Injury or inflammation affecting sensory neurons in dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spontaneous firing and neuropathic pain. Recent results indicate that, following chronic compression of DRG (CCD treatment), both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by concurrent activity in cAMP-PKA and cGMP-PKG signaling pathways. We report here that dissociation produces a pattern of hyperexcitability in small DRG neurons similar to that produced by CCD treatment, manifest as decreased action potential (AP) current threshold, increased AP duration, repetitive firing to depolarizing pulses and spontaneous firing, and resting depolarization. A novel feature of this hyperexcitability is its early expression (within 2h). Both forms of injury increase electrophysiological responsiveness of neurons to activation of cAMP-PKA and cGMP-PKG pathways, as indicated by enhancement of hyperexcitability by agonists of these pathways in dissociated or CCD-treated neurons but not in control neurons. Although inflammatory signals are known to activate cAMP-PKA pathways, dissociation-induced hyperexcitability is unlikely to be triggered by signals released from inflammatory cells recruited to the DRG, because of insufficient time for recruitment during the dissociation procedure. Inhibition by specific antagonists indicates that continuing activation of cAMP-PKA and cGMP-PKG pathways is required to maintain hyperexcitability after dissociation. The reduction of hyperexcitability by blockers of adenylyl cyclase and soluble guanylyl cyclase after dissociation suggests a continuing release of autocrine and/or paracrine factors from dissociated neurons and/or satellite cells, which activate both cyclases and help to maintain acute, injury-induced hyperexcitability of DRG neurons.