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. 2016 May 12;12:1744806916646784.
doi: 10.1177/1744806916646784. Print 2016.

Interleukin-1β Overproduction Is a Common Cause for Neuropathic Pain, Memory Deficit, and Depression Following Peripheral Nerve Injury in Rodents

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Free PMC article

Interleukin-1β Overproduction Is a Common Cause for Neuropathic Pain, Memory Deficit, and Depression Following Peripheral Nerve Injury in Rodents

Wen-Shan Gui et al. Mol Pain. .
Free PMC article

Abstract

Background: Chronic pain is often accompanied by short-term memory deficit and depression. Currently, it is believed that short-term memory deficit and depression are consequences of chronic pain. Here, we test the hypothesis that the symptoms might be caused by overproduction of interleukin-1beta (IL-1β) in the injured nerve independent of neuropathic pain following spared nerve injury in rats and mice.

Results: Mechanical allodynia, a behavioral sign of neuropathic pain, was not correlated with short-term memory deficit and depressive behavior in spared nerve injury rats. Spared nerve injury upregulated IL-1β in the injured sciatic nerve, plasma, and the regions in central nervous system closely associated with pain, memory and emotion, including spinal dorsal horn, hippocampus, prefrontal cortex, nucleus accumbens, and amygdala. Importantly, the spared nerve injury-induced memory deficits, depressive, and pain behaviors were substantially prevented by peri-sciatic administration of IL-1β neutralizing antibody in rats or deletion of IL-1 receptor type 1 in mice. Furthermore, the behavioral abnormalities induced by spared nerve injury were mimicked in naïve rats by repetitive intravenous injection of re combinant rat IL-1β (rrIL-1β) at a pathological concentration as determined from spared nerve injury rats. In addition, microglia were activated by both spared nerve injury and intravenous injection of rrIL-1β and the effect of spared nerve injury was substantially reversed by peri-sciatic administration of anti-IL-1β.

Conclusions: Neuropathic pain was not necessary for the development of cognitive and emotional disorders, while the overproduction of IL-1β in the injured sciatic nerve following peripheral nerve injury may be a common mechanism underlying the generation of neuropathic pain, memory deficit, and depression.

Keywords: Neuropathic pain; depression; interleukin-1β; microglia; peripheral nerve injury; short-term memory deficit.

Figures

Figure 1.
Figure 1.
Mechanical allodynia, memory deficit, and depressive behavior induced by SNI in rats. (a) The time courses of paw withdrawal thresholds on ipsilateral (Ipsi) and contralateral (Contra) sides in SNI (n = 44) and sham-operate (n = 38) rats are shown. Operations were performed on day 0. The short-term memory index assessed with novel object recognition test (b) and the floating time with the forced swim test (c) in SNI group and in sham group were measured before and 12 to 15 days after SNI. **P < .01; ***P < .001 vs. sham group; ##P < .01 vs. SNI group before operation. (d, e) Paw withdrawal thresholds in ipsilateral side measured at 12 days after SNI were correlated with neither short-term memory index nor the floating time in the 44 SNI rats.
Figure 2.
Figure 2.
IL-1β is increased in the injured sciatic nerve, plasma, spinal dorsal horn, hippocampus, prefrontal cortex, nucleus accumbens, and amygdala following SNI. (a–f) Western blots show IL-1β expression in different nerve tissues as indicated in sham and 1 day, 3 days, and 7 days after SNI in rats (n = 5–6 in each group). (g) The specificity of anti-IL-1β used in the present study was identified by pre-incubation with rrIL-1β. The pre-incubated antibody detects very weak signal in blot with proteins from injured sciatic nerve. (h and i) The concentrations of IL-1β in the injured sciatic nerve tissue and plasma at different time points following SNI detected by ELISA (n = 6–7 in each group). **P < .01; ***P < .001 vs. sham group. SNI: spared nerve injury; SDH: spinal dorsal horn; NAcc: nucleus accumbens; AMG: amygdala.
Figure 3.
Figure 3.
Peri-sciatic application of IL-1β neutralizing antibody at injured sciatic nerve prevents the abnormal behaviors induced by SNI in rats. Paw withdrawal threshold (a, b), recognition index for STM (c), and floating time (d) in different groups in rats are shown (n = 7–12/group). Anti: Anti-IL-1β; I: ipsilateral; C: contralateral; no antibody and IgG were applied in Con + sham group; *P < .05; **P < .01 ***P < .001 vs. Con + sham group; #P < .05; ##P < .01; ###P < .001 vs. I-IgG + SNI group. SNI: spared nerve injury.
Figure 4.
Figure 4.
Peri-sciatic application of anti-IL-1β at injured sciatic nerve prevents the overexpression of IL-1β induced by SNI in rats. (a, b) The Western blots show the expression of IL-1β in SDH, hippocampus, PFC, NAcc, and AMG in the different treatment groups as indicated (n = 5–6 in each group). Anti: Anti-IL-1β; *P < .05; **P < .01 ***P < .001 vs. sham group; #P < .05; ##P < .01; ###P < .001 vs. IgG + SNI group. SNI: spared nerve injury; SDH: spinal dorsal horn; NAcc: nucleus accumbens; AMG: amygdala.
Figure 5.
Figure 5.
Genetic deletion of IL-1R1 prevents both abnormal behaviors and the overexpression of IL-1β induced by SNI in mice. (a–d) Paw withdrawal threshold, recognition index for STM, and floating time in wild type (WT) mice with or without SNI and IL-1R1 knockout (KO) mice with SNI or without SNI are shown (n = 7–12/group). (e) The Western blots show the expression of IL-1β in SDH, hippocampus, PFC, NAcc, and AMG in the different groups as indicated (n = 5–6 in each group). *P < .05; **P < .01; ***P < .001 vs. WT naïve mice; #P < .05; ##P < .01; ###P < .001 vs. WT + SNI mice. SNI: spared nerve injury; SDH: spinal dorsal horn; NAcc: nucleus accumbens; AMG: amygdala.
Figure 6.
Figure 6.
Intravenous injection of IL-1β induces mechanical allodynia, memory deficit, and depressive behavior and upregulates IL-1β in CNS in rats. (a) PWTs in bilateral handpaws decreased in the rats receiving tail-intravenous injection of rrIL-1β (100 ng/ml, 150 μl in volume per rat, t.i.d, for 7 days, n = 31) but not in the rats with vehicle injection (n = 30) in the same way. rrIL-1β or vehicle was injected at day 0. (b, c) The recognition index for STM and the floating time measured two weeks after first rrIL-1β or vehicle injection in the same cohort of rats are shown. (d, e) Paw withdrawal thresholds in left side measured at 13 days were correlated with neither short-term memory index nor the floating time in the 31 rats receiving injection of rrIL-1β. (f) The expression of IL-1β in different regions of CNS was increased as assessed after behavioral tests. *P < .05; **P < .01 ***P < .001 vs. vehicle group. SDH: spinal dorsal horn; NAcc: nucleus accumbens; AMG: amygdala.
Figure 7.
Figure 7.
The activation of microglia in the spinal dorsal horn or CNS regions is interfered by the change of peripheral IL-1β signaling. (a–c) Representative pictures showing that microglia were activated in different regions of the CNS at 12 days following SNI (a) and was blocked by peri-sciatic application of IL-1β neutralizing antibody (b) (n = 3/group). Iba1 is a microglial marker. (c) Tail-intravenous injection of rrIL-1β but not vehicle induced the activation of microglia. (n = 3–4/group). (d) Bar graph summarizing the number of Iba1 positive cells area in various regions of the CNS in different treatment groups. *P < .05; **P < .01; ***P < .001 vs. sham group. ##P < .01; ###P < .001 vs. IgG + SNI group. SDH: spinal dorsal horn; NAcc: nucleus accumbens; AMG: amygdala.

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