title: Spinal ephrinB/EphB signalling contributed to remifentanil-induced hyperalgesia via NMDA receptor.
abstract: BACKGROUND
  One of the major unresolved issues in treating pain is the paradoxical hyperalgesia produced by opiates, and accumulating evidence implicate that EphBs receptors and ephrinBs ligands are involved in mediation of spinal nociceptive information and central sensitization, but the manner in which ephrinB/EphB signalling acts on spinal nociceptive information networks to produce hyperalgesia remains enigmatic. The objective of this research was to investigate the role of ephrinB/EphB signalling in remifentanil-induced hyperalgesia (RIH) and its downstream effector.
  
  
  METHODS
  We characterized the remifentanil-induced pain behaviours by evaluating thermal hyperalgesia and mechanical allodynia in a rat hind paw incisional model. Protein expression of EphB1 receptor and ephrinB1 ligand in spinal dorsal horn cord was determined by Western blotting, and Fos was determined by immunohistochemistry assay, respectively. To figure out the manner in which ephrinB/EphB signalling acts with N-methyl-d-aspartic acid (NMDA) receptor, we used MK-801, an antagonist of NMDA receptor, trying to suppressed the hyperalgesia induced by ephrinB1-Fc, an agonist of ephrinB/EphB.
  
  
  RESULTS
  Continuing infusion of remifentanil produced a thermal hyperalgesia and mechanical allodynia, which was accompanied with increased protein expression of spinal-level EphB1 receptor, ephrinB1 ligand and Fos; what appeared above was suppressed by pretreatment with EphB1-Fc, an antagonist of ephrinB/EphB or MK-801, and increased pain behaviours induced by intrathecal injection of ephrinB1-Fc, an agonist of ephrinB/EphB, were suppressed by MK-801.
  
  
  CONCLUSIONS
  Our findings indicated that ephrinB/EphB signalling is involved in RIH. EphrinB/EphB signalling might be the upstream of NMDA receptor.
authors.affiliation: Department of Anesthesiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: W S
authors.initials: WS
authors.lastname: Xia
authors.forename: Y N
authors.initials: YN
authors.lastname: Peng
authors.forename: L H
authors.initials: LH
authors.lastname: Tang
authors.forename: L S
authors.initials: LS
authors.lastname: Jiang
authors.forename: L N
authors.initials: LN
authors.lastname: Yu
authors.forename: X L
authors.initials: XL
authors.lastname: Zhou
authors.forename: F J
authors.initials: FJ
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Yan
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D036387:Ephrin-B1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D036225:Receptor, EphB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077208:Remifentanil; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D036387:Ephrin-B1; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D036225:Receptor, EphB1; D000077208:Remifentanil
references.citation: J Neurochem. 2006 Jul;98(1):1-10
references.pmid: 16805791
references.citation: Peptides. 2000 Jan;21(1):151-72
references.pmid: 10704732
references.citation: Pain. 1996 Mar;64(3):493-502
references.pmid: 8783314
references.citation: Nat Rev Mol Cell Biol. 2002 Jul;3(7):475-86
references.pmid: 12094214
references.citation: Vet Anaesth Analg. 2003 Oct;30(4):250-6
references.pmid: 12925182
references.citation: Mol Pain. 2009 Jun 12;5:29
references.pmid: 19523204
references.citation: J Neurosci. 2000 Dec 1;20(23):8578-84
references.pmid: 11102461
references.citation: Anesthesiology. 2000 Feb;92(2):465-72
references.pmid: 10691234
references.citation: Pain Physician. 2008 Mar;11(2 Suppl):S133-53
references.pmid: 18443637
references.citation: Br J Anaesth. 2003 Dec;91(6):842-9
references.pmid: 14633756
references.citation: J Pharmacol Toxicol Methods. 1994 Dec;32(4):197-200
references.pmid: 7881133
references.citation: J Addict Dis. 2011 Jul-Sep;30(3):258-70
references.pmid: 21745048
references.citation: J Med Chem. 1991 Jul;34(7):2202-8
references.pmid: 2066993
references.citation: Anesthesiology. 2010 May;112(5):1234-49
references.pmid: 20395829
references.citation: PLoS One. 2012;7(8):e40930
references.pmid: 22879882
references.citation: Physiol Rev. 2009 Apr;89(2):707-58
references.pmid: 19342617
references.citation: Neuroreport. 2003 Jan 20;14(1):1-7
references.pmid: 12544821
references.citation: Anesthesiology. 1993 Nov;79(5):881-92
references.pmid: 7902032
references.citation: Am J Ther. 2010 Sep-Oct;17(5):498-510
references.pmid: 20844348
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Neuropharmacology. 2013 Dec;75:164-71
references.pmid: 23911743
references.citation: Nat Neurosci. 2003 Apr;6(4):339-40
references.pmid: 12640461
references.citation: J Neurosci Methods. 1994 Jul;53(1):55-63
references.pmid: 7990513
references.citation: Pain. 2008 Sep 30;139(1):168-180
references.pmid: 18448254
references.citation: Nat Neurosci. 2009 Jan;12(1):15-20
references.pmid: 19029886
references.citation: Med Clin North Am. 2007 Mar;91(2):199-211
references.pmid: 17321281
references.citation: Cell. 2000 Dec 8;103(6):945-56
references.pmid: 11136979
references.citation: Pain. 1995 Sep;62(3):259-274
references.pmid: 8657426
references.citation: Pain. 1988 Jan;32(1):77-88
references.pmid: 3340425
references.citation: Science. 2009 Jul 10;325(5937):207-10
references.pmid: 19590003
references.citation: Br J Anaesth. 1996 Mar;76(3):341-3
references.pmid: 8785129