Substantia gelatinosa (SG) neurons receive synaptic inputsfrom primary afferent Aδ- and C-fibers, where nociceptiveinformation is integrated and modulated by numerous neurotransmittersor neuromodulators. A number of studies werededicated to the molecular mechanism underlying the modulationof excitability or synaptic plasticity in SG neurons andrevealed that second messengers, such as cAMP and cGMP,play an important role. Recently, cAMP and cGMP wereshown to downregulate each other in heart muscle cells.However, involvement of the crosstalk between cAMP andcGMP in neurons is yet to be addressed. Therefore, weinvestigated whether interaction between cAMP and cGMPmodulates synaptic plasticity in SG neurons using slice patchclamprecording from rats. Synaptic activity was measuredby excitatory post-synaptic currents (EPSCs) elicited by stimulationonto dorsal root entry zone. Application of 1 mM of 8-bromoadenosine 3,5-cyclic monophosphate (8-Br-cAMP) or8-bromoguanosine 3,5-cyclic monophosphate (8-Br-cGMP)for 15 minutes increased EPSCs, which were maintained for30 minutes. However, simultaneous application of 8-BrcAMPand 8-Br-cGMP failed to increase EPSCs, whichsuggested antagonistic cross-talk between two second messengers.Application of 3-isobutyl-1-methylxanthine (IBMX)that prevents degradation of cAMP and cGMP by blockingphosphodiesterase (PDE) increased EPSCs. Co-applicationof cAMP/cGMP along with IBMX induced additionalincrease in EPSCs. These results suggest that second messengers,cAMP and cGMP, might contribute to development ofchronic pain through the mutual regulation of the signaltransduction.