Altered formalin-induced pain and Fos induction in the periaqueductal grey of preadolescent rats following neonatal LPS exposure.

Ihssane Zouikr,Christopher V Dayas,Kenneth W Beagley,Erin J Campbell,Morgan H James,Deborah M Hodgson,Vicki L Clifton,Allan Siegel

doi:10.1371/journal.pone.0098382

Ihssane Zouikr, Christopher V Dayas + Show 6 more

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https://doi.org/10.1371/journal.pone.0098382

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Abstract

Animal and human studies have demonstrated that early pain experiences can produce alterations in the nociceptive systems later in life including increased sensitivity to mechanical, thermal, and chemical stimuli. However, less is known about the impact of neonatal immune challenge on future responses to noxious stimuli and the reactivity of neural substrates involved in analgesia. Here we demonstrate that rats exposed to Lipopolysaccharide (LPS; 0.05 mg/kg IP, Salmonella enteritidis) during postnatal day (PND) 3 and 5 displayed enhanced formalin-induced flinching but not licking following formalin injection at PND 22. This LPS-induced hyperalgesia was accompanied by distinct recruitment of supra-spinal regions involved in analgesia as indicated by significantly attenuated Fos-protein induction in the rostral dorsal periaqueductal grey (DPAG) as well as rostral and caudal axes of the ventrolateral PAG (VLPAG). Formalin injections were associated with increased Fos-protein labelling in lateral habenula (LHb) as compared to medial habenula (MHb), however the intensity of this labelling did not differ as a result of neonatal immune challenge. These data highlight the importance of neonatal immune priming in programming inflammatory pain sensitivity later in development and highlight the PAG as a possible mediator of this process.

Highlights

Neonatal pain experiences such as hindpaw incision or inflammation are known to produce developmentally regulated changes in the nociceptive pathways, and subsequently exaggerated responses to future noxious and non-noxious stimuli [1,2,3]
We have shown that LPS-induced behavioural hyperalgesia observed at postnatal day (PND) 22 is accompanied by increased plasma corticosterone responses and changes in the intrinsic properties of spinal dorsal horn neurons [10]
Pairwise comparisons revealed that LPS treated rats displayed significantly higher flinching responses during the late phase at 20 min post formalin injection when compared to their matched saline control group (p,.05; Figure 1A)

Summary

Introduction

Neonatal pain experiences such as hindpaw incision or inflammation are known to produce developmentally regulated changes in the nociceptive pathways, and subsequently exaggerated responses to future noxious and non-noxious stimuli [1,2,3]. Both clinical and animal studies have shown that changes in endogenous pain modulation can occur as a consequence of neonatal inflammatory pain [4,5,6]. The effects of neonatal pain experiences on processing of pain later in life are well documented, the impact of neonatal exposure to mild stimuli, such as lipopolysaccharide (LPS), on subsequent inflammatory pain responses is less well understood. We have shown that LPS-induced behavioural hyperalgesia observed at postnatal day (PND) 22 is accompanied by increased plasma corticosterone responses and changes in the intrinsic properties of spinal dorsal horn neurons [10]

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