrosine phosphorylated NR2B protein in hippocampus significantly enhanced in IBS-like rats. Accordingly, genistein, a specific inhibitor of tyrosine kinases, dose-dependently blocked the facilitation of hippocampal LTP in IBS-like rats. Furthermore, EMG data revealed that intra-hippocampal injection of Ro 25-6981 dose-dependently attenuated the visceral hypersensitivity. In conclusion, hippocampal NR2B-NMDAs are responsible for the facilitation of CA1 LTP via tyrosine phosphorylation, which leads to visceral hypersensitivity.
Subject(s)
Chronic Pain/physiopathology , Hippocampus/physiopathology , Irritable Bowel Syndrome/physiopathology , Long-Term Potentiation/physiology , Receptors, N-Methyl-D-Aspartate/metabolism , Visceral Pain/physiopathology , Animals , CA1 Region, Hippocampal/drug effects , CA1 Region, Hippocampal/physiopathology , Chronic Pain/drug therapy , Disease Models, Animal , Excitatory Amino Acid Antagonists/pharmacology , Genistein/pharmacology , Hippocampus/drug effects , Hyperalgesia/drug therapy , Hyperalgesia/physiopathology , Irritable Bowel Syndrome/drug therapy , Long-Term Potentiation/drug effects , Male , Phenols/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/metabolism , Rats, Sprague-Dawley , Synapses/drug effects , Synapses/physiology , Visceral Pain/drug therapyABSTRACT
The roles of spinal N-methyl-d-aspartic acid receptor 2B (NR2B) subunit in central sensitization of chronic visceral pain were investigated. A rat model with irritable bowel syndrome (IBS) was established by colorectal distention (CRD) on post-natal days 8-14. Responses of the external oblique muscle of the abdomen to CRD were measured to evaluate the sensitivity of visceral pain in rats. The sensitivity of visceral pain significantly increased in IBS-like rats. Expressions of spinal NR2B subunit and phosphorylated NR2B subunit significantly increased by 50-55% in IBS-like rats when compared with those in control rats. Ro 25-6981, a selective antagonist of NR2B subunit, has a dose-dependent anti-allodynic and anti-hyperalgesic effect without causing motor dysfunction in IBS-like rats. Furthermore, the activation mechanism of the spinal NR2B subunit in chronic visceral pain was also investigated. Spinal administration of genistein, a specific inhibitor of tyrosine kinases, also decreased the visceral pain hypersensitivity of IBS-like rats in a dose-dependent manner. In addition, the expression of phosphorylated NR2B subunit was decreased after spinal administration of Ro 25-6981 or genistein in IBS-like rats. In conclusion, tyrosine kinase activation-induced phosphorylation of NR2B subunit may play a crucial role in central sensitization of chronic visceral pain.
Subject(s)
Receptors, N-Methyl-D-Aspartate/metabolism , Spinal Cord/metabolism , Tyrosine/metabolism , Visceral Pain/pathology , Animals , Animals, Newborn , Disease Models, Animal , Dose-Response Relationship, Drug , Electromyography , Excitatory Amino Acid Antagonists/therapeutic use , Genistein/pharmacology , Irritable Bowel Syndrome/complications , Male , Pain Measurement , Phenols/therapeutic use , Phosphorylation/physiology , Piperidines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Rats , Rats, Sprague-Dawley , Time Factors , Visceral Pain/etiologyABSTRACT
OBJECTIVE: To study the effect of chronic noise exposure on expression of N-methyl-D-aspartic acid receptor 2B (NR2B) and tau phosphorylation in hippocampus of rats. METHODS: Twenty-four male SD rats were divided in control group and chronic noise exposure group. NR2B expression and tau phosphorylation in hippocampus of rats were detected after chronic noise exposure (100 dB SPL white noise, 4 h/d×30d) and their mechanisms underlying neuronal apoptosis in hippocampus of rats with TUNEL staining. RESULTS: The NR2B expression decreased significantly after chronic noise exposure which resulted in tau hyperphosphorylation and neural apoptosis in hippocampus of rats. Immunohistochemistry showed that the tau hyperphosphorylation was most prominent in dentate gyrus (DG) and CA1 region of rat hippocampus. CONCLUSION: The abnormality of neurotransmitter system, especially Glu and NR2B containing NMDA receptor, and tau hyperphosphorylation in hippocampus of rats, may play a role in chronic noise-induced neural apoptosis and cognition impairment.
Subject(s)
Hippocampus/metabolism , Noise/adverse effects , Receptors, N-Methyl-D-Aspartate/metabolism , tau Proteins/metabolism , Animals , Apoptosis , Hippocampus/cytology , Male , Neurons/cytology , Neurons/metabolism , Phosphorylation , Rats , Rats, Sprague-DawleyABSTRACT
<p><b>OBJECTIVE</b>To study the effect of chronic noise exposure on expression of N-methyl-D-aspartic acid receptor 2B (NR2B) and tau phosphorylation in hippocampus of rats.</p><p><b>METHODS</b>Twenty-four male SD rats were divided in control group and chronic noise exposure group. NR2B expression and tau phosphorylation in hippocampus of rats were detected after chronic noise exposure (100 dB SPL white noise, 4 h/d×30d) and their mechanisms underlying neuronal apoptosis in hippocampus of rats with TUNEL staining.</p><p><b>RESULTS</b>The NR2B expression decreased significantly after chronic noise exposure which resulted in tau hyperphosphorylation and neural apoptosis in hippocampus of rats. Immunohistochemistry showed that the tau hyperphosphorylation was most prominent in dentate gyrus (DG) and CA1 region of rat hippocampus.</p><p><b>CONCLUSION</b>The abnormality of neurotransmitter system, especially Glu and NR2B containing NMDA receptor, and tau hyperphosphorylation in hippocampus of rats, may play a role in chronic noise-induced neural apoptosis and cognition impairment.</p>
