Related Experiment Video
Updated: Jul 16, 2026
A Preterm Rat Model for Pain Studies
Published on: February 9, 2024
Sex differences in formalin-induced pain in prenatally stressed infant rats
Irina P Butkevich1, Gordon A Barr, Elena A Vershinina
1Laboratory of Ontogeny of Nervous System, I.P. Pavlov Institute of Physiology, The Russian Academy of Sciences, St. Petersburg 199034, Russia. but@kolt.infran.ru
Insights
Prenatal stress increases pain sensitivity in male infant rats, but not females, affecting formalin test responses. This suggests hormonal and neuronal changes contribute to sex-specific pain processing in early development.
Area of Science:
- Neuroscience
- Developmental Biology
- Pain Research
Background:
- Prenatal stress is a known factor influencing offspring neurodevelopment and behavior.
- Pain perception and processing can be altered by early life experiences.
- Sexual dimorphism in pain pathways is established, but its developmental origins are not fully understood.
Purpose of the Study:
- To investigate the impact of prenatal stress on nociceptive responses in infant rats.
- To determine if prenatal stress induces sex-specific alterations in pain sensitivity.
- To explore the relationship between hormonal changes, neuronal activity, and pain behavior in stressed and non-stressed infant rats.
Main Methods:
- Utilized the formalin test to assess nociceptive responses in 7-day-old Long-Evans hooded rats.
- Compared behavioral outcomes (flinching, shaking) between prenatally stressed and non-stressed male and female pups.
- Examined neural correlates, including Fos-like immunoreactivity and serotonin levels, in the spinal cord dorsal horn.
Main Results:
- Prenatally stressed pups exhibited enhanced biphasic responses in the formalin test compared to controls.
- Male prenatally stressed pups showed significantly greater pain sensitivity in the second phase than non-stressed males.
- No significant differences in pain sensitivity were observed between prenatally stressed and non-stressed females.
- Stressed males displayed an enhanced second-phase response compared to stressed females.
Conclusions:
- Prenatal stress induces sex-specific alterations in pain processing in infant rats.
- Decreased perinatal testosterone levels in prenatally stressed males may contribute to heightened pain sensitivity.
- The observed sexual dimorphism in pain response mechanisms is evident even before the influence of activational sex hormones.
Abstract:
The aim of this work was to study the effects of prenatal stress on nociceptive responses in the formalin test in female and male infant (7-day-old) Long-Evans hooded rats. Prenatally stressed infant rats displayed biphasic flinching+ shaking behavior whereas non-stressed animals showed only a weak second phase. Pain sensitivity in prenatally stressed males was significantly greater than that of prenatally non-stressed males during the second phase only; there were no differences in pain sensitivity between prenatally stressed and non-stressed females. Moreover prenatally stressed male rats pups demonstrated that the second phase of the response to formalin was enhanced relative to the second phase in stressed females. The current and previous data [Butkevich IP, Barr GA, Mikhailenko VA, Otellin VA. Increased formalin-induced pain and expression of fos neurons in the lumbar spinal cord of prenatally stressed infants rats. Neurosci Lett 2006a;403:222-226] show increased tonic pain in prenatally stressed infant rats and a large increase in the number of formalin-induced fos-like immunoreactivity in the spinal cord dorsal horn. There is a concomitant decrease in serotonin-like immunoreactivity in the lumbar spinal cord dorsal horn [Butkevich IP, Barr GA, Otellin VA. Effect of prenatal stress on behavioral and neural indices of formalin-induced pain in infant rats. Abstracts, 35th Annual Meeting of Soc. For Neurosci. 2005a. Program No. 512.4 Washington, DC: Society for Neuroscience]. Given the decreased level of perinatal testosterone in prenatally stressed rats to which infant males are more sensitive than females, we suggest that these hormonal, behavioral and neuronal indices are strongly interrelated in prenatally stressed 7-day-old rat pups and that the decreased surge of testosterone may contribute to the increased behavioral response in the second phase in male rat pups. Mechanisms underlying the behavioral pain response induced by inflammation in prenatally stressed rat pups are characterized by sexual dimorphism even prior to the activational effects of sex hormones.
