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<p>The serotonergic system plays a central role in pain modulation, exerting inhibitory or facilitatory effects depending on receptor subtype and developmental stage. Early-life pain (ELP), particularly during neonatal neurodevelopment, can disrupt serotonergic maturation and increase susceptibility to chronic pain in adulthood. This systematic review evaluated rodent models of early-life serotonergic perturbations—pharmacological, environmental, and immunological—and their effects on nociception and long-term vulnerability to chronic pain. A systematic search was conducted in PubMed, Web of Science, Scopus, and Science Direct (2000–2025) following PRISMA guidelines. Eligible studies (i) used rodent models, (ii) assessed early-life pain or stress, (iii) evaluated serotonergic function, and (iv) reported nociceptive outcomes. From 9,814 records, eight experimental studies met criteria: seven in rats and one in mice. Interventions included SSRIs (fluoxetine, escitalopram), tricyclic antidepressants (desipramine), serotonin depletion (pCPA, 5,7-DHT), 5-HT1A agonists (buspirone), and exposure to anti-5-HT antibodies. Environmental stressors such as maternal separation and prenatal stress were also examined. Pain was assessed using formalin (4 studies), hot plate (2), von Frey and Hargreaves (1), and flinch-jump (1). Most studies reported heightened nociceptive sensitivity after early-life serotonergic disruption (e.g., maternal separation, serotonin depletion, adolescent fluoxetine), whereas some interventions normalized or reduced hyperalgesia (e.g., buspirone, prenatal fluoxetine). Methodological quality was moderate, with consistent reporting of ethical approval and procedures but frequent lack of sample size justification, blinding, attrition, or adverse event monitoring. Although none of the included studies employed formal chronic pain models, they consistently reported long-lasting alterations in nociceptive sensitivity and serotonergic maturation, which are mechanisms known to increase vulnerability to persistent nociceptive sensitization rather than chronic pain.</p><p><i>Registration information</i>: The systematic review protocol was registered with PROSPERO: CRD420251133004.</p>

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Serotonin-related rodent models of early-life exposure relevant for neurodevelopmental vulnerability to altered adult nociception: systematic review

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月10日

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  • Gabrielly Santos Pereira,
  • Ravena Carolina de Carvalho,
  • Marcelo Lourenço da Silva

摘要

The serotonergic system plays a central role in pain modulation, exerting inhibitory or facilitatory effects depending on receptor subtype and developmental stage. Early-life pain (ELP), particularly during neonatal neurodevelopment, can disrupt serotonergic maturation and increase susceptibility to chronic pain in adulthood. This systematic review evaluated rodent models of early-life serotonergic perturbations—pharmacological, environmental, and immunological—and their effects on nociception and long-term vulnerability to chronic pain. A systematic search was conducted in PubMed, Web of Science, Scopus, and Science Direct (2000–2025) following PRISMA guidelines. Eligible studies (i) used rodent models, (ii) assessed early-life pain or stress, (iii) evaluated serotonergic function, and (iv) reported nociceptive outcomes. From 9,814 records, eight experimental studies met criteria: seven in rats and one in mice. Interventions included SSRIs (fluoxetine, escitalopram), tricyclic antidepressants (desipramine), serotonin depletion (pCPA, 5,7-DHT), 5-HT1A agonists (buspirone), and exposure to anti-5-HT antibodies. Environmental stressors such as maternal separation and prenatal stress were also examined. Pain was assessed using formalin (4 studies), hot plate (2), von Frey and Hargreaves (1), and flinch-jump (1). Most studies reported heightened nociceptive sensitivity after early-life serotonergic disruption (e.g., maternal separation, serotonin depletion, adolescent fluoxetine), whereas some interventions normalized or reduced hyperalgesia (e.g., buspirone, prenatal fluoxetine). Methodological quality was moderate, with consistent reporting of ethical approval and procedures but frequent lack of sample size justification, blinding, attrition, or adverse event monitoring. Although none of the included studies employed formal chronic pain models, they consistently reported long-lasting alterations in nociceptive sensitivity and serotonergic maturation, which are mechanisms known to increase vulnerability to persistent nociceptive sensitization rather than chronic pain.

Registration information: The systematic review protocol was registered with PROSPERO: CRD420251133004.