Physiology & Behavior

Volume 194, 1 October 2018, Pages 497-504

Lipopolysaccharide-mediated inflammatory priming potentiates painful post-traumatic trigeminal neuropathy

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https://doi.org/10.1016/j.physbeh.2018.06.021

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Abstract

We explored the molecular and behavioral effects of a perineural Lipopolysaccharide (LPS)-mediated inflammatory priming on the development and maintenance of painful post-traumatic trigeminal neuropathy (PPTTN) following infra-orbital nerve chronic constriction injury (CCI-IoN) in rats. Rats were pretreated with repetitive perineural injections in the vicinity of the IoN of either LPS or vehicle (Vhcl) before being submitted to CCI-IoN. Orofacial pain-like behaviors (response to Von Frey Filament testing and spontaneous isolated face grooming) were measured during the period of LPS injections (three weeks) and following CCI-IoN surgery (two weeks). Local LPS administration induced an early pain-like behavior (i.e. an increase in spontaneous pain [SP] or mechanical static allodynia [MSA]) in both conditions, and following CCI-IoN, MSA and SP developed earlier and more severely in LPS-pretreated rats than in the control group. Ipsilateral increases of key neuropathic pain mRNA markers in the IoN parenchyma, trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) were observed in CCI-IoN injured animals as compared to controls. Although no significant molecular differences could be observed within the IoN parenchyma between LPS and Vhcl-pretreated animals, a significant increase of key inflammatory cytokine Interleukin 1 beta (IL − 1β) could be found in the TG of LPS-pretreated CCI-injured animals versus controls. Finally, a higher increase of inducible nitric oxide synthase (iNOS) in ipsilateral Sp5C of LPS-pretreated animals was observed as compared to Sp5C of Vhcl-pretreated animals. These results suggest a key role of inflammatory priming in the development and maintenance of PPTTN implicating IL-1β/iNOS-dependent central sensitization mechanisms.

Introduction

Neuropathic pain (NP) induced by injury or disease of the peripheral and central nervous systems often results in major distress and significant alterations in quality of life. In the orofacial region, trigeminal post-traumatic neuropathic pain also referred to as painful post-traumatic trigeminal neuropathy (PPTTN) is one of the most common forms of NP. Accumulating evidence suggests that local neuroinflammation in the peripheral and/or central nervous system, characterized by immune and/or glial activation, plays a key role in the development and maintenance of NP [[1], [2], [3], [4]]. Recent studies also suggest that bacterial infections induce pain through direct or indirect effects on sensory neurons [5, 6]. Most of the common orofacial pain conditions (resulting from dental caries, abscesses, periodontal diseases, trauma or iatrogenic interventions) are caused by microorganisms triggering inflammatory reactions and exposing primary afferent neurons to algogenic substances. Some of these molecules are known to drive phenotypic and functional changes in neurons and glia, immune and vascular cells in the peripheral or central nervous system. For instance, Lipopolysaccharide (LPS) is a Gram-negative bacteria-derived pro-inflammatory saccharide containing three structural components, of which lipid A is the only one to be recognized by the innate immune system [7] through a receptor complex that includes LPS binding protein, CD14, Toll-Like Receptor 4 (TLR4), and MD2 [8], responsible for the development of critical immune responses via LPS/TLR4 signaling stimulation [9].

This pain is attributed to sensitization of nociceptors by either direct and/or indirect effects of bacteria such as inflammatory mediators released by immune cells [10]. Such persistent local inflammatory-mediated sensitization can lead to chronic peripheral and central sensitization [11, 12], well-known mechanisms of NP development [13], especially following subsequent nerve injury. Indeed, [14] who provided an initial exploration of whether prior peripheral inflammatory events may set the stage for exaggerated pain responses to subsequent challenges, found that prior spinal microglial activation by LPS-intraperitoneal injections could contribute to future enhanced pain responses.

Moreover, activation of Toll-Like Receptor 4 (TLR4)-mediated signaling pathway by lipopolysaccharide, has recently been shown to disrupt the blood–nerve barrier, which could be implicated in post-traumatic neuropathic pain development [15]. From a clinical standpoint, we recently suggested that preexisting inflammatory pain could be a risk factor for NP development [16].

Using the model of infra-orbital nerve chronic constriction injury (CCI-IoN), the present study explores the influence of local preexisting neuroinflammation (inflammatory priming) on the development and maintenance of PPTTN in rats, from biomolecular, immunohistochemical and behavioral perspectives.

Section snippets

Animals

Adult male Sprague-Dawley rats (200–250 g) purchased from Laboratoires Janvier (Le Genest-Saint-Isle, France) were housed in a-controlled environment (12/12-h light/dark cycle, light on at 7:00 A.M., T = 22 ± 1 °C) with ad libitum food and water. All the experiments complied with French and International laws and policies regarding the use of animals in neuroscientific research (European Communities Council Directive #87848, Octobre 1987, Ministère de l'Agriculture et de la Forêt, Service…

Mechanical static allodynia

Repeated perineural injections of LPS mediated a significant increase in pain response scores between 1 and 22 days after the first injection, translating as increased MSA, as compared to Vhcl-injected control rats (Fig. 1 A–F). Initially, at day 1, a significant increase in pain scores in LPS-treated rats was observed only for VFF-mediated mechanical stimulations of 6 g or higher (Fig. 1 D–F) whereas at day 8 (following twice-weekly injections of LPS) increased pain scores were observed for…

Discussion

The results from this study suggest that the local neuroinflammation developed following LPS administration in the vicinity of the infra-orbital nerve of naïve rats can induce an inflammatory priming resulting in earlier and more severe neuropathic pain-like behavior in CCI-IoN injured rats. Such effects could be mediated by molecular changes at the central level (TG and Sp5C) but not in the periphery (IoN).

To exclude the effect of progesterone and other female sex hormones we choose to carry…

Acknowledgements

This work was supported by funding from the Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris-Diderot (Paris VII). The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this article.…

Funding

This work was institutionally funded by the University of Paris Diderot, UFR Odontology, to which authors are affiliated. The authors declare no conflict of interest.…

Author contributions

WD and YB designed the research; WD, AM and NM collected the data. WD, NM and YB analyzed the data. YB, NM and WD drafted the manuscript. All authors commented on the manuscript and approved the final version.…