Peripherally Acting μ-Opioid Receptor Agonists Attenuate Ongoing Pain-associated Behavior and Spontaneous Neuronal Activity after Nerve Injury in Rats.

Abstract

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.

• Authors: Vinod Tiwari, Michael Anderson, Fei Yang, Vineeta Tiwari, Qin Zheng, Shao-Qiu He, Tong Zhang, Bin Shu, Xueming Chen, Shaness A Grenald, Kimberly E Stephens, Zhiyong Chen, Xinzhong Dong, Srinivasa N Raja, Yun Guan
• Journal: Anesthesiology (Anesthesiology) Vol. 128 Issue 6 Pg. 1220-1236 (06 2018) ISSN: 1528-1175 [Electronic] United States
• PMID: 29601322 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Receptors, Opioid, mu

Topics

• Analgesics, Opioid (pharmacology, therapeutic use)
• Animals
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neuralgia (drug therapy, physiopathology, psychology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, mu (agonists, physiology)
• Spinal Nerves (drug effects, physiology)