Striatal-enriched protein tyrosine phosphatase modulates nociception: evidence from genetic deletion and pharmacological inhibition.
The information from nociceptors is processed in the dorsal horn of the spinal cord by complex circuits involving excitatory and inhibitory interneurons. It is well documented that GluN2B and ERK1/2 phosphorylation contributes to central sensitization. Striatal-enriched protein tyrosine phosphatase (STEP) dephosphorylates GluN2B and ERK1/2, promoting internalization of GluN2B and inactivation of ERK1/2. The activity of STEP was modulated by genetic (STEP knockout mice) and pharmacological (recently synthesized STEP inhibitor, TC-2153) approaches. STEP(61) protein levels in the lumbar spinal cord were determined in male and female mice of different ages. Inflammatory pain was induced by complete Freund's adjuvant injection. Behavioral tests, immunoblotting, and electrophysiology were used to analyze the effect of STEP on nociception. Our results show that both genetic deletion and pharmacological inhibition of STEP induced thermal hyperalgesia and mechanical allodynia, which were accompanied by increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Striatal-enriched protein tyrosine phosphatase heterozygous and knockout mice presented a similar phenotype. Furthermore, electrophysiological experiments showed that TC-2153 increased C fiber-evoked spinal field potentials. Interestingly, we found that STEP(61) protein levels in the lumbar spinal cord inversely correlated with thermal hyperalgesia associated with age and female gender in mice. Consistently, STEP knockout mice failed to show age-related thermal hyperalgesia, although gender-related differences were preserved. Moreover, in a model of inflammatory pain, hyperalgesia was associated with increased phosphorylation-mediated STEP(61) inactivation and increased pGluN2B(Tyr1472) and pERK1/2(Thr202/Tyr204)levels in the lumbar spinal cord. Collectively, the present results underscore an important role of spinal STEP activity in the modulation of nociception.
Departament de Biologia Cel·lular, Immunologia i Neurociències, Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain Centro de Investigaciones Biomédicas en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country (UPV/EHU), Bizkaia, Spain Departament de Ciències Mèdiques, Facultat de Medicina, Universitat de Girona, Girona, Catalonia, Spain Department of Chemistry, Yale University, New Haven, CT, USA Child Study Center, Yale School of Medicine, Yale University, New Haven, CT, USA.
Garikoitz
G
Azkona
Ana
A
Saavedra
Zigor
Z
Aira
David
D
Aluja
Xavier
X
Xifró
Tyler
T
Baguley
Jordi
J
Alberch
Jonathan A
JA
Ellman
Paul J
PJ
Lombroso
Jon J
JJ
Azkue
Esther
E
Pérez-Navarro
D000818:Animals; D001582:Benzothiepins / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006930:Hyperalgesia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D017288:Pain Threshold / Q000187:drug effects*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000172:deficiency* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
C559038:8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine; D001582:Benzothiepins; D004791:Enzyme Inhibitors; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C082101:Ptpn5 protein, mouse