TY - JOUR
T1 - Peripherally Acting μ-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats
AU - Tiwari, Vinod
AU - Anderson, Michael
AU - Yang, Fei
AU - Tiwari, Vineeta
AU - Zheng, Qin
AU - He, Shao Qiu
AU - Zhang, Tong
AU - Shu, Bin
AU - Chen, Xueming
AU - Grenald, Shaness A.
AU - Stephens, Kimberly E.
AU - Chen, Zhiyong
AU - Dong, Xinzhong
AU - Raja, Srinivasa N.
AU - Guan, Yun
N1 - Funding Information:
This study was supported by grants from the National Institutes of Health (Bethesda, Maryland): R01NS70814 (Y.G.), R01NS26363 (S.N.R.), and R21NS99879 (Y.G.). This work was facilitated by the Pain Research Core funded by the Blaustein Fund and the Neurosurgery Pain Research Institute at Johns Hopkins University (Baltimore, Maryland).
Publisher Copyright:
© 2018, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Background: Ongoing neuropathic pain is difficult to treat. The authors examined whether dermorphin [D-Arg2, Lys4] (1-4) amide, a peripherally acting μ-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 ± 61.3 vs. 322.1 ± 45.0 s, 10 mg/kg, n = 9, P = 0.009; mice: 437.8 ± 59.4 vs. 351.3 ± 95.9 s, 2 mg/kg, n = 8, P = 0.047). Topical ganglionic application of dermorphin [D-Arg2, Lys4] (1-4) amide (5 μM, 1 μl, 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 (10 mg/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 ± 0.7 g, 10 mg/kg, n = 8, P = 0.002) in nerve-injured rats, but the effect diminished after repeated administrations. Conclusions: Peripherally acting μ-opioids may attenuate ongoing pain-related behavior and its neurophysiologic correlates. Yet, repeated administrations cause antiallodynic tolerance.
AB - Background: Ongoing neuropathic pain is difficult to treat. The authors examined whether dermorphin [D-Arg2, Lys4] (1-4) amide, a peripherally acting μ-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 ± 61.3 vs. 322.1 ± 45.0 s, 10 mg/kg, n = 9, P = 0.009; mice: 437.8 ± 59.4 vs. 351.3 ± 95.9 s, 2 mg/kg, n = 8, P = 0.047). Topical ganglionic application of dermorphin [D-Arg2, Lys4] (1-4) amide (5 μM, 1 μl, 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 (10 mg/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 ± 0.7 g, 10 mg/kg, n = 8, P = 0.002) in nerve-injured rats, but the effect diminished after repeated administrations. Conclusions: Peripherally acting μ-opioids may attenuate ongoing pain-related behavior and its neurophysiologic correlates. Yet, repeated administrations cause antiallodynic tolerance.
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U2 - 10.1097/ALN.0000000000002191
DO - 10.1097/ALN.0000000000002191
M3 - Article
C2 - 29601322
AN - SCOPUS:85053930541
VL - 128
SP - 1220
EP - 1236
JO - Anesthesiology
JF - Anesthesiology
SN - 0003-3022
IS - 6
ER -