Neonatal procedural pain affects state, but not trait anxiety behavior in adult rats

Kort, Anne R de; Joosten, Elbert A.J.; Patijn, Jacob; Tibboel, Dick; Hoogen, Nynke J. van den

doi:10.1002/dev.22210

Cited by 13 publications

(18 citation statements)

References 42 publications

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“…Our results show that adult skin injury does indeed produce a marked increase in evoked theta S1–mPFC connectivity, highly correlated to behavioural pain sensitivity in both ELP and control groups, but this increase is prolonged in ELP, lasting for 4 days compared to only one day in controls. Our data suggests that the connection between sensory and affective pain processing is enhanced in ELP rats which may underpin the wider social, emotional and cognitive life-long impact of ELP beyond increased pain perception (Ranger et al, 2018; de Kort et al, 2021; Ririe et al, 2021).…”

Section: Discussionmentioning

confidence: 72%

Early life pain experience changes adult functional pain connectivity in the rat somatosensory and the medial prefrontal cortex

Chang

Fabrizi

Fitzgerald

2022

Preprint

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Early life pain experience (ELP) alters adult pain behaviour and increases injury induced pain hypersensitivity, but the effect of ELP upon adult functional brain connectivity is not known. We have performed continuous local field potential (LFP) recording in the awake adult male rats to test the effect of ELP upon functional cortical connectivity related to pain behaviour. Somatosensory cortex (S1) and medial prefrontal cortex (mPFC) LFPs evoked by mechanical hindpaw stimulation were recorded simultaneously with pain reflex behaviour for 10 days after adult skin injury. We show that, post adult injury, S1 LFP delta and gamma energy and S1 LFP delta/gamma frequency modulation are significantly increased in ELP rats compared to controls. Adult injury also induces increases in S1-mPFC functional connectivity which is significantly prolonged in ELP rats, lasting 4 days compared to 1 day in controls. Importantly, the increases in LFP energy and connectivity in ELP rats were directly correlated with increased behavioural pain hypersensitivity. Thus, early life pain (ELP) alters adult brain functional connectivity, both within and between cortical areas involved in sensory and affective dimensions of pain. The results reveal altered brain connectivity as a mechanism underlying the effects of early life pain upon adult pain perception.Significance StatementPain and stress in early life has a lasting impact upon pain behaviour and may increase vulnerability to chronic pain in adults. Here we record pain-related cortical activity and simultaneous pain behaviour in awake adult male rats previously exposed to pain in early life. We show that functional connectivity within and between the somatosensory cortex and the medial prefrontal cortex is increased in these rats and that these increases are correlated with their behavioural pain hypersensitivity. The results reveal that early life pain alters adult brain connectivity, which may explain the impact of childhood pain upon adult chronic pain vulnerability.

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Section: Discussionmentioning

confidence: 72%

Early life pain experience changes adult functional pain connectivity in the rat somatosensory and the medial prefrontal cortex

Chang

Fabrizi

Fitzgerald

2022

Preprint

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“…Neonatal repetitive needle pricking leads to acute hypersensitivity and increased duration of post-operative recovery after re-injury in adulthood ( 12 – 17 , 23 ). Here, we show that selective neonatal agonism of the 5-HT1aR using buspirone reduces the acute hypersensitivity associated with neonatal procedural pain, whereas antagonizing the 5-HT3R using ondansetron attenuates the long-term consequences of neonatal procedural pain.…”

Section: Discussionmentioning

confidence: 99%

“…The open field test was used to evaluate locomotor activity and anxiety-related behavior in adulthood (at 8 weeks of age) ( 23 ). Briefly, individual animals were placed into the center of a plexiglass square arena (100 × 100 × 40cm), and allowed to explore the environment for 20 min.…”

Section: Methodsmentioning

confidence: 99%

“…The Elevated Zero Maze (EZM) was used to assess anxiety-related behavior ( 23 ). Briefly: a black annular maze (100 cm diameter, 10 cm path width) was placed 70 cm above floor level, with four equal quadrants (two opposite quadrants are “closed” by black Perspex walls, two remaining quadrants are “open”).…”

Section: Methodsmentioning

confidence: 99%

“…Both clinical and fundamental studies have provided evidence for neonatal painful stimulation induced alterations in the developing nociceptive network, resulting in subsequent long-term alterations in pain sensitivity ( 3 , 8 – 11 ) and exacerbated sensitivity after re-injury in adulthood ( 12 – 17 ). Neonatal procedural pain induced effects are not limited to the nociceptive network but also affect anxiety behavior amongst others ( 18 – 23 ), suggesting a common neurocircuitry that regulates both pain and anxiety behavior is involved.…”

Section: Introductionmentioning

confidence: 99%

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Selective Targeting of Serotonin 5-HT1a and 5-HT3 Receptors Attenuates Acute and Long-Term Hypersensitivity Associated With Neonatal Procedural Pain

et al. 2022

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Neonatal painful procedures causes acute pain and trigger long-term changes in nociceptive processing and anxiety behavior, highlighting the need for adequate analgesia during this critical time. Spinal serotonergic receptors 5-HT1a and 5-HT3 play an important role in modulating incoming nociceptive signals in neonates. The current study aims to attenuate acute and long-term hypersensitivity associated with neonatal procedural pain using ondansetron (a 5-HT3 antagonist) and buspirone (a 5-HT1a agonist) in a well-established rat model of repetitive needle pricking. Sprague-Dawley rat pups of both sexes received ondansetron (3 mg/kg), buspirone (3 mg/kg) or saline prior to repetitive needle pricks into the left hind-paw from postnatal day 0–7. Control animals received tactile stimulation or were left undisturbed. Acute, long-term, and post-operative mechanical sensitivity as well as adult anxiety were assessed. Neonatal 5-HT1a receptor agonism completely reverses acute hypersensitivity from P0-7. The increased duration of postoperative hypersensitivity after re-injury in adulthood is abolished by 5-HT3 receptor antagonism during neonatal repetitive needle pricking, without affecting baseline sensitivity. Moreover, 5-HT1a and 5-HT3 receptor modulation decreases adult state anxiety. Altogether, our data suggests that targeted pharmacological treatment based on the modulation of spinal serotonergic network via the 5-HT1a and 5-HT3 receptors in neonates may be of use in treatment of neonatal procedural pain and its long-term consequences. This may result in a new mechanism-based therapeutic venue in treatment of procedural pain in human neonates.

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Effects of different types of neonatal pain on somatosensory and cognitive development in male juvenile rats

Ling,

Wang,

Zheng

et al. 2023

Brain and Behavior

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BackgroundPremature infants are inevitably exposed to painful events, including repetitive procedures, inflammation, or mixed stimulation that may induce long‐term behavioral outcomes. Here, we set up three neonatal painful models to investigate their long‐term effect on somatosensation and cognition.MethodsThree types of neonatal pain models in rat were set up. Rat pups were randomly assigned to four groups. The needling pain (NP) group received repetitive needle pricks on the paws from the day of birth (PD0) to postnatal day 7 (PD7) to mimic the diagnostic and therapeutic procedures. The inflammatory pain (IP) group received the injection of carrageenan into the left hindpaw at PD3 to induce IP in peripheral tissues. The mixed pain group received a combination of the NP and IP (NIP). The control (CON) group was untreated. We performed behavioral and biochemical testing of juvenile rats (PD21–PD26).ResultsThe NIP group showed a longer hypersensitivity than the NP group, when given a secondary inflammatory stimulation. NP led to insensitivity to anxiety‐causing stimuli and impairment of fear memory both aggravated by NIP. NP reduced the expression of synapse‐related molecules (GluN1/PSD95/GFAP) in the medial prefrontal cortex, and NIP exacerbated this decrease. The corticosterone secretion in the NIP group increased after the behavioral task, compared with those in other three groups.ConclusionA combination of NP with inflammation occurring in the neonatal period might aggravate the adverse effects of each on somatosensory and cognitive development of rats, the mechanism of which might be associated with the increase of corticosterone secretion and the dysregulation of synaptic molecules.

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Neonatal procedural pain affects state, but not trait anxiety behavior in adult rats

Cited by 13 publications

References 42 publications

Early life pain experience changes adult functional pain connectivity in the rat somatosensory and the medial prefrontal cortex

Early life pain experience changes adult functional pain connectivity in the rat somatosensory and the medial prefrontal cortex

Selective Targeting of Serotonin 5-HT1a and 5-HT3 Receptors Attenuates Acute and Long-Term Hypersensitivity Associated With Neonatal Procedural Pain

Effects of different types of neonatal pain on somatosensory and cognitive development in male juvenile rats

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