Hippocampal NR2B-containing NMDA receptors enhance long-term potentiation in rats with chronic visceral pain.
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.
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China.
Yu
Y
Chen
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China.
Ai-qin
AQ
Chen
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China.
Xiao-qing
XQ
Luo
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China.
Li-xia
LX
Guo
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China.
Ying
Y
Tang
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China.
Cheng-jia
CJ
Bao
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China.
Ling
L
Lin
Fujian Medical University, Department of Physiology and Pathophysiology, Laboratory of Pain Research, Key Laboratory of Brain Aging and Neurodegenerative Diseases, Neuroscience Research Center, Fuzhou City, Fujian Province 350108, PR China. Electronic address: chunlin77550@126.com.
Chun
C
Lin
D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000503:physiopathology; D059350:Chronic Pain / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D043183:Irritable Bowel Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D059265:Visceral Pain / Q000188:drug therapy / Q000503:physiopathology*
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D019833:Genistein; D011505:Protein-Tyrosine Kinases
Chronic visceral pain; Hippocampus; Irritable bowel syndrome; Long-term potentiation; N-methyl-d-aspartic acid receptor 2B subunit; Tyrosine kinase