Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases.
Adenylyl cyclase types 1 (AC1) and 8 (AC8), the two major calmodulin-stimulated adenylyl cyclases in the brain, couple NMDA receptor activation to cAMP signaling pathways. Cyclic AMP signaling pathways are important for many brain functions, such as learning and memory, drug addiction, and development. Here we show that wild-type, AC1, AC8, or AC1&8 double knockout (DKO) mice were indistinguishable in tests of acute pain, whereas behavioral responses to peripheral injection of two inflammatory stimuli, formalin and complete Freund's adjuvant, were reduced or abolished in AC1&8 DKO mice. AC1 and AC8 are highly expressed in the anterior cingulate cortex (ACC), and contribute to inflammation-induced activation of CREB. Intra-ACC administration of forskolin rescued behavioral allodynia defective in the AC1&8 DKO mice. Our studies suggest that AC1 and AC8 in the ACC selectively contribute to behavioral allodynia.
Wei
Feng
F
Department of Anesthesiology, Washington University Pain Center, Washington University, St. Louis, MO 63108, USA.
Qiu
Chang Shen
CS
Kim
Susan J
SJ
Muglia
Lisa
L
Maas
James W
JW
Pineda
Victor V
VV
Xu
Hai Ming
HM
Chen
Zhou Feng
ZF
Storm
Daniel R
DR
Muglia
Louis J
LJ
Zhuo
Min
M
D000262:Adenylyl Cyclases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000201:enzymology* / Q000503:physiopathology; D002147:Calmodulin / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005620:Freund's Adjuvant; D006930:Hyperalgesia / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000201:enzymology* / Q000503:physiopathology; D010146:Pain / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D010147:Pain Measurement; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D005620:Freund's Adjuvant; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8