title: PICK1 Regulates the Expression and Trafficking of AMPA Receptors in Remifentanil-Induced Hyperalgesia.
abstract: Remifentanil is used widely in clinical anesthesia because it induces more rapid and more common hyperalgesia than other opioid analgesics. Activation of N-methyl-D-aspartate (NMDA) receptors takes a pivotal part in remifentanil-induced hyperalgesia. Like NMDA receptors, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are excitatory ion glutamate receptors in postsynaptic membrane, which are involved in the transmission of both acute and chronic pain. Protein interacting with C kinase 1 (PICK1) plays an important role in NMDA receptor-mediated internalization of glutamate receptor 2 (GluR2)-containing AMPARs and contributes to the induction and maintenance of inflammation-induced pain. This study aimed to test the hypothesis that PICK1 contributes to remifentanil-induced hyperalgesia by regulating AMPAR expression and trafficking in the spinal cord.
  
  
  
  Using a rat model of remifentanil-induced hyperalgesia by intravenous infusion of remifentanil, we first measured changes in mechanical and thermal hyperalgesia at 24 hours before remifentanil infusion and 2, 6, 24, and 48 hours after infusion. PICK1 mRNA and protein expression and AMPAR subunit expression and trafficking in the spinal cord were then detected by reverse transcription-qualitative polymerase chain reaction, immunohistochemistry, and Western blot. In addition, we knocked down PICK1 expression by intrathecal administration of PICK1 antisense oligodeoxynucleotide to investigate the effects of PICK1 deficiency on remifentanil-induced hyperalgesia and the expression and trafficking of AMPARs.
  
  
  
  A significant time-group interaction was found for nociceptive thresholds (paw withdrawal threshold and paw withdrawal latency; all P < .0001). Remifentanil infusion induced distinct hyperalgesia at different time points (P < .0001), which was partly reversed by PICK1 knockdown (P < .007). Besides, remifentanil infusion increased the expression of PICK1 mRNA and protein (P < .0001) and the membrane GluR1 and GluR2 internalization in spinal dorsal horn neurons (P < .0011). More importantly, PICK1 deficiency could attenuate remifentanil-induced GluR2 internalization in the spinal cord dorsal horn (P < .01) but had no effect on remifentanil-induced membrane GluR1 expression (P ≥ .985).
  
  
  
  These results indicate that PICK1 deficiency might reverse remifentanil-induced hyperalgesia through regulating GluR2-containing AMPAR expression and trafficking in the spinal cord dorsal horn.
authors.affiliation: From the Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, China.
authors.forename: Zhifen
authors.initials: Z
authors.lastname: Wang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.forename: Keliang
authors.initials: K
authors.lastname: Xie
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Tang
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.forename: Jiying
authors.initials: J
authors.lastname: Ao
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Suqian
authors.initials: S
authors.lastname: Guo
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
mesh_terms: D000701:Analgesics, Opioid / Q000633:toxicity; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D003598:Cytoskeletal Proteins; D005786:Gene Expression Regulation; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism*; D008297:Male; D009687:Nuclear Proteins / Q000502:physiology*; D010880:Piperidines / Q000633:toxicity*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000378:metabolism; D000077208:Remifentanil
chemical_list: D000701:Analgesics, Opioid; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D010880:Piperidines; D018091:Receptors, AMPA; D000077208:Remifentanil