Selective Targeting of Serotonin 5-Ht1a and 5-Ht3 Receptors Attenuates Acute and Long-Term Hypersensitivity Associated with Neonatal Procedural Pain

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

*Corresponding author for this work

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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.
Original languageEnglish
Article number872587
Number of pages14
JournalFrontiers in pain research (Lausanne, Switzerland)
Publication statusPublished - 27 Apr 2022

Bibliographical note

Funding Information:
The authors would like to thank Wouter Gerrits (Department of Translational Neuroscience, Maastricht University) for providing technical support during experiments and surgeries.

Funding Information:
AK received financial support for this research provided by the Pain Knowledge Centre from Maastricht and an institutional grant from University Maastricht, School of Mental Health and Neuroscience.

Publisher Copyright:
Copyright © 2022 de Kort, Joosten, Patijn, Tibboel and van den Hoogen.


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