Involvement of PKA-dependent upregulation of nNOS-CGRP in adrenomedullin-initiated mechanistic pathway underlying CFA-induced response in rats.
We have previously shown that intrathecal administration of the adrenomedullin (AM) receptor antagonist AM(22-52) produces a long-lasting anti-hyperalgesia effect. This study examined the hypothesis that AM recruits other pronociceptive mediators in complete Freund's adjuvant (CFA)-induced inflammation. Injection of CFA in the hindpaw of rat produced an increase in the expression of nNOS in dorsal root ganglion (DRG) and the spinal dorsal horn. An intrathecal administration of AM(22-52), but not the CGRP antagonist BIBN4096BS, abolished the CFA-induced increase of nNOS. Moreover, AM-induced increase of CGRP was inhibited by the nNOS inhibitors L-NAME and 7-nitroindazole in cultured ganglion explants. Addition of AM to ganglion cultures induced an increase in nNOS protein, which was attenuated by the PKA inhibitor H-89. Treatment with AM also concentration-dependently increased cAMP content and pPKA protein level, but not its non-phosphorylated form, in cultured ganglia. In addition, nNOS was shown to be co-localized with the AM receptor components calcitonin receptor-like receptor and receptor activity-modifying protein 2- and 3 in DRG neurons. The present study suggests that the enhanced activity of nitric oxide (NO) mediates the biological action of AM at the spinal level and that AM recruits NO-CGRP via cAMP/PKA signaling in a mechanistic pathway underlying CFA-induced hyperalgesia.
Provincial Key Laboratory of Developmental Biology and Neuroscience, Fujian Normal University, Fuzhou, Fujian, 350108, China.
Dongmei
D
Wang
Liqin
L
Ruan
Yanguo
Y
Hong
Jean-Guy
JG
Chabot
Rémi
R
Quirion
D053607:Adrenomedullin / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005620:Freund's Adjuvant / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000378:metabolism; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009924:Organ Culture Techniques; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D012668:Trigeminal Ganglion / Q000378:metabolism; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D007191:Indazoles; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D053607:Adrenomedullin; D009569:Nitric Oxide; D005620:Freund's Adjuvant; D052248:Nitric Oxide Synthase Type I; D017868:Cyclic AMP-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester