Spinal cord protein interacting with C kinase 1 is required for the maintenance of complete Freund's adjuvant-induced inflammatory pain but not for incision-induced post-operative pain.
Protein interacting with C kinase 1 (PICK1) is a PDZ-containing protein that binds to AMPA receptor (AMPAR) GluR2 subunit and protein kinase Cα (PKCα) in the central neurons. It functions as a targeting and transport protein, presents the activated form of PKCα to synaptic GluR2, and participates in synaptic AMPAR trafficking in the nervous system. Thus, PICK1 might be involved in many physiological and pathological processes triggered via the activation of AMPARs. We report herein that PICK1 knockout mice display impaired mechanical and thermal pain hypersensitivities during complete Freund's adjuvant (CFA)-induced inflammatory pain maintenance. Acute transient knockdown of spinal cord PICK1 through intrathecal injection of PICK1 antisense oligodeoxynucleotide had a similar effect. In contrast, knockout and knockdown of spinal cord PICK1 did not affect incision-induced guarding pain behaviors or mechanical or thermal pain hypersensitivities. We also found that PICK1 is highly expressed in dorsal horn, where it interacts with GluR2 and PKCα. Injection of CFA into a hind paw, but not a hind paw incision, increased PKCα-mediated GluR2 phosphorylation at Ser880 and GluR2 internalization in dorsal horn. These increases were absent when spinal cord PICK1 was deficient. Given that dorsal horn PKCα-mediated GluR2 phosphorylation at Ser880 and GluR2 internalization contribute to the maintenance of CFA-induced inflammatory pain, our findings suggest that spinal PICK1 may participate in the maintenance of persistent inflammatory pain, but not in incision-induced post-operative pain, through promoting PKCα-mediated GluR2 phosphorylation and internalization in dorsal horn neurons.
Atianjoh
Fidelis E
FE
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA Department of Pediatrics, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Yaster
Myron
M
Zhao
Xiuli
X
Takamiya
Kogo
K
Xia
Jun
J
Gauda
Estelle B
EB
Huganir
Richard L
RL
Tao
Yuan-Xiang
YX
D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000494:pharmacology; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D005620:Freund's Adjuvant / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced* / Q000150:complications* / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000494:pharmacology; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use; D010149:Postoperative Pain / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; C091822:Prkcabp protein, mouse; D018091:Receptors, AMPA; D012694:Serine; D005620:Freund's Adjuvant; C104722:glutamate receptor ionotropic, AMPA 2