Developmental Fluoxetine Exposure Normalizes the Long-Term Effects of Maternal Stress on Post-Operative Pain in Sprague-Dawley Rat Offspring

Early life events can significantly alter the development of the nociceptive circuit. In fact, clinical work has shown that maternal adversity, in the form of depression, and concomitant selective serotonin reuptake inhibitor (SSRI) treatment influence nociception in infants. The combined effects of maternal adversity and SSRI exposure on offspring nociception may be due to their effects on the developing hypothalamic-pituitary-adrenal (HPA) system. Therefore, the present study investigated long-term effects of maternal adversity and/or SSRI medication use on nociception of adult Sprague-Dawley rat offspring, taking into account involvement of the HPA system. Dams were subject to stress during gestation and were treated with fluoxetine (2×/5 mg/kg/day) prior to parturition and throughout lactation. Four groups of adult male offspring were used: 1. Control+Vehicle, 2. Control+Fluoxetine, 3. Prenatal Stress+Vehicle, 4. Prenatal Stress+Fluoxetine. Results show that post-operative pain, measured as hypersensitivity to mechanical stimuli after hind paw incision, was decreased in adult offspring subject to prenatal stress alone and increased in offspring developmentally exposed to fluoxetine alone. Moreover, post-operative pain was normalized in prenatally stressed offspring exposed to fluoxetine. This was paralleled by a decrease in corticosteroid binding globulin (CBG) levels in prenatally stressed offspring and a normalization of serum CBG levels in prenatally stressed offspring developmentally exposed to fluoxetine. Thus, developmental fluoxetine exposure normalizes the long-term effects of maternal adversity on post-operative pain in offspring and these effects may be due, in part, to the involvement of the HPA system

Mean (±SEM) PWTs in male offspring exposed to mechanical stimuli (g) after incision of the left hind paw.

<p>There was an overall interaction effect of time*condition*treatment observed for PWT to mechanical stimuli after incision. Also main effects of condition and treatment were observed. Significant differences were shown by post hoc correction and denoted by a, b, c, d and e symbols (A). Contralateral PWT were not affected by paw incision (B), since there were no differences observed between the groups. Area under the curve (AUC) analysis (C) of the ipsilateral PWT graphs in A, showed a main effect of condition (#) and a main effect of treatment (##). Contralateral AUC (D) showed a trend for a main effect of condition with control offspring having a tendency for lower PWT than stress offspring (^$). DPI: days post incision, CV: control vehicle, CF: control fluoxetine, SV: stress vehicle, SF: stress fluoxetine (<i>N</i> = 8/12 per group).</p

Mean (±SEM) distances that the animals travelled in the open arena at the age of eight weeks.

<p>There were no differences in distances between the groups. CV: control vehicle, CF: control fluoxetine, SV: stress vehicle, SF: stress fluoxetine (<i>N</i> = 8–12/group).</p

Mean (±SEM) serum levels of fluoxetine (ng/mL) and norfluoxetine (ng/mL) during the postnatal period. (P = postnatal day).

<p>(<i>N</i> = 7–11).</p

Mean (±SEM) and AUC of serum levels of corticosterone and CBG of male offspring.

<p>A time*condition interaction effect was observed in control offspring, but not stress offspring, having a higher corticosterone level at the 8 week time-point (<b>A</b>, *). There was a main effect of time on serum corticosterone levels and post hoc corrections showed that the levels at 8 weeks were significantly higher than levels at all other time-points (<b>A</b>, #). No effect of condition or treatment was observed on AUC of serum corticosterone levels (<b>B</b>). A condition*treatment interaction effect, with lower serum CBG levels in SV offspring, compared to SF and CV offspring (<b>C</b>, *). A main effect of time was observed and post hoc correction showed that this was attributable to the decrease in serum CBG at DPI1 (<b>C</b>, #). A significant interaction effect of condition*treatment was shown in AUC of CBG serum levels, with lower AUC values for SV offspring, compared to SF offspring (<b>D</b>, *). DPI: days post incision, CV: control vehicle, CF: control fluoxetine, SV: stress vehicle, SF: stress fluoxetine (<i>N</i> = 8/12 per group).</p

Mean (±SEM) PWTs to von Frey stimuli (g), reflecting sensitivity of the hind paws to mechanical stimuli at the age of 4 weeks.

<p>No differences were observed in PWT for the left and right hind paw between the groups. CV: control vehicle, CF: control fluoxetine, SV: stress vehicle, SF: stress fluoxetine (<i>N</i> = 8–12/group).</p