title: A novel role of spinal astrocytic connexin 43: mediating morphine antinociceptive tolerance by activation of NMDA receptors and inhibition of glutamate transporter-1 in rats.
abstract: OBJECTIVE
  Connexin 43 (Cx43) has been reported to be involved in neuropathic pain, but whether it contributes to morphine antinociceptive tolerance remains unknown. The present study investigated the role of spinal Cx43 in the development of morphine tolerance and its mechanisms in rats.
  
  
  METHODS
  Morphine tolerance was induced by intrathecal (i.t.) administration of morphine (15 μg) daily for seven consecutive days. The analgesia effect was assessed by hot-water tail-flick test. Expression of proteins was detected by Western blot and immunohistochemistry assay.
  
  
  RESULTS
  Chronic morphine markedly increased the expression of spinal Cx43. Gap26, a specific Cx43 mimic peptide, attenuated not only morphine antinociceptive tolerance, but also the up-regulation of spinal Cx43 expression, the activation of astrocytes, and N-methyl-D-aspartic acid (NMDA) receptors (NR1 and NR2B subunits), as well as the decreased GLT-1 expression induced by chronic morphine. MK-801, a noncompetitive NMDA receptors antagonist, suppressed the chronic morphine-induced spinal Cx43 up-regulation, astrocytes activation and decline of GLT-1 expression.
  
  
  CONCLUSIONS
  The spinal astrocytic Cx43 contributes to the development of morphine antinociceptive tolerance by activating astrocytes and NMDA receptors, and inhibiting GLT-1 expression. We also demonstrate that the role of interaction between the spinal astrocytic Cx43 and neuronal NMDA receptors is important in morphine tolerant rats.
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Shen
authors.forename: Li-Qiu
authors.initials: LQ
authors.lastname: Mo
authors.forename: Fen
authors.initials: F
authors.lastname: Hu
authors.forename: Pei-Xi
authors.initials: PX
authors.lastname: Chen
authors.forename: Rui-Xian
authors.initials: RX
authors.lastname: Guo
authors.forename: Jian-Qiang
authors.initials: JQ
authors.lastname: Feng
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D018031:Connexin 43 / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology* / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D018031:Connexin 43; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; C514423:Gap 26 peptide; D005904:Glial Fibrillary Acidic Protein; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D009020:Morphine
keywords: Astrocyte; Connexin 43; Glutamate transporter-1; Morphine tolerance; N-methyl-D-aspartic acid receptor