Cortex glial cells activation, associated with lowered mechanical thresholds and motor dysfunction, persists into adulthood after neonatal pain

Abstract

We investigated if changes in glial activity in cortical areas that process nociceptive stimuli persisted in adult rats after neonatal injury. Neonatal pain was induced by repetitive needle prickling on the right paw, twice per day for 15 days starting at birth. Wistar rats received either neonatal pain or tactile stimulation and were tested behaviorally for mechanical withdrawal thresholds of the paws and gait alterations, after 15 (P15) or 180 (P180) days of life. Brains from rats on P15 and P180 were immunostained for glial markers (GFAP, MCP-1, OX-42) and the following cortical areas were analyzed for immunoreactivity density: prefrontal, anterior insular, anterior cingulated, somatosensory and motor cortices. Withdrawal thresholds of the stimulated paw remained decreased on P180 after neonatal pain when compared to controls. Neonatal pain animals showed increased density for both GFAP and MCP-1 staining, but not for OX-42, in all investigated cortical areas on both experimental times (P15 and P180). Painful stimuli in the neonatal period produced pain behaviors immediately after injury that persisted in adult life, and was accompanied by increase in the glial markers density in cortical areas that process and interpret pain. Thus, long-lasting changes in cortical glial activity could be, at least in part, responsible for the persistent hyperalgesia in adult rats that suffered from neonatal pain.

Repeated neonatal needle‐prick stimulation increases inflammatory mechanical hypersensitivity in adult rats

“…The sensitive period in regard to long‐term alterations in nociceptive responses is limited to the first 7–10 days of life in the rat (Ren et al, 2005). However the detection of a more precise age in neonatal rats and the study of the effects of pain and stress interactions in these animals would contribute to a better understanding of this important topic so in this study we used a model with painful stimuli from PND 2 to PND 15 (Sanada et al, 2014; Carmo Ede et al, 2016; Nuseir et al, 2017).…”

“…Many studies have demonstrated that the neurogenic effects of early repetitive noxious experiences are limited to PND 1 (postnatal day 1) and PND 8 (Malheiros et al, 2014; Amaral et al, 2015; den Hoogen et al, 2017) and that repetitive stimulation of the nociceptive system in a rat model using needle pricks in the hind‐paw closely mimics the clinical situation of infants in NICU (den Hoogen et al, 2017). In contrast, repeated procedural pain during the first 14–15 days of life in rat pups resulted in impairment of long‐term memory (Nuseir et al, 2017) and sensory and motor functions (Sanada et al, 2014; Carmo Ede et al, 2016). In fact, rat pups are born premature and the first week of their lives corresponds to gestation weeks 24–36 in human babies (Anand et al, 1999; Andreollo et al, 2012; Dutta and Sengupta, 2016) while week two corresponds to newborn human babies (Sengupta, 2013), so we chose to study the effect of painful stimuli during the first 15 days.…”

“…At the spinal cord level, alterations of spinal nociceptive processing (Ririe et al, 2008), changes in the dorsal horn circuits (Beggs et al, 2002), and altered gene expression (Ren et al, 2005; van den Hoogen et al, 2018b) were described in rats. At the brain level, long‐lasting changes in brain function, such as exploration and motivation (Low and Fitzgerald, 2012), or memory (Nuseir et al, 2017) and in brain structure, like increased glial activity in cortical areas that process pain behaviours (Sanada et al, 2014), were also described in adult rats after early‐life pain experience.…”

Role of the Prefrontal Cortex in Pain Processing

“…Painful stimuli in the neonatal period produces pain behaviors immediately after injury that persist into adult life, and is accompanied by an increase in glial activation in cortical areas that process or interpret pain. These results suggest a role of glial cells in the PFC, in the chronification of pain [ 200 ].…”

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals

“…The American Veterinary Medical Association (AVMA) has stated that “animal pain and suffering are clinically important conditions that adversely affect an animal's quality of life” (American Veterinary Medical Association, ). In addition to the negative impact that occurs at the time of the painful insult, untreated pain in both human and animal neonates may cause hypersensitivity to subsequent painful procedures (McCracken, Waran, Mitchinson, & Johnson, ; Page, ; Taddio, Goldbach, Ipp, Stevens, & Koren, ; Taddio, Katz, Ilersich, & Koren, ) and an increased propensity for long‐term pain (Hermann, Hohmeister, Demirakca, Zohsel, & Flor, ; Miranda et al., ; Page, ; Ren et al., ; Sanada et al., ; Walker, Tochiki, & Fitzgerald, ). These nociceptive responses can be alleviated with the appropriate use of analgesia during the initial painful stimulus (Page, ; Taddio et al., ).…”