Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections.
Spinal activation of the cAMP pathway produces mechanical hyperalgesia, sensitizes nociceptive spinal neurons, and phosphorylates the transcription factor cAMP-responsive element binding protein (CREB), which initiates gene transcription. This study examined the role of the cAMP pathway in a model of chronic muscle pain by assessing associated behavioral changes and phosphorylation of CREB. Bilateral mechanical hyperalgesia of the paw was induced by administering two injections of acidic saline, 5 d apart, into the gastrocnemius muscle of male Sprague Dawley rats. Interestingly, the increases in immunoreactivity for CREB and phosphorylated CREB (p-CREB) in the spinal dorsal horn occur 24 hr, but not 1 week, after the second injection of acidic saline compared with pH 7.2 intramuscular injections. Spinal blockade of adenylate cyclase prevents the expected increase in p-CREB that occurs after intramuscular acid injection. The reversal of mechanical hyperalgesia by adenylate cyclase or protein kinase A inhibitors spinally follows a similar pattern with reversal at 24 hr, but not 1 week, compared with the vehicle controls. The p-CREB immunoreactivity in the superficial dorsal horn correlates with the mechanical withdrawal threshold such that increases in p-CREB are associated with decreases in threshold. Therefore, activation of the cAMP pathway in the spinal cord phosphorylates CREB and produces mechanical hyperalgesia associated with intramuscular acid injections. The mechanical hyperalgesia and phosphorylation of CREB depend on early activation of the cAMP pathway during the first 24 hr but are independent of the cAMP pathway by 1 week after intramuscular injection of acid.
Hoeger-Bement
Marie K
MK
Graduate Program in Physical Therapy and Rehabilitation Science, Neuroscience Graduate Program, Pain Research Program, University of Iowa, Iowa City, Iowa 52242, USA.
Sluka
Kathleen A
KA
D000143:Acids / Q000008:administration & dosage*; D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002908:Chronic Disease; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005356:Fibromyalgia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007273:Injections, Intramuscular; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000503:physiopathology
D000143:Acids; D000067956:Adenylyl Cyclase Inhibitors; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; C017759:9-(tetrahydro-2-furyl)-adenine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000225:Adenine