Genetic reduction of chronic muscle pain in mice lacking calcium/calmodulin-stimulated adenylyl cyclases.
BACKGROUND
The Ca2+/calmodulin-stimulated adenylyl cyclase (AC) isoforms AC1 and AC8, couple NMDA receptor activation to cAMP signaling pathways in neurons and are important for development, learning and memory, drug addiction and persistent pain. AC1 and AC8 in the anterior cingulate cortex (ACC) and the spinal cord were previously shown to be important in subcutaneous inflammatory pain. Muscle pain is different from cutaneous pain in its characteristics as well as conducting fibers. Therefore, we conducted the present work to test the role of AC1 and AC8 in both acute persistent and chronic muscle pain.


RESULTS
Using an acute persistent inflammatory muscle pain model, we found that the behavioral nociceptive responses of both the late phase of acute muscle pain and the chronic muscle inflammatory pain were significantly reduced in AC1 knockout (KO) and AC1&8 double knockout (DKO) mice. Activation of other adenylyl cyclases in these KO mice by microinjection of forskolin into the ACC or spinal cord, but not into the peripheral tissue, rescued the behavioral nociceptive responses. Additionally, intra-peritoneal injection of an AC1 inhibitor significantly reduced behavioral responses in both acute persistent and chronic muscle pain.


CONCLUSIONS
The results of the present study demonstrate that neuronal Ca2+/calmodulin-stimulated adenylyl cyclases in the ACC and spinal cord are important for both late acute persistent and chronic inflammatory muscle pain.
Vadakkan
Kunjumon I
KI
Department of Physiology, Faculty of Medicine, University of Toronto Centre for the Study of Pain, University of Toronto, ON, Canada. kunjumon.vadakkan@utoronto.ca
Wang
Hansen
H
Ko
Shanelle W
SW
Zastepa
Evelyn
E
Petrovic
Michele J
MJ
Sluka
Kathleen A
KA
Zhuo
Min
M
D000262:Adenylyl Cyclases / Q000235:genetics*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D002147:Calmodulin / Q000378:metabolism*; D002908:Chronic Disease; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000503:physiopathology; D010146:Pain / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology
D002147:Calmodulin; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8; D002118:Calcium