Calcium/calmodulin-dependent kinase II mediates NO-elicited PKG activation to participate in spinal reflex potentiation in anesthetized rats

Gin Den Chen, Mei Lin Peng, Pei Yi Wang, Shin Da Lee, Hung Ming Chang, Shwu Fen Pan, Mei Jung Chen, Kwong Chung Tung, Cheng Yuan Lai, Tzer Bin Lin

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)


Calcium/calmodulin protein kinase (CaMK)-dependent nitric oxide (NO) and the downstream intracellular messenger cGMP, which is activated by soluble guanylate cyclase (sGC), are believed to induce long-term changes in efficacy of synapses through the activation of protein kinase G (PKG). The aim of this study was to examine the involvement of the CaMKII-dependent NO/sGC/PKG pathway in a novel form of repetitive stimulation-induced spinal reflex potentiation (SRP). A single-pulse test stimulation (TS; 1/30 Hz) on the afferent nerve evoked a single action potential, while repetitive stimulation (RS; 1 Hz) induced a long-lasting SRP that was abolished by a selective Ca 2+/CaMKII inhibitor, autocamtide 2-related inhibitory peptide (AIP). Such an inhibitory effect was reversed by a relative excess of nitric oxide synthase (NOS) substrate, L-arginine. In addition, the RS-induced SRP was abolished by pretreatment with the NOS inhibitor, NG-nitro-L- arginine-methyl ester (L-NAME). The sGC activator, protoporphyrin IX (PPIX), reversed the blocking effect caused by L-NAME. On the other hand, a sGC blocker, 1H-[1, 2, 4]oxadiazolo[4, 3-α]quinoxalin-1-one (ODQ), abolished the RS-induced SRP. Intrathecal applications of the membrane-permeable cGMP analog, 8-bromoguanosine 3′,5′-cyclic monophosphate sodium salt monohydrate (8-Br-cGMP), reversed the blocking effect on the RS-induced SRP elicited by the ODQ. Our findings suggest that a CaMKII-dependent NO/sGC/PKG pathway is involved in the RS-induced SRP, which has pathological relevance to hyperalgesia and allodynia.

Original languageEnglish
Pages (from-to)R487-R493
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number2
Publication statusPublished - Feb 2008
Externally publishedYes


  • Cyclic monophosphate sodium salt monohydrate
  • Soluble guanylate cyclase
  • Spinal cord
  • Spinal reflex potentiation
  • Windup

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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