Adult spinal opioid receptor μ1 expression after incision is altered by early life repetitive tactile and noxious procedures in rats

Abstract

Clinical and experimental data suggests that noxious stimulation at critical stages of development results in long‐term changes on nociceptive processing in later life. Here, we use an established, well‐documented rat model of repetitive noxious procedures closely mimicking the clinical situation in the NICU. In order to understand molecular changes underlying the long‐term consequences of repetitive stimulation of the developing nociceptive system the present study aims to analyze the presence of the µ‐opioid‐receptor‐1 (OPRM1). Neonatal rats received either four needle pricks per day in the left hind‐paw from postnatal day 0–7 as a model of procedural pain in infancy. Control pups were handled in the same way but were instead tactile stimulated, or were left undisturbed. At the age of 8 weeks, all animals received an ipsilateral hind‐paw incision as a model for post‐operative pain, and mechanical sensitivity was tested at multiple time‐points. Before, and 1 or 5 days post‐incision, spinal cord tissue was collected for immunostaining of opioid receptor OPRM1. Semi‐quantitative immunocytochemical analysis of superficial laminae in lumbar spinal dorsal horn revealed that: (1) early life repetitive tactile or noxious procedures do not alter baseline levels of OPRM1 staining intensity and (2) early life repetitive tactile or noxious procedures lead to a decrease in OPRM1 staining intensity 5 days after incision in adulthood compared to undisturbed controls. We conclude that early life repetitive tactile or noxious procedures affect the intensity of OPRM1‐immunoreactivity in the lumbar superficial spinal cord dorsal horn after adulthood injury, without affecting baseline intensity. © 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 78: 417–426, 2018

Repetitive noxious stimuli during early development affect acute and long-term mechanical sensitivity in rats

“…Previous studies by our group using this model did not show mechanical hyposensitivity in later life. 17,23,29 However, several studies have suggested changes in nociception in adulthood after early life maternal separation, 30,31 showing reduction in sensitivity in adult females after neonatal maternal separation. 31 Possibly, the cumulative separation stress and needle pricks led to hyposensitivity as observed here.…”

Anatomical changes in descending serotonergic projections from the rostral ventromedial medulla to the spinal dorsal horn following repetitive neonatal painful procedures

“…The decrease in spinal 5-HT staining intensity may contribute to the sensitized spinal nociceptive network after neonatal procedural pain due to lower levels of descending serotonergic projections and serotonin levels in the dorsal horn. Despite the observed anatomical and biochemical changes in the spinal nociceptive network after procedural neonatal pain, mechanical sensitivity at baseline is unaltered after neonatal procedural pain (de Kort, Joosten, Patijn, Tibboel, & van den Hoogen, 2021b; Knaepen et al, 2013;van den Hoogen et al, 2016;van den Hoogen, van Reij, Patijn, Tibboel, & Joosten, 2018). In line with this, depletion of descending serotonergic projections does not alter mechanical or thermal sensitivity (Minor et al, 1988;Palm et al, 2008;Wei et al, 2010).…”

Methadone effectively attenuates acute and long-term consequences of neonatal repetitive procedural pain in a rat model

“…Mechanical sensitivity during development and after re-injury in adulthood After weaning at the age of 3 weeks, mechanical sensitivity was tested weekly until adulthood using Plantar application of Von Frey filaments as described previously. 18,21,33 In short, animals were placed individually in Plexiglass chambers on a mesh floor and left to habituate. A range of Von Frey filaments (0.4, 0.6, 1.0, 2.0, 4.0, 6.0, 8.0, 15.0 and 26.0 g) was applied for 5 s onto the midplantar surface of both hind paws, starting with 1.0 g. If no response was observed, the filament with a larger force was applied next.…”

“…[14][15][16][17][18][19][20] The changes in pain behaviour have been correlated to underlying changes in spinal and supraspinal anatomy and functionality. 14,17,21,22 Previously, we have shown that neonatal repetitive procedural pain leads to spinal hyperexcitability, expressed as an increased firing of secondary pain transmission neurons. 17 This increase in firing is possibly linked to N-methyl-D-aspartate receptor (NMDA-R)-mediated central sensitization lasting into adulthood.…”