Background: Ongoing neuropathic pain is difficult to treat. The authors examined whether dermorphin [D-Arg2, Lys4] (1-4) amide, a peripherally acting mu-opioid receptor agonist, attenuates ongoing pain-associated manifestations after nerve injury in rats and mice. Methods: Using conditioned place preference assay, the authors tested whether animals show a preference to the environment associated with drug treatment. Wide-dynamic range and dorsal root ganglion neuronal activities were measured by electrophysiology recording and calcium imaging. Results: Nerve-injured animals stayed longer in dermorphin [D-Arg2, Lys4] (1-4) amide-paired chamber after conditioning than during preconditioning (rats: 402.4 +/- 6 .3 vs. 322.1 +/- 5.0s, 10 mg/kg, n = 9, P = 0.009; mice: 437.8 +/- 59.4 vs. 351.3 +/- 95.9s, 2 mg/kg, n = 8, P = 0.047). Topical ganglionic application of dermorphin [D-Arg2, Lys4] (1-4) amide (5 mu M, 1 mu l, n = 5) reduced the numbers of small-diameter dorsal root ganglion neurons that showed spontaneous activity (1.1 +/- 0.4 vs. 1.5 +/- 0.3, P = 0.044) and that were activated by test stimulation (15.5 +/- 5.5 vs. 28.2 +/- 8.2, P = 0.009) after injury In neuropathic rats, dermorphin [D-Arg2, Lys4] (1-4) amide (10mg/kg, n = 8) decreased spontaneous firing rates in wide-dynamic range neurons to 53.2 +/- 46.6% of predrug level, and methylnaltrexone (5 mg/kg, n = 9) blocked dermorphin [D-Arg2, Lys4] (1-4) amide-induced place preference and inhibition of wide-dynamic range neurons. Dermorphin [D-Arg2, Lys4] (1-4) amide increased paw withdrawal threshold (17.5 +/- 2.2 g) from baseline (3.5 +/- 0.7g, 10 mg/kg, n = 8, P = 0.002) in nerve-injured rats, but the effect diminished after repeated administrations. Conclusions: Peripherally acting mu-opioids may attenuate ongoing pain-related behavior and its neurophysiologic correlates. Yet, repeated administrations cause antiallodynic tolerance. (ANESTHESIOLOGY 2018; 128:1220-36)