BDNF contributes to the neonatal incision-induced facilitation of spinal long-term potentiation and the exacerbation of incisional pain in adult rats
Introduction
Both clinical and preclinical studies have demonstrated that tissue injury during a critical period in early life leads to an exacerbated pain hypersensitivity after repeated noxious stimulation or injury (Gong et al., 2016; Schwaller et al., 2015; Soens et al., 2015; Valeri et al., 2016), suggesting that the neonatal tissue damage may induce a long-term “priming” of pain circuits, which is proposed as a contributor of exaggerated pain response to the repeated trauma. Spinal dorsal horn may play a vital role in the neonatal incision-induced exacerbation of adult incisional pain, for the reason that the spinal dorsal horn-mediated priming of adult pain sensitivity is revealed by electrical stimulation of the tibial nerve without adult repeated incision (Beggs et al., 2012). However, the underlying mechanisms remain unclear.
Spinal microglial reactivity is elevated in adult incision with previous neonatal incision (Beggs et al., 2012; Schwaller et al., 2015). Spinal microglia can synthesize and secrete brain-derived neurotrophic factor (BDNF), which can modify neuronal axonal growth, dendritic maturation and synaptic plasticity, thus participates in many types of pain (Benarroch, 2015). Especially, we have previously found that spinal BDNF contributes to neuropathic pain in adult rats with spinal nerve ligation (Ding et al., 2015; Geng et al., 2010), and spinal nerve ligation-evoked neuropathic pain and incisional pain both arise, at least partly, from injuries to peripheral nerves (Kehlet et al., 2006). Moreover, only microglia-derived BDNF leads to neuropathic pain in adult rodents by shifting the neuron-glia interactions (Coull et al., 2005; Zhao et al., 2006). Additionally, spinal microglia-secreted BDNF is involved in immune profile switches in adolescent mice with neonatal peripheral nerve injury (McKelvey et al., 2015). However, the potential role of spinal BDNF in neonatal incision-induced exacerbation of adult incisional pain is unknown.
A growing body of evidence shows that neonatal injury alters synaptic function within adult spinal nociceptive circuits. Adult spinal projection neurons from neonatal incised mice exhibit a significant increase in the efficacy of primary afferent synapses (Li et al., 2013, 2015). Neonatal incision facilitates the long-term potentiation (LTP) in adult projection neurons (Li and Baccei, 2016). Moreover, it has been proved that BDNF is essential in several protocols-induced LTP in adult spinal cord and some brain regions (Garraway and Huie, 2016; Meis et al., 2012; Sakata et al., 2013). Also, we have previously documented that BDNF induces spinal LTP in mature spinal cord (Ding et al., 2015). However, whether microglia-derived BDNF regulates spinal LTP in neonatal incision-induced exacerbation of adult incisional pain is still unknown.
In this study, we investigated whether the upregulation of spinal BDNF contributes to the facilitation of spinal LTP and plays a role in neonatal incision-facilitated adult incisional pain. Our results show that the repeated incisions in neonatal period and adulthood produce a remarkable upregulation of spinal BDNF, at least partly derived from microglia, which facilitates both BDNF- and electrical-induced spinal LTP and exacerbates pain hypersensitivity. Thus, spinal BDNF may combine the alternations of microglial reactivity and synaptic plasticity in adult rats subjected to repeated incisions.
Section snippets
Chemicals, antibodies, and animals
BDNF (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in 0.9% sterile saline as a 0.5 μg/μl stock solution. Tropomyosin related kinase B-immunoglobulin G fusion protein (TrkB-Fc) (R&D systems, Minneapolis, USA) and IgG (Sigma-Aldrich) were dissolved in 0.01 M phosphate buffer saline (PBS) containing 0.1% bovine serum albumin (BSA) as a concentrated stock solution (1 μg/μl). The stock solution was stored at −20 °C, and freshly diluted to working concentration. Minocycline (Sigma-Aldrich) was
Neonatal incision enhances the adult incision-induced pain hypersensitivity and microglial activity in the spinal dorsal horn
To confirm the impact of neonatal incision to adult incision-induced pain hypersensitivity, the paw withdrawal threshold (PWT) and thermal withdrawal latency (PWL) were observed before and after adult hindpaw incision. For the reason that neonatal incision increased baseline pain thresholds of adult rats (Walker et al., 2015), the mechanical and heat pain thresholds were shown as percentage change from baseline in our study. We found that the PWT and PWL were both decreased by 15–63% in adult
Discussion
Several studies suggest a vital role of spinal BDNF in long-term effects of neonatal injury (Beggs et al., 2012; McKelvey et al., 2015). Spinal microglia, which can secrete BDNF, are activated in adult incision rats with previous neonatal incision (nIN-IN rats) (Beggs et al., 2012). Here we provide evidence showing that spinal BDNF plays an important role in neonatal incision-primed adult incisional pain, consistent with previous findings that spinal BDNF contributes to chronic pain in adults (
Conflicts of interest
The authors declare that they have no competing interests.
Authors' contributions
X. Ding carried out the ELISA, the real-time PCR and the electrophysiological studies, participated in the design of the study and drafted the manuscript. Y.-J. Liang participated in the immunohistochemical studies. L. Su participated in the statistical analysis and the behavioral tests. F.F. Liao and D. Fang participated in the behavioral tests. J. Tai participated in the design of the study and the statistical analysis of data. G.-G. Xing contributed to the conception and design of the study,
Acknowledgments
The present work was supported by grants from the National Natural Science Foundation of China (81500942, 81671085, 81371237 and 61527815) and the Beijing Talents Fund (2015000021469G204).
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