title: Spinal astrocytic activation contributes to both induction and maintenance of pituitary adenylate cyclase-activating polypeptide type 1 receptor-induced long-lasting mechanical allodynia in mice.
abstract: BACKGROUND
  Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors are present in the spinal dorsal horn and dorsal root ganglia, suggesting an important role of PACAP-PACAP receptors signaling system in the modulation of spinal nociceptive transmission. We have previously reported that a single intrathecal injection of PACAP or a PACAP specific (PAC1) receptor selective agonist, maxadilan, in mice induced dose-dependent aversive behaviors, which lasted more than 30 min, and suggested that the maintenance of the nociceptive behaviors was associated with the spinal astrocytic activation.
  
  
  RESULTS
  We found that a single intrathecal administration of PACAP or maxadilan also produced long-lasting hind paw mechanical allodynia, which persisted at least 84 days without affecting thermal nociceptive threshold. In contrast, intrathecal application of vasoactive intestinal polypeptide did not change mechanical threshold, and substance P, calcitonin gene-related peptide, or N-methyl-D-aspartate induced only transient mechanical allodynia, which disappeared within 21 days. Western blot and immunohistochemical analyses with an astrocytic marker, glial fibrillary acidic protein, revealed that the spinal PAC1 receptor stimulation caused sustained astrocytic activation, which also lasted more than 84 days. Intrathecal co-administration of L-α-aminoadipate, an astroglial toxin, with PACAP or maxadilan almost completely prevented the induction of the mechanical allodynia. Furthermore, intrathecal treatment of L-α-aminoadipate at 84 days after the PAC1 stimulation transiently reversed the mechanical allodynia accompanied by the reduction of glial fibrillary acidic protein expression level.
  
  
  CONCLUSIONS
  Our data suggest that spinal astrocytic activation triggered by the PAC1 receptor stimulation contributes to both induction and maintenance of the long-term mechanical allodynia.
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yokai
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Japan tkmphm10@m.kufm.kagoshima-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kurihara
authors.affiliation: Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima City, Japan.
authors.forename: Atsuro
authors.initials: A
authors.lastname: Miyata
mesh_terms: D000272:Adipates / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology*; D007278:Injections, Spinal; D019476:Insect Proteins / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000819:agonists / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology*
chemical_list: D000272:Adipates; D005904:Glial Fibrillary Acidic Protein; D019476:Insect Proteins; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D047428:Protein Kinase Inhibitors; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; C069147:maxadilan protein, insect; C029900:adipic acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: ERK; GFAP; JNK; MAP kinase; PAC1 receptor; PACAP; c-Jun-N-terminal kinase; extracellular signal-regulated kinase; glial fibrillary acidic protein