Up-regulation of CXCR4 expression contributes to persistent abdominal pain in rats with chronic pancreatitis.
Background Pain in patients with chronic pancreatitis is critical hallmark that accompanied inflammation, fibrosis, and destruction of glandular pancreas. Many researchers have demonstrated that stromal cell-derived factor 1 (also named as CXCL12) and its cognate receptor C-X-C chemokine receptor type 4 (CXCR4) involved in mediating neuropathic and bone cancer pain. However, their roles in chronic pancreatic pain remain largely unclear. Methods Chronic pancreatitis was induced by intraductal injection of trinitrobenzene sulfonic acid to the pancreas. Von Frey filament tests were conducted to evaluate pancreas hypersensitivity of rat. Expression of CXCL12, CXCR4, NaV1.8, and pERK in rat dorsal root ganglion was detected by Western blot analyses. Dorsal root ganglion neuronal excitability was assessed by electrophysiological recordings. Results We showed that both CXCL12 and CXCR4 were dramatically up-regulated in the dorsal root ganglion in trinitrobenzene sulfonic acid-induced chronic pancreatitis pain model. Intrathecal application with AMD3100, a potent and selective CXCR4 inhibitor, reversed the hyperexcitability of dorsal root ganglion neurons innervating the pancreas of rats following trinitrobenzene sulfonic acid injection. Furthermore, trinitrobenzene sulfonic acid-induced extracellular signal-regulated kinase activation and Nav1.8 up-regulation in dorsal root ganglias were reversed by intrathecal application with AMD3100 as well as by blockade of extracellular signal-regulated kinase activation by intrathecal U0126. More importantly, the trinitrobenzene sulfonic acid-induced persistent pain was significantly suppressed by CXCR4 and extracellular signal-regulated kinase inhibitors. Conclusions The present results suggest that the activation of CXCL12-CXCR4 signaling might contribute to pancreatic pain and that extracellular signal-regulated kinase-dependent Nav1.8 up-regulation might lead to hyperexcitability of the primary nociceptor neurons in rats with chronic pancreatitis.
1 Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China.
Hong-Yan
HY
Zhu
2 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China.
Xuelian
X
Liu
1 Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China.
Xiuhua
X
Miao
1 Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China.
Di
D
Li
1 Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China.
Shusheng
S
Wang
1 Center for Translation Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, P.R. China.|2 Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, P.R. China.
Guang-Yin
GY
Xu
D015746:Abdominal Pain / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D001596:Benzylamines; D002478:Cells, Cultured; D000080027:Cyclams; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010147:Pain Measurement; D050500:Pancreatitis, Chronic / Q000150:complications*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D019380:Anti-HIV Agents; D001596:Benzylamines; C486264:Cxcr4 protein, rat; D000080027:Cyclams; D006571:Heterocyclic Compounds; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; C088327:plerixafor
CXCR4; Dorsal root ganglion; Nav1.8; chronic pain; chronic pancreatitis