Effects of Repetitive Exposure to Pain and Morphine Treatment on the Neonatal Rat Brain

Abstract

Background: Untreated exposure to pain in preterm neonates might damage the vulnerable premature brain and alter development. Pain treatment is limited because analgesic agents may also have adverse neurodevelopmental consequences in newborns. Objective: To study the effects of neonatal pain and morphine treatment on the developing brain in a neonatal rat model. Methods: Newborn rats were randomly assigned to: treatment with formalin injections (group 1), saline injections (group 2) and controls receiving no injections (group 3). Treatment was given on postnatal days 1–3 (model A), 1–5 (model B) and 10–12 (model C). Brains were studied histologically and protein expression was evaluated (protein kinase C epsilon and doublecortin). Effects of preemptive morphine treatment were studied in the same models (models A+M and B+M). Results: Formalin injections resulted in increased apoptotic scores in models A and B. Saline injections increased the number of degenerative cells only in model B. Morphine showed protective effects in formalin-treated animals of model A+M and saline-treated animals of model B+M only. In model C, no neurodegenerative effects were detected. The protein expression of doublecortin showed a pain-related upregulation in the thalamus region, whereas protein kinase C epsilon expression was upregulated in the cortex. Conclusions: Severe inflammatory pain and pain caused by repetitive injections in neonatal rats may cause major changes in the developing brain during the first week of life. Morphine may only protect the newborn brain against these changes in specific situations.

Invasive Procedures in Preterm Children: Brain and Cognitive Development at School Age

“…21,22 Repeated stimulation of physiologically immature neurons can lead to excitotoxic damage and increased neuronal cell death. 23,24 24 (24) (12) 0 (0) 12 (24) Child Characteristics n = 101 n = 49 n = 51 P Value…”

Behavioral effects of perinatal opioid exposure

“…Adequate intra-and postoperative analgesia not only modifies the stress response but also has been shown to reduce morbidity and mortality (Lonnqvist and Morton, 2005). Repetitive untreated pain and distress may impair the premature brain and have short-and long-term negative consequences (Duhrsen et al, 2013;Walker, 2014). For example, the effects of neonatal inflammatory pain resulted in decreased locomotor activity in adult rats, and this effect was reduced by morphine pretreatment (Bhutta et al, 2001).…”

“…Additionally, morphine treatment may protect the developing brain from severe pain-induced pathological changes, although only under certain conditions (Duhrsen et al, 2013). Postnatal morphine treatment results in enhanced tail flick latency and a reduced ethanol preference, suggesting an additional positive impact (Duhrsen et al, 2013).…”

Impact of Recurring Technical Pain-Associated Stress in Preterm Infants

“…These outcomes are maintained by records from animal models that have stated both inflammatory pain and stable injections to elevate apoptosis in the neonatal rat brain (Anand KJ & Garg S 2007;Duhrsen L & Simons SH 2013). Afterward, recurring focus to procedural ache appears to impact neonatal brain development.…”

“…Elevated figures of skinflouting procedures were linked with leaner cortical gray substance in 21 beyond 66 cerebral areas evaluated at 7 years of age, mostly involving the frontal and parietal lobes (Duhrsen L, Simons SH, Dzietko M 2013).…”