Elsevier

Neuropharmacology

Volume 137, 15 July 2018, Pages 114-132
Neuropharmacology

BDNF contributes to the neonatal incision-induced facilitation of spinal long-term potentiation and the exacerbation of incisional pain in adult rats

https://doi.org/10.1016/j.neuropharm.2018.04.032Get rights and content

Highlights

  • Neonatal incision exacerbates incisional pain and microglial reactivity in adult rats.

  • The mRNA and protein expression of spinal BDNF is upregulated by neonatal incision.

  • Spinal LTP induced by BDNF or HFS are facilitated by neonatal incision.

  • Minocycline attenuates spinal LTP facilitation via BDNF.

Abstract

Neonatal surgical injury exacerbates spinal microglial reactivity, modifies spinal synaptic function, leading to exaggerated pain hypersensitivity after adult repeated incision. Whether and how the alteration in microglial reactivity and synaptic plasticity are functionally related remain unclear. Previously, we and others have documented that spinal brain-derived neurotrophic factor (BDNF), secreted from microglia, contributes to long-term potentiation (LTP) in adult rodents with neuropathic pain. Here, we demonstrated that the mRNA and protein expression of spinal BDNF are significantly upregulated in adult rats subjected to neonatal incision and adult repeated incision (nIN-IN). Neonatal incision facilitates spinal LTP induced by BDNF or high frequency electrical stimulation after adult incision, including a decreased induction threshold and an increased magnitude of LTP. Coincidently, inhibition of spinal BDNF abrogates the LTP facilitation, alleviates the mechanical allodynia and thermal hyperalgesia in nIN-IN rats. By contrast, spinal application of exogenous BDNF in the adult rats with a single neonatal incision mimics the LTP facilitation and pain hypersensitivity, which have been found in nIN-IN rats. Exogenous BDNF-induced exacerbation of pain hypersensitivity could be blocked by BDNF inhibitor. In addition, blockade of microglial reactivity by intrathecal application of minocycline attenuates the elevation of BDNF and the LTP facilitation, and also, alleviates pain hypersensitivity in nIN-IN rats. In conclusion, spinal BDNF, at least partly derived from microglia, contributes to the neonatal incision-induced facilitation of spinal LTP and to the exacerbation of incisional pain in adult rats. Thus, spinal BDNF may combine the changes of microglial reactivity and synaptic plasticity in nIN-IN 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.single bondF. 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).

References (85)

  • J.L. LaPrairie et al.

    Long-term impact of neonatal injury in male and female rats: sex differences, mechanisms and clinical implications

    Front. Neuroendocrinol.

    (2010)
  • V. Lessmann

    Neurotrophin secretion: current facts and future prospects

    Prog. Neurobiol.

    (2003)
  • J. Li et al.

    Neonatal tissue damage facilitates nociceptive synaptic input to the developing superficial dorsal horn via NGF-dependent mechanisms

    Pain

    (2011)
  • J. Li

    Deficits in glycinergic inhibition within adult spinal nociceptive circuits after neonatal tissue damage

    Pain

    (2013)
  • Y.L. Liu

    Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK

    Neuropharmacology

    (2007)
  • Y. Nagakura

    The sensitization of a broad spectrum of sensory nerve fibers in a rat model of acute postoperative pain and its response to intrathecal pharmacotherapy

    Pain

    (2008)
  • H. Nakata et al.

    Brain-derived neurotrophic factor regulates AMPA receptor trafficking to post-synaptic densities via IP3R and TRPC calcium signaling

    FEBS Lett.

    (2007)
  • S. Ohnami

    Role of voltage-dependent calcium channel subtypes in spinal long-term potentiation of C-fiber-evoked field potentials

    Pain

    (2011)
  • E.M. Pogatzki

    Effect of plantar local anesthetic injection on dorsal horn neuron activity and pain behaviors caused by incision

    Pain

    (2002)
  • X.X. Qu

    Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain

    Exp. Neurol.

    (2009)
  • L.J. Rygh

    Different increase in C-fibre evoked responses after nociceptive conditioning stimulation in sham-operated and neuropathic rats

    Neurosci. Lett.

    (2000)
  • J. Sandkuhler et al.

    Hyperalgesia by synaptic long-term potentiation (LTP): an update

    Curr. Opin. Pharmacol.

    (2012)
  • M.K. Song

    The facilitating effect of systemic administration of Kv7/M channel blocker XE991 on LTP induction in the hippocampal CA1 area independent of muscarinic activation

    Neurosci. Lett.

    (2009)
  • Z.W. Suo

    Striatal-enriched phosphatase 61 inhibited the nociceptive plasticity in spinal cord dorsal horn of rats

    Neuroscience

    (2017)
  • F. Svendsen

    Behavioural effects of LTP-inducing sciatic nerve stimulation in the rat

    Eur. J. Pain

    (1999)
  • S.M. Walker

    Persistent changes in peripheral and spinal nociceptive processing after early tissue injury

    Exp. Neurol.

    (2016)
  • S.M. Walker

    Hindpaw incision in early life increases the hyperalgesic response to repeat surgical injury: critical period and dependence on initial afferent activity

    Pain

    (2009)
  • G.G. Xing

    Long-term synaptic plasticity in the spinal dorsal horn and its modulation by electroacupuncture in rats with neuropathic pain

    Exp. Neurol.

    (2007)
  • B. Ying

    Involvement of spinal glia in tetanically sciatic stimulation-induced bilateral mechanical allodynia in rats

    Biochem. Biophys. Res. Commun.

    (2006)
  • P.K. Zahn

    Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain

    Pain

    (2005)
  • Y. Zhang

    Estrogen facilitates spinal cord synaptic transmission via membrane-bound estrogen receptors implications for pain hypersensitivity

    J. Biol. Chem.

    (2012)
  • J. Zhao

    Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain

    Mol. Cell. Neurosci.

    (2006)
  • L.J. Zhou

    BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn

    Exp. Neurol.

    (2008)
  • H.Q. Zhu

    Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats

    Exp. Neurol.

    (2015)
  • M. Zimmermann

    Ethical guidelines for investigations of experimental pain in conscious animals

    Pain

    (1983)
  • M. Zimmermann

    Pathobiology of neuropathic pain

    Eur. J. Pharmacol.

    (2001)
  • A. Balkowiec et al.

    Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons

    J. Neurosci.

    (2002)
  • S. Beggs

    Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity

    Brain

    (2012)
  • E.E. Benarroch

    Brain-derived neurotrophic factor Regulation, effects, and potential clinical relevance

    Neurology

    (2015)
  • C. Bian

    Involvement of CX3CL1/CX3CR1 signaling in spinal long term potentiation

    PLoS One

    (2015)
  • T.J. Brennan

    Characterization of a rat model of incisional pain

    Pain

    (1996)
  • M. Canossa

    Neurotrophin release by neurotrophins: implications for activity-dependent neuronal plasticity

    Proc. Natl. Acad. Sci. U. S. A

    (1997)
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