cAMP and cGMP contribute to sensory neuron hyperexcitability and hyperalgesia in rats with dorsal root ganglia compression.
Numerous studies have implicated the cAMP-protein kinase A (PKA) pathway in producing hyperexcitability of dorsal root ganglia (DRG) sensory neurons under conditions associated with pain. Evidence is presented for roles of both the cAMP-PKA and cGMP-protein kinase G (PKG) pathways in maintaining neuronal hyperexcitability and behavioral hyperalgesia in a neuropathic pain model: chronic compression of the DRG (CCD treatment). Lumbar DRGs were compressed by a steel rod inserted into the intervertebral foramen. Thermal hyperalgesia was revealed by shortened latencies of foot withdrawal to radiant heat. Intracellular recordings were obtained in vitro from lumbar ganglia after in vivo DRG compression. Activators of the cAMP-PKA pathway, 8-Br-cAMP and Sp-cAMPS, and of the cGMP-PKG pathway, 8-Br-cGMP and Sp-cGMPS, increased the hyperexcitability of DRG neurons already produced by CCD treatment, as shown by further decreases in action potential threshold and increased repetitive discharge during depolarization. The adenylate cyclase inhibitor, SQ22536, the PKA antagonist, Rp-cAMPS, the guanylate cyclase inhibitor, ODQ, and the PKG inhibitor, Rp-8-pCPT-cGMPS, reduced the hyperexcitability of CCD DRG neurons. In vivo application of PKA and PKG antagonists transiently depressed behavioral hyperalgesia induced by CCD treatment. Unexpectedly, application of these agonists and antagonists to ganglia of naïve, uninjured animals had little effect on electrophysiological properties of DRG neurons and no effect on foot withdrawal, suggesting that sensitizing actions of these pathways in the DRG are enabled by prior injury or stress. The only effect observed in uncompressed ganglia was modest depolarization of DRG neurons by PKA and PKG agonists. CCD treatment also depolarized DRG neurons, but CCD-induced depolarization was not affected by agonists or antagonists of these pathways.
Song
Xue-Jun
XJ
Department of Neurobiology, Parker College Research Institute, 2500 Walnut Hill Lane, Dallas, TX 75229, USA. song@parkercc.edu
Wang
Zheng-Bei
ZB
Gan
Qiang
Q
Walters
Edgar T
ET
D000200:Action Potentials; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000293:injuries* / Q000503:physiopathology*; D006930:Hyperalgesia / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D009475:Neurons, Afferent; D011843:Radiculopathy / Q000150:complications / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000242:Cyclic AMP; D006152:Cyclic GMP