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. 2013 Sep;74(3):490-5.
doi: 10.1002/ana.23928. Epub 2013 Sep 4.

Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma

Zhen-Zhong Xu  1 , Xing-Jun Liu, Temugin Berta, Chul-Kyu Park, Ning Lü, Charles N Serhan, Ru-Rong Ji
Affiliations

Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma

Zhen-Zhong Xu et al. Ann Neurol. 2013 Sep.

Abstract

Prevalence of neuropathic pain is high after major surgery. However, effective treatment for preventing neuropathic pain is lacking. Here we report that perisurgical treatment of neuroprotectin D1/protectin D1 (NPD1/PD1), derived from docosahexaenoic acid, prevents nerve injury-induced mechanical allodynia and ongoing pain in mice. Intrathecal post-treatment of NPD1/PD1 also effectively reduces established neuropathic pain and produces no apparent signs of analgesic tolerance. Mechanistically, NPD1/PD1 treatment blocks nerve injury-induced long-term potentiation, glial reaction, and inflammatory responses, and reverses synaptic plasticity in the spinal cord. Thus, NPD1/PD1 and related mimetics might serve as a new class of analgesics for preventing and treating neuropathic pain.

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Figures

Figure 1
Figure 1. NPD1/PD1 protects evoked and ongoing neuropathic pain symptoms after nerve injury in mice
(A, B) Local peri-surgical pretreatment of NPD1/PD1 (300 ng per mouse, peri-sciatic nerve) prevents CCI-induced mechanical allodynia (A) and ongoing pain (B). (A) The two-way ANOVA showed significant overall between-group differences between the NPD1 and vehicle groups, F(1,113) = 118, p < 0.0001, and between sham and vehicle groups, F(1,80) = 98.77, p < 0.0001. Post hoc analysis of each time point revealed significant differences between NPD1- and vehicle-treated mice from 3 to 28 days. *P<0.05, compared to sham control, #P<0.05, compared to corresponding vehicle (PBS) control, n = 5-12 mice. (B) Spinal clonidine (10 μg, i.t.)-induced chamber preference in CCI mice, as indicated by time spent in each chamber, is eliminated by the NPD1/PD1 pretreatment. $P<0.05, n = 5-9 mice. (C-E) Local peri-surgical pretreatment of NPD1/PD1 (300 ng/mouse, peri-sciatic nerve) protects axotomy-induced autotomy and stump pain. Incidence (C) and score (D) of autotomy in vehicle and NPD1/PD1-treated mice. *P<0.05, compared to vehicle, n = 7 mice. (E) Stump pain (mechanical allodynia) induced by a von Frey hair (0.07 g) in vehicle and NPD1/PD1-treated mice. *P<0.05, compared to sham control, #P<0.05, compared to corresponding vehicle control, n = 5-7 mice.
Figure 2
Figure 2. Local NPD1/PD1 prevents nerve injury-induced LTP, glial reaction, and cytokine/chemokine expression in the spinal cord dorsal horn
(A) LTP of the sciatic nerve transection-evoked field potentials (C-fiber stimulation) in the dorsal horns of anesthetized mice after pretreatment of vehicle (PBS), NPD1/PD1 (300 ng), and RvE1 (300 ng). The two-way ANOVA showed significant overall between-group differences between the NPD1 and vehicle groups, F(1,240) = 34.49, p =0.0004, and between RvE1 and vehicle groups, F(1,240) = 8.421, p=0.0198. *P<0.05 vs. PBS, n=5 mice. (B) Iba1 immunostaining in the dorsal horns of sham control and CCI mice (1 week) with pretreatment of PBS or NPD1/PD1. Scale, 50 μm. (C) Number of Iba1+ cells in the dorsal horn. *P<0.05, compared to sham, #P<0.05, compared to corresponding vehicle control, n=6 mice. (D) Expression of GFAP, IL-1β, and CCL2 mRNAs in the dorsal horns of sham control mice and SNL mice (3 days) with pretreatment of vehicle or PD1. *P<0.05, compared to sham, #P<0.05, compared to corresponding vehicle control, n=4 mice. (E) Expression of p-p38 and pERK in the dorsal horn of sham mice and CCI mice (1 week) with pretreatment of vehicle or PD1. *P<0.05, compared to sham, #P<0.05, compared to corresponding vehicle control, n=3-5 mice. All the results are mean ± SEM.
Figure 3
Figure 3. Spinal post-treatment of NPD1/PD1 reduces nerve injury-induced neuropathic pain and normalizes spinal cord synaptic plasticity
(A) Intrathecal injection of NPD1/PD1 (20, 100, 500 ng), 2 weeks after nerve injury, dose-dependently reduces CCI-induced mechanical allodynia. The two-way ANOVA showed significant overall between-group differences between the vehicle and NPD1 groups, F(1,60) = 6.039, p =0.0302 for 20 ng group, F(1,60) = 16.23, p =0.0017 for 100 ng group, and F(1,60) = 42.72, p<0.0001 for 500 ng group. However, there's no significant difference between the vehicle and DHA (100 μg) group, F(1,55) = 0.1275, p =0.7278. Bonferroni post hoc tests revealed that CCI-induced mechanical allodynia was significantly reduced by NPD1 treatment in a dose-dependent manner. *P<0.05, compared to corresponding vehicle (PBS) control, n = 6~7 mice. BL, baseline before nerve injury. (B) Dose-dependent inhibition of CCI-induced mechanical allodynia by NPD1/PD1 (i.t., 20-500 ng ≈ 0.06-1.4 nmol) and gabapentin (i.t., 10-100 μg ≈ 58.4-584.1 nmol). Mechanical allodynia was tested 3 h after the drug injection. PWT, paw withdrawal threshold. Note that the effective doses of gabapentin are much higher than that of NPD1/PD1. (C) Repeated injections of NPD1/PD1 (100 ng, i.t., once a day for 5 days) produces sustained reduction of CCI-induced mechanical allodynia, tested 1 h after each injection. The two-way ANOVA showed significant difference between the NPD1 and vehicle group, F(1,60) = 81.12, p<0.0001. Post hoc tests revealed that CCI-induced mechanical allodynia was significantly reduced by each NPD1 treatment. *P<0.05, compared to corresponding vehicle (PBS) control, n = 6 mice. (D) Traces of spontaneous excitatory postsynaptic currents (sEPSCs) in lamina II neurons of spinal cord slices of CCI mice (1 week) before and after NPD1/PD1 perfusion. Trace 1, 2, and 3 (top panel) show sEPSCs before NPD1/PD1 treatment, during NPD1/PD1 treatment, and after washout, respectively. Low panels are enlargements of traces (1, 2, and 3) in the up panel. (E) sEPSC frequency and amplitude in spinal cord slices from SNL and CCI mice. Note that nerve injury-induced increases in sEPSC frequency and amplitude are normalized by NPD1. *P<0.05, #P<0.05, n=5-10 neurons. Results are mean ± SEM.
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