The cAMP pathway, which can be activated by extracellular signals, hormones and neurotransmitters, plays a significant role in pain transmission. The cAMP pathway activates protein kinase A (PKA). PKA then phosphorylates the NMDA receptor, making it more effective, and the cAMP-response-element-element-binding protein (CREB), resulting in gene transcription. Previous studies all investigates short- term hyperalgesia with significant tissue damage and inflammation. The role of cAMP in chronic muscle pain is unknown.
Specific aim #1 will determine if blockade of the cAMP pathway reverses mechanical hyperalgesia in a chronic muscle pain model. This will be determined by blocking the cAMP pathway by intrathecally administering inhibitors of 1) adenylate cyclase or 2) PKA and then measuring the effect on mechanical hyperalgesia.
Specific aim #2 will determine if the NMDA receptor and CREB are phosphorylated in the spinal cord in chronic muscle pain. This will be determined by conducting immunohistochemical stains and western blots for phosphorylation of 1) the PKA site of the NMDA receptor (NR1) and 2) CREB. It is expected that phosphorylation will increase in the chronic pain and that blocking PKA will decrease mechanical hyperalgesia and the phosphorylation of CREB and the NMDA receptor.
| Bement, Marie K Hoeger; Sluka, Kathleen A (2005) Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner. Arch Phys Med Rehabil 86:1736-40 |
| Hoeger-Bement, Marie K; Sluka, Kathleen A (2003) Phosphorylation of CREB and mechanical hyperalgesia is reversed by blockade of the cAMP pathway in a time-dependent manner after repeated intramuscular acid injections. J Neurosci 23:5437-45 |
