Noxious stimulation can trigger persistent sensitization of somatosensory systems that involves memory-like mechanisms. Here we report that noxious stimulation of the mollusc Aplysia produces transcription-dependent, long-term hyperexcitability (LTH) of nociceptive sensory neurons that requires a nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway. Injection of cGMP induced LTH, whereas antagonists of the NO-cGMP-PKG pathway prevented pinch-induced LTH. Co-injection of calcium/cAMP-responsive-element (CRE) blocked both pinch-induced LTH and cAMP-induced LTH, but antagonists of protein kinase A (PKA) failed to block pinch-induced LTH. Thus the NO-cGMP-PKG pathway and at least one other pathway, but not the cAMP-PKA pathway, are critical for inducing LTH after brief, noxious stimulation.