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

Abstract

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.

Increased Aggression, Improved Spatial Memory, and Reduced Anxiety-Like Behaviour in Adult Male Mice Exposed to Fluoxetine Early in Life

“…Perinatal stress leads to behavioural and neurophysiological changes that last into adulthood [69,70,71,72]. More importantly, the combination of stress and Flx affects offspring outcomes differently than either one alone [73,74,75]. Therefore, behavioural changes previously reported after perinatal Flx administration could result from the interaction of stress and Flx exposure rather than as a consequence of Flx administration alone.…”

“…Maternal stress alone is known to be able to affect fetal development and the child's health as well as longer-term behavioural outcomes (for a review see [92] and [93]). Furthermore, studies that examine long-term outcomes of early Flx exposure have shown that perinatal stress and Flx exposure interact and significantly affect the animals as adolescents and adults [73,74,75,89,94]. While beyond the scope of this study, the long-term consequences of maternal stress and Flx exposure on the offspring, separately and in combination, should be examined.…”

Developmental exposure to SSRIs, in addition to maternal stress, has long-term sex-dependent effects on hippocampal plasticity

“…Restraint of dams in the stress group took place three times daily in transparent plastic cylinders under bright light for 45 min (between 8 and 10 a.m., 12 and 2 p.m., and 4 and 6 p.m.) on GD15-20 and twice on GD21 as previously described (Pawluski et al 2012c;Rayen et al 2011;Van den Hove et al 2005). This time period during pregnancy is when stress can result in postpartum depressive-like behavior in the dam (O'Mahony et al 2006;Smith et al 2004) and, thus was used as a model of maternal stress/depression, as previously described (Knaepen et al 2013;Pawluski et al 2012c;Rayen et al 2011Rayen et al , 2013Rayen et al , 2014. Litters were culled to five males and five females on postpartum day 1 (P1; birth day=P0).…”

Long-Term Outcomes of Developmental Exposure to Fluoxetine: A Review of the Animal Literature

“…Though this test has some issues in that it is potentially confounded by motivation or anxiety, the same rats also showed reduced thermal sensitivity in the hot-plate test [50], which likely cannot be explained by such factors. However, Lisboa et al [35] showed that female and male mice exposed throughout pregnancy and lactation were not different from controls in terms of thermal sensitivity [35], and Knaepen et al [53] observed no effect of postnatal FLX exposure on sensitivity to thermal (or mechanical) stimuli in male rats, though the treatments used in both studies likely resulted in a substantially lower concentration of FLX than the one used by Lee. Thermal sensitivity was also assessed in a study by Vartazarmian et al [54], in which male and female guinea pigs were exposed to FLX throughout the entirety of gestation by implanting osmotic mini-pumps into the pregnant sow.…”

“…Postnatal FLX has also been found to reverse some other behavioural alterations caused by prenatal maternal stress, including depression-like and anxiety-like behaviours in adolescent rats [38,68], and to offset the effects of prenatal maternal stress on postoperative pain. Specifically, stress dulled the hypersensitivity to mechanical stimuli induced by hindpaw incision, whereas postnatal FLX exposure intensified this postoperative pain [53]. In combination, the effects appeared to cancel out, leaving offspring no different from normal.…”